Note: Descriptions are shown in the official language in which they were submitted.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-1-
HETEROCYCLE SUBSTITUTED DIPHENYL
LEUKOTRIENE ANTAGONISTS
CROSS REFERENCE TO RELATED APPLICATION
This case claims the priority benefit of United States
Provisional Patent Application Serial No. 60/164,703, filed
11 November 1999, the disclosure of which is incorporated
herein by reference.
BACKGROUND OF THE INVENTION
The metabolic routes in which various compounds are
biosynthesized from arachidonic acid, are collectively
called the "Arachidonic Acid Cascade."
Leukotriene B4 (LTB4) is one of many products resulting
from the arachidonic acid cascade.
Moreover, LTB4 in high concentration has been detected
at the sites of various inflammatory conditions, for
example, rheumatism, spinal arthritis (see Klickstein L.B.,
Shapleigh, C. and Goetzl, E. J. (1980) J. Clin. Invest., 66,
1166-1170), gout (Rae, S. A., Davidson, E. M. and Smith, M.
J. H. (1982) Lancet II 1122-1123), psoriasis (see Grabbe,
J., Czarnetzki, B. M., Rosenbach, T. and Mardin, M. (1984)
J. Invest. Dermatol., 82, 477-479), ulcerative colitis (see
Sharon, P. and Stenson, W. F. (1984) Gastroenterology 86,
453-460). and respiratory disease (see 0'Driscoll, B. R.,
Cromwell, O. and Kay, A. B. (1984) Clin. Exp., Immunol., 55,
397-404). The facts described above show that LTB4 is
deeply related to various forms of inflammation. It has
been suggested that compounds antagonizing LTB4 activity may
be valuable in the treatment of
inflammatory diseases caused by tissue degrading enzymes and
reactive chemicals liberated by tissue-infiltrating and
aggregating polymorphonuclear leukocytes.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-2-
For example, PCT Japanese National Publication No. 6-
502164 describes novel monocylic or bicyclic aryl compounds
are selectively antagonistic to LTB4 and are useful for
treatment of rheumatoid arthritis, gout, psoriasis and
inflammatory bowel disease. Japanese Unexamined Patent
Publication (Kokai) No. 4-244023 describes that omega 6
series unsaturated fatty acids such as 'y-linolenic acid are
useful for treatment of arrhythmia, acute myocardial
infarction etc, by inhibiting production of LTB4. Japanese
Unexamined Patent Publication No. 5-310668 describes that a
novel leucine derivative has an inhibitory action to LTA4
hydrolase and is useful for treatment and prophylaxis of
allergic diseases such as bronchial asthma, various
inflammatory diseases, and ischemia-reperfusion disorders.
Japanese Unexamined Patent Publication (Kokai) No. 1-190656
discloses that novel leukotriene B3 dimethyl amide has an
antagonistic action to LTB4 and is useful as anti-
inflammatory drug, anti-rheumatic drug and gout-treatment
drug.
The article, "Second Generation Leukotriene B4 Receptor
Antagonists Related to SC-41930: Heterocyclic Replacement of
the Methyl Ketone Pharmacophore", J. Med Chem, 1995, 38,
p.858-868 by Penning, Thomas D. et. al.; describes
heterocycle substituted LTB4 antagonists.
Pyrazole LTB4 antagonists are disclosed in the article,
"Leukotriene B4 (LTB4) Receptor Antagonists: A Series of
(Hydroxyphenyl)pyrazoles" by Richard W. Harper, et. al., J.
Med Chem, 1994, 37, pgs. 2411-2420.
Leukotriene B4 antagonists, inclusive of diphenyl
ethers such as 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid, are
described in United States Patent No. 5,462,954, the
disclosure of which is incorporated herein by reference.
The same type of leukotriene B4 antagonists are described in
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-3-
the article, "Synthetic and Structure/Activity Studies on
Acid-Substituted 2-Arylphenols: Discovery of 2-[2-Propyl-3-
[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-
propoxy]phenoxy]benzoic Acid, a High-Affinity Leukotriene B4
Receptor Antagonist" by J. Scott Sawyer, et. al., Journal of
Medicinal Chemistry, 1995, 38, pgs. 4411-4432.
These diphenyl ether leukotriene B4 antagonists, in
combination with a 2',2'-difluoronucleoside analog (e. g.,
GEMCITABINE HC1) , have also been found to have utility in
the treatment of various cancers, as further described in
Provisional Patent Application Serial Number 60/164786,
filed 11 November 1999, the disclosure of which is
incorporated herein by reference.
Currently, anti-inflammatory drugs are classified as
steroidal and non-steroidal. Although these drugs provide
anti-inflammatory action they all have drawbacks which limit
their use. A more recent approach to the moderation of
inflammation focuses on blocking the action of arachidonic
acid metabolites.
Leukotriene B4 antagonists are useful for a wide
variety of Inflammatory Diseases, but it is expected that
various of these antagonists will show superior results with
particular disease states. This is one reason it is
desirable to develop new leukotriene B4 antagonists such as
the compounds of this invention.
SUI~ARY OF THE INVENTION
The present invention is directed to novel heterocycle
substituted diphenyl compounds of formula (I)
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-4-
H
R2
R~ y~CH2)~Y2 R~
(I~ .
Another aspect of this invention are pharmaceutical
compositions containing the compounds of formula (I).
Another aspect of this invention is a method of using
the compounds of the invention in the prevention and
treatment of LTBg induced illnesses.
Another aspect of this invention is a compound of
formula (I) for use as a medicament in the treatment or
prevention of Inflammatory Diseases.
Another aspect of this invention is a process for
preparing a compound of Formula (I).
DETAILED DESCRIPTION
I. Definitions:
The term, "Acidic Group" means an organic group which
when attached as the "Z" substituent of formula (I) or the
"Z2" substituent of formula (II) acts as a proton donor
capable of hydrogen bonding. An illustrative acidic group
is carboxyl.
The term, "Active Ingredient" means the diphenyl
leukotriene B4 antagonist compounds generically described by
formula I and formula II or the list of specific diphenyl
compounds disclosed, infra., as well as the salts, solvates,
and prodrugs of such compounds.
The term, "alkenyl" means a monovalent radical of the
generic formula CnH2n such as ethenyl, n-propenyl,
isopropeneyl, n-butenyl, isobutenyl, 2-butenyl, and
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-5-
3-butenyl.
The term, "alkyl" by itself or as part of another
substituent means, unless otherwise defined, a straight or
branched chain monovalent hydrocarbon radical such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary
butyl, sec-butyl, n-pentyl, and n-hexyl.
The term, "alkaryl" means an aryl radical substituted
with an alkyl or substituted aryl group, for example:
In the term, "C6-C20 alkaryl" the numerical subscripts refer
to the total number of carbon atoms in the radical.
The term, "C6-C20 aralkyl" means an alkyl radical
substituted with an aryl or substituted aryl group, for
example:
H3C,
In the term, "C6-C20 aralkyl" the numerical subscripts refer
to the total number of carbon atoms in the radical.
The term, "carbocyclic group" refers to a five, six,
seven, or eight membered saturated, unsaturated or aromatic
ring containing only carbon and hydrogen (e. g., benzene,
cyclohexene, cyclohexane, cyclopentane).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-6-
The term, "cycloalkyl" means a carbocyclic non-
aromatic monovalent radical such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl.
The term, "halo" means fluoro, chloro, bromo, or iodo.
The term, "heterocyclic radical(s)" refers to a radical
having a saturated, unsaturated or aromatic five membered
substituted or unsubstituted ring containing from 1 to 4
hetero atoms.
The term, "Inflammatory Diseases" refers to diseases
such as inflammatory bowel disease, sepsis, septic shock,
adult respiratory distress syndrome, pancreatitis, trauma-
induced shock, bronchial asthma, allergic rhinitis,
rheumatoid arthritis, cystic fibrosis, stroke, acute
bronchitis, chronic bronchitis, acute bronchiolitis, chronic
bronchiolitis, osteoarthritis, gout, spondylarthropathris,
ankylosing spondylitis, Reiter's syndrome, psoriatic
arthropathy, enterapathric spondylitis, Juvenile arthropathy
or juvenile ankylosing spondylitis, reactive arthropathy,
infectious or post-infectious arthritis, gonoccocal
arthritis, tuberculous arthritis, viral arthritis, fungal
arthritis, syphilitic arthritis, Lyme disease, arthritis
associated with "vasculitic syndromes", polyarteritis
nodosa, hypersensitivity vasculitis, Luegenec's
granulomatosis, polymyalgin rheumatica, joint cell
arteritis, calcium crystal deposition arthropathris, pseudo
gout, non-articular rheumatism, bursitis, tenosynomitis,
epicondylitis (tennis elbow), carpal tunnel syndrome,
repetitive use injury (typing), miscellaneous forms of
arthritis, neuropathic joint disease (charco and joint),
hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura,
hypertrophic osteoarthropathy, multicentric
reticulohistiocytosis, arthritis associated with certain
diseases, surcoilosis, hemochromatosis, sickle cell disease
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-
and other hemoglobinopathries, hyperlipoproteineimia,
hypogammaglobulinemia, hyperparathyroidism, acromegaly,
familial Mediterranean fever, Behat's Disease, systemic
lupus erythrematosis, or relapsing polychondritis and
related diseases which comprises administering to a mammal
in need of such treatment a therapeutically effective amount
of the compound of formula I in an amount sufficient to act
as an antagonist for leukotriene B4 and its deleterious
products.
The term, "LTBg antagonist" means a pharmaceutical
agent capable of preventing or reducing to a therapeutically
significant degree the adverse activity of LTB4 in mammals
and having a average CDllb/CD18 ICSO(nM) assay result of
10000 or less and preferably of 100 or less.
The term, "mammal" includes human.
The term, "N-sulfonamidyl" means the radical:
C N S R12
II " II
O O
where R12 is C1-C10 alkyl, aryl, C1-C6 alkyl
substituted aryl, C6-C20 alkaryl, or C6-C20 aralkyl.
The term, "substituted alkyl" means an alkyl group
further substituted with one or more radicals) selected
from halo, C1-C6 alkyl, aryl, benzyl, C2-C6 alkenyl, C2-C6
alkynyl, C3-Cg cycloalkyl, C1-Cg alkoxy, C1-C6 haloalkyl
(e. g., -CF3).
The term, "substituted aryl" means an aryl group
further substituted with one or more radicals) selected
from halo, C1-C6 alkyl, aryl, benzyl, C2-C6 alkenyl, C2-C6
alkynyl, C3-Cg cycloalkyl, C1-Cg alkoxy, C1-C6 haloalkyl
(e. g., -CF3).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
_g_
The term, "tetrazolyl" refers to an acidic group
represented by either of the formulae:
N N HN N
N~ NH N~ N
II. Compounds of the Invention:
The present invention is directed to novel
heterocyclic substituted diphenyl compounds of formula (I)
OH
R3
R2
Y~H
z n Y2 Y~
R4 R1
wherein:
X is selected from the group consisting of,
(i) a five membered substituted or unsubstituted
heterocyclic radical containing from 1 to 4 hetero
atoms independently selected from sulfur, nitrogen or
oxygen; or
(ii) a fused bicyclic radical wherein a carbocyclic
group is fused to two adjacent carbon atoms of the five
membered heterocyclic radical, (i);
Y1 is a bond or divalent linking group containing 1 to 9
atoms;
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-g_
Y2 and Y3 are divalent linking groups independently selected
from -CH2-, -O-, and -S-;
Z is an Acidic Group;
R1 is C1-C10 alkyl, aryl, C3-C10 cycloalkyl,
C2-C10 alkenyl, C2-C10 alkynyl, C6-C20 aralkyl, C6-C20
alkaryl, C1-C1p haloalkyl, C6-C2p aryloxy, or C1-C10 alkoxy;
R2 is hydrogen, halogen, C1-C10 haloalkyl, C1-C10 alkoxy,
C1-C10 alkyl, C3-Cg cycloalkyl, Acidic Group, or
-(CH2)1_~(Acidic Group);
R3 is hydrogen, halogen, C1-C10 alkyl, aryl, C1-C10
haloalkyl, C1-C10 alkoxy, C1-C10 aryloxy, C3-Cg cycloalkyl;
R4 is C1-Cg alkyl, C3-C4 cycloalkyl,
-(CH2)1_~(cycloalkyl), C2-C4 alkenyl, C2-Cg alkynyl, benzyl,
or aryl; and
n is 0, 1, 2, 3, 4, 5, or 6;
or a pharmaceutically acceptable salt, solvate, or prodrug
derivative thereof.
III. Preferred Compounds of the Invention:
III A. Preferred X substituents:
A "substituted heterocyclic radical" is preferably
Substitued with from 1 to 3 groups independently selected
from hydrogen, halo, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10
alkoxy, aryl, or C6-C20 aryloxy.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-10-
Preferred Group 1 of X substituent (symbol, "PG1-X")
Preferred compounds of the invention are those wherein
X is a heterocyclic radical selected from the group
consisting of substituents represented by the following
structural formulae:
R11 ~ R11 ~ R11
O/ ~ S/ ~ N
R10
N R11 ~ N R11 ~ R11
~N
O ' S ' O/
R11 R11 N-N R11
S/ ~ N/ ~ O
R10
N N R11 ~ NvRl1
~N N
S , N/ ~ N/
R10 R10
-N R11 ~~R11 ~R11
N/ , N/N ' N\S/N
R10 R10
~~R11 N
N N N ~ N
S/ \O/
> >
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-11-
~R11 ~R11 N~R11
N ~ N ~ N
> >
S/ O/ S~
R10
N N N/
\ ~ \\
N~S/N ~ N\O/N ~ N R11
O/ ' S/ ' N~
H
R10
R11
J
N
and
R11 R10
where R10 is a radical selected from hydrogen or
C1-Cg alkyl; and R11 is a radical selected from hydrogen,
halo, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, aryl,
or C6-C20 aryloxy. Preferred R10 groups are hydrogen,
methyl, or phenyl. Moreover, any of the above heterocyclic
radicals illustrated by structural formulae may attach to
the diphenyl leukotriene antagonist of formulae (I) by any
monovalent bond originating on a suitable carbon or nitrogen
atom in its ring structure.
For example, the pyrrole radical may attach to the
diphenyl molecule by a single bond originating at any carbon
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-12-
atom or any nitrogen atom which has less than three bonds in
the hererocyclic ring;
Location of attachment bond for pyrrole,
N N N
H , H
A preferred form of the substituent X is a fused
bicyclic radical wherein a carbocyclic group is fused to two
adjacent carbon atoms of the five membered heterocyclic
radical, for example:
N
and H
III B. Preferred Group 2 of X substituent (symbol, "PG2-
X" )
Most preferred as the X substituents are the heterocyclic
radicals;
N S
CH3 N O
~ ' , or
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-13-
III C. Excluded X substituents:
The heterocyclic radical X of Formula (I) does not
include 3-bromo-1,2,4 thiadiazole since the LTB4 antagonist
activity of compounds containing this radical is considered
too low to be an aspect of this invention.
III D. Preferred Y1 substituents:
Y1 is a bond or divalent linking group containing 1 to
9 atoms independently selected from carbon, hydrogen,
sulfur, nitrogen, and oxygen;
Preferred Group 1 of Y1 substituent (symbol, "PG1-Y1")
Preferred compounds of the invention are those wherein
Y1 is a divalent linking group selected from the group
consisting of substituents represented by the following
formulae:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-14-
O , S ,
S02 ,
z
O
S S N
~,3
o ~ O
N C
R13 ' O '
C C
H2 H2 '
O~
H2 '
S--H ,
2
N C ,
H2
R13
O
C
H2
O and
C C
H
O
where R13 is hydrogen, methyl, or ethyl;
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-15-
The above divalent groups may be used in their forward
or reversed positions. For example, the group;
C
H2 '
O
may be positioned as either,
R2
TT R3
1 O
Z or
in the displayed fragment of formula (I).
III E. Preferred Group 2 of Y1 substituent (symbol, "PG2-
Y1 ~~ )
The most preferred divalent Y1 substituent is the
group;
O
III F. Preferred Group 1 of Y2 substituent (symbol, "PG1-
YZ") and Preferred Group 1 of Y3 substituent (symbol, "PG1-
Y3,~ )
The Y2 and Y3 substituents are preferably selected from
-S- and -0-.
III G. Preferred Group 2 of YZ substituent (symbol, "PG2-
Y2") and Preferred Group 2 of Y3 substituent (symbol, "PG2-
Y3 ., )
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-16-
Most preferably both Y2 and Y3 are the group;
O
III H. Preferred Group 1 of Z substituent
(symbol, "PG1-Z"):
Z is the Acidic Group as previously defined. Preferred
is an acidic group selected from the following:
C N S R12
II " II
tetrazolyl,
-S03H,
O
OH
,
P
OH
O
O P OH
OH
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-17-
o
C OH or
HO
N
where R12 is C1-C10 alkyl, aryl, C6-C20 alkaryl, or C6-C20
aralkyl. Preferred R12 groups are represented by the
formulae:
and
III I. Preferred Group 2 of Z substituent
(symbol, "PG2-Z"):
Highly preferred are the acidic groups; -5-
tetrazolyl,
N-acyl sulfonamide, -S03H, and carboxyl.
III J. Preferred Group 3 of Z substituent
(symbol, "PG3-Z"):
Carboxyl is the most preferred Z substituent.
III K. Preferred Group 1 of n subscript variable
(symbol, "PG1-n")
The most preferred integer values for the divalent
linking group, -(CH2)n- , are n=1, n=2, and n=3.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-18-
III L. Preferred Group 2 of n subscript variable
(symbol, "PG2-n")
The most preferred integer value of n for the
divalent linking group, -(CH2)n- is n = 1.
III M. Preferred Group 1 of R1 substituent (symbol, "PG1-
R1" )
A preferred R1 group is methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, and 2-propenyl; with n-
propyl being most preferred.
III N. Preferred Group 1 of R2 substituent
(symbol, "PG1-R2")and Preferred Group 1 of R3 substituent
(symbol, "PG1-R3"):
Preferred R2 and R3 groups are those wherein R2 and
R3 are independently selected from hydrogen or methyl,
ethyl, methoxy, ethoxy, halo, or -CF3; with R2 and R3 both
being hydrogen as most preferred.
III O. Preferred Group 1 of R4 substituent
(symbol, "PG1-R4":)
Preferred R4 substituents are ethyl, propyl, and
isopropyl.
III P. Combinations of substituents of the compound of
Formula (I):
The substituents of formula (I) are defined as "Z",
"X", "n", "R1", "R2", "R3", "R4", "Y1", "Y2", and "Y3".
Moreover, as described in the preceding section, within
each of the defined substituents of Formula (I) are
"preferred" and "most preferred" subgroups which define
the variety of substituents to be used in the definition
of LTB4 antagonists of the invention. These preferred
subgroups are defined by designations such as "PG1-R4" as
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-19-
recited above. It is often advantageous to use
combinations of preferred groups or combinations of
preferred groups together with the general definition of
variables given in Formula (I). Suitable combinations of
substituents are shown in the following three Tables
(viz., R-Table, Y-Table & XZn-Table).
The following R-Table is used to select combinations
of general and preferred groupings of the variables R1,
R2, R3 and R4 for substitution in formula (I), as follows:
R-Table
R variables R1 R2 R3 R4
Combination group group group group
Code choice choice choice choice
R01 R1 R2 R3 R4
R02 R1 R2 R3 PG1-R4
R03 R1 R2 PG1-R3 R4
R04 R1 R2 PG1-R3 PG1-R4
R05 R1 PG1-R2 R3 R4
R06 R1 PG1-R2 R3 PG1-R4
R07 R1 PG1-R2 PG1-R3 R4
R08 R1 PG1-R2 PG1-R3 PG1-R4
R09 PG1-R1 R2 R3 R4
R10 PG1-01 R2 R3 PG1-R4
R11 PG1-R1 R2 PG1-R3 R4
R12 PG1-R1 R2 PG1-R3 PG1-R4
R13 PG1-R1 PG1-R2 R3 R4
R14 PG1-R1 PG1-R2 R3 PG1-R4
R15 PG1-R1 PG1-R2 PG1-R3 R4
R16 PG1-R1 PG1-R2 PG1-R3 PG1-R4
Thus, for example, the substituent combination, "R14"
describes a substituent combinatorial choice for Formula
(I) wherein R1 is selected from the preferred set of
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-20-
variables, "PG1-R1", that is, methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, and 2-propenyl; the R2
substituent is selected from the preferred set of
variables, "PG1-R2", that is, hydrogen or methyl, ethyl,
methoxy, ethoxy, halo, or -CF3; the variable R3 has the
scope defined in the generic formula (I), and the
substituents suitable for R4 are selected from the
preferred group, "PG1-R4" having the preferred set of
variables, ethyl, propyl, and isopropyl.
The following Y-Table is used to select broad and
preferred groupings of the variables Y1, Y2, and Y3 for
substitution in formula (I), as follows:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-21-
Y-Table
Y variables Y1 group Y2 group Y3 group
combination choice choice choice
code
Y01 Y1 Y2 Y3
Y02 Y1 Y2 PG1-Y3
Y03 Y1 Y2 PG2-Y3
Y04 Y1 PG1-Y2 Y3
Y05 Y1 PG2-Y2 Y3
Y06 Y1 PG1-Y2 PG1-Y3
Y07 Y1 PG1-Y2 PG2-Y3
Y08 Y1 PG2-Y2 PG1-Y3
Y09 Y1 PG2-Y2 PG2-Y3
Y10 PG1-Y1 Y2 Y3
Y11 PG1-Y1 Y2 PG1-Y3
Y12 PG1-Y1 Y2 PG2-Y3
Y13 PG1-Y1 PG1-Y2 Y3
Y14 PG1-Y1~ PG1-Y2 PG1-Y3
Y15 PG1-Y1 PG1-Y2 PG2-Y3
Y16 PG1-Y1 PG2-Y2 Y3
Y17 PG1-Y1 PG2-Y2 PG1-Y3
Y18 PG1-Y1 PG2-Y2 PG2-Y3
Y19 PG2-Y1 Y2 Y3
Y20 PG2-Y1 Y2 PG1-Y3
Y21 PG2-Y1 Y2 PG2-Y3
Y22 PG2-Y1 PG1-Y2 Y3
Y23 PG2-Y1 PG1-Y2 PG1-Y3
Y24 PG2-Y1 PG1-Y2 PG2-Y3
Y25 PG2-Y1 PG2-Y2 Y3
Y26 PG2-Y1 PG2-Y2 PG1-Y3
Y27 PG2-Y1 PG2-Y2 PG2-Y3
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-22-
The following XZn-Table is used to select broad and
preferred groupings of the variables X, Z, and n for
substitution in formula (I), as follows:
XZn-Table
XZn variables X Z n integer
combination group Group group
code choice Choice choice
XZn01 X Z n
XZn02 X Z PG1-n
XZn03 X Z PG2-n
XZn04 X PG1-Z n
XZn05 X PG2-Z n
XZn06 X PG3-Z n
XZn07 X PG1-Z PG1-n
XZn08 X PG2-Z PG1-n
XZn09 X PG3-Z PG1-n
XZnlO X PG1-Z PG2-n
XZnl1 X PG2-Z PG2-n
XZnl2 X PG3-Z PG2-n
XZnl3 PG1-X Z n
XZnl4 PG1-X Z PG1-n
XZnlS PG1-X Z PG2-n
XZnl6 PG1-X PG1-Z n
XZnl7 PG1-X PG2-Z n
XZnl8 PG1-X PG3-Z n
XZnl9 PG2-X PG1-Z PG1-n
XZn20 PG2-X PG2-Z PG1-n
XZn21 PG2-X PG3-Z PG1-n
XZn22 PG2-X PG1-Z PG2-n
XZn23 PG2-X PG2-Z PG2-n
XZn24 PG2-X PG3-Z PG2-n
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-23-
How to Use the Tables:
Any of the individual 16 combinations of the R
substituents depicted in the R-Table may be used in
combination with any of the 27 individual combinations of
Y substituents depicted in the Y-Table, which may be used
with any of the 24 combinations of XZn substituents
depicted in the XZn-Table. For example, the substituent
combination choice "R07, Y21, XZn03" defines substituent
set selections for a subset of formula (I) useful in the
practice of the invention.
III Q. Preferred compounds of the invention are
described by formula (II):
X2
O ~ ~O
R21 Z2
(II)
wherein;
X2 is a heterocyclic radical selected from,
N S
CH3 N O
' or
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-24-
_~
R21 is ethyl, 2-propen-1-yl, 3-propen-1-yl, n-propyl,
iso-propyl, n-butyl, sec-butyl, or tert-butyl; and
R22 is hydrogen, n-butyl, sec-butyl, flouro, chloro,
-CF3, or tert-butyl.
Z2 is carboxyl, tetrazolyl, N-sulfonamidyl.
Preferred Compounds of the Invention:
III R. Specific compounds preferred as LTB4 antagonists
are represented by the following structural formulae:
(C1)
/=N OH
O ~
i
O~O ~ O
COOH
(C2):
H ~HCI
~N~ OH
N ~
i
O'~O \ O
COOH
(C3 )
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-25-
/=N OH
S ~
O~O ~ I O
COOH
(C4)
,H
N'N OH
O'~O \ O
COOH
(C5)
N'O OH
OHO ~ O
COOH
(C6)
H
,N'N~ OH
N
O~O \ O
COOH
(C7):
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-26-
OH
~N W / /
O~O ~ ~ O w
COOMe
(C8)
OH
S, ~ ~ / ~ / ~
/ oho \ O
COOH
(C9 )
N- OH
-N ~
/ /
/ O~O ~ ~ O ~
COOH
(C10)
CN OH
s ~ ~ / I /
/ O~o \ O
COOH
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-27-
(C11)
O OH
N~ I
O~O ~ ~ O
COONa
(C12 )
OH
O, ~ w / ~ / ~
/ O~O \ O
COOH
(C13)
OH
O ~
/ /
O~O \ I O
COOH
(C14)
O OH
O~O w I O
COONa
(C15)
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-28-
OH
I
HCI ~ O~O ~ O
COOH
(C16)
OH
i
ono ~ I o ~
COOH
(C17 )
N~N OH
N
I~ ~I ~I
O'~O ~ O
COOH
(C18):
N=N off
S ,
i i
~ ono w I o w
COOH
(C19):
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-29-
.S-N OH
N~ I
I~ ~I ~I
O~O \ O
COOH
(C20)
~N'N OH
S ~ ~ i
ono ~ I o
COOH
(C21)
~I ~I
O~O O
COOH
(C22)
~N OH
O ~ ~ i
~ ono ~ I o ~
COOH
(C23)
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-30-
OH
S
I\ /I /I
/ O'~O \ O \
COOH
and all acid, salt, solvate and prodrug derivatives thereof.
III S. Highly Preferred Compounds of the Invention are as
follows:
OH
\ / I /
O~O \ O
COOH
O OH
\ / /
O ~\/~ O \
COONa
OH
S, ~ \ / ~ / ~
/ O~O \ O
COOH
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-31-
N- OH
-N ~
O~O ~ ~ O ~
COOH
OH
O, ~ w
O~O ~ O
COOH
OH
O'~O ~ O
COOH
and all acid, salt, solvate and prodrug derivatives thereof.
The salts of the above diphenyl LTB4 antagonists of the
invention, represented by formulae (I) and (II) and the
specific compounds set out by structural formulae in
sections IIIR and IIIS herein, are an additional aspect of
the invention. The compounds of the invention possess an
Acidic Groups) and at these sites various salts may be
formed which are more water soluble and/or physiologically
suitable than the parent compound in its acid form.
Representative pharmaceutically acceptable salts, include
but are not limited to, the alkali and alkaline earth salts
such as lithium, sodium, potassium, calcium, magnesium,
aluminum and the like. Sodium salts are particularly
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-32-
preferred. Salts are conveniently prepared from the free
acid by treating the acid form in solution with a base or by
exposing the acid to an ion exchange resin. For example,
the (Acidic Group) of the Z of Formula (I) may be selected
as -C02H and salts may be formed by reaction with
appropriate bases (e.g., NaOH, KOH) to yield the
corresponding sodium or potassium salt.
Included within the definition of pharmaceutically
acceptable salts are the relatively non-toxic, inorganic and
organic base addition salts of compounds of the present
invention, for example, ammonium, quaternary ammonium, and
amine cations, derived from nitrogenous bases of sufficient
basicity to form salts with the LTBg antagonist compounds of
this invention (see, for example, S. M. Berge, et al.,
"Pharmaceutical Salts," J. Phar. Sci., 66: 1-19 (1977)).
Certain compounds of the invention may possess one or
more chiral centers and may thus exist in optically active
forms. All such stereoisomers as well as the mixtures
thereof are intended to be included in the invention. If a
particular stereoisomer is desired, it can be prepared by
methods well known in the art, for example, by using
stereospecific reactions with starting materials which
contain the asymmetric centers and are already resolved or,
alternatively, by methods which lead to mixtures of the
stereoisomers and subsequent resolution by known methods.
For example, a racemic mixture may be reacted with a single
enantiomer of some other compound. This changes the racemic
form into a mixture of diastereomers. Then, because the
diastereomers have different melting points, different
boiling points, and different solubilities, they can be
separated by conventional means, such as crystallization.
Prodrugs are derivatives of the compounds of Formula
(I) and (II), supra., which have chemically or metabolically
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-33-
cleavable groups and become by solvolysis or under
physiological conditions the compounds of the invention
which are pharmaceutically active in vivo. Derivatives of
the compounds of this invention have activity in both their
acid and base derivative forms, but the acid derivative form
often offers advantages of solubility, tissue compatibility,
or delayed release in a mammalian organism (see, Bundgard,
H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam
1985). Prodrugs include acid derivatives well known to
practitioners of the art, such as, for example, esters
prepared by reaction of the parent acidic compound with a
suitable alcohol, or amides prepared by reaction of the
parent acid compound with a suitable amine. Simple
aliphatic or aromatic esters derived from acidic groups
pendent on the compounds of this invention are preferred
prodrugs. In some cases it is desirable to prepare double
ester type prodrugs such as (acyloxy) alkyl esters or
((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred
esters as prodrugs.are methyl, ethyl, propyl, isopropyl, n-
butyl, isobutyl, tent-butyl, morpholinoethyl, and N,N-
diethylglycolamido.
Esters of carboxylic acids are preferred prodrugs of
the compounds of the invention (viz., the compounds of
Formula I, Formula II and the specific compounds set out in
Section IIIR and IIIS, herein).
Methyl ester prodrugs may be prepared by reaction of
the acid form of a compound of formula (I) in a medium such
as methanol with an acid or base esterification catalyst
(e.g., NaOH, H2S04). Ethyl ester prodrugs are prepared in
similar fashion using ethanol in place of methanol.
N,N-diethylglycolamido ester prodrugs may be prepared
by reaction of the sodium salt of a compound of Formula (I)
(in a medium such as dimethylformamide) with 2-chloro-N,N-
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-34-
diethylacetamide (available from Aldrich Chemical Co.,
Milwaukee, Wisconsin USA; Item No. 25,099-6).
Morpholinylethyl ester prodrugs may be prepared by
reaction of the sodium salt of a compound of Formula (I) (in
a medium such as dimethylformamide) 4-(2-
chloroethyl)morpholine hydrochloride (available from Aldrich
Chemical Co., Milwaukee, Wisconsin USA, Item No. C4,220-3).
Preferred compounds of the invention are compounds of
Formula (I), or Formula (II) or the specific compounds of
sections IIIR and IIIS shown above by structural formula;
wherein the acid, salt and prodrug derivatives thereof are
respectively selected from: carboxylic acid, sodium salt,
and ester prodrug.
IV. Method of Making the Compounds of the Invention
General reaction schemes (not represented to be
specific Examples) applicable for synthesis of the LTB4
antagonist compounds represented by formula (I) are set
out below. Numerous literature references and Chemical
Abstract registry numbers (e.g., RN 152609-60-4) are
supplied as additional aids for preparing reagents used in
practicing the synthesis schemes of the invention.
REACTION SCHEMES FOR MAKING
THE COMPOUNDS OF THE INVENTION
The following scheme illustrates a process for making Example
(1), a 4-substituted oxazole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-35-
Scheme 1
O OH
benzyl bromide, Cs2C03, DMF
O~CI
(26)
known compound: RN# 156005-61-7
R. W. Harper et aL, J. Med. Chem. 1994, 37(15), 2411
HO ~ O ~ (30)
0 0
COOMe
~O~CI
known compound: RN 152609-76-2
J. S. Sawyer et al., J. Med. Chem. 1995, 38, 4411
(2$) K2C03, Nal, 2-butanone
OII
O O ~ O~CF3
i~0
~ o~'CF
O -O ~ s
COOMe TFA, H20, CH3CN
(32)
0 0
HO ~ ~ / / 1) Tf20, 2,6-lutidine
O~O \ I O \ I 2) formamide
COOMe
(34)
/= N O
BF3 Et20, EtSH
O~O \ O \
COOMe
(36)
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-36-
/= N H
O~
/ I / I ~ ) NaOH
/ O~O \ O \ 2) HCI
COOMe
(38)
/= N H
O ~
O~\/~O \ I O \
COOH
Known chloride (26) may be alkylated with benzyl bromide to
provide chloride (28). Reaction with known ester (30),
catalyzed by a suitable base, provides acetophenone (32).
Oxidation with bis(trifluoroacetoxy)iodobenzene gives alpha-
hydroxy ketone (34), that may be cyclized with triflic
anhydride and formamide to give the 4-substituted oxazole
(36). Debenzylation with boron trifluoride etherate and
ethanethiol gives oxazole (38), that is hydrolyzed and
protonated to provide Example (1).
Scheme 2
The following scheme illustrates a process for making Example
(2), a 5(4)-substituted imidazole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-37-
Scheme 2
0 0
I I I 1) LiHMDS, TMSCI, THF
/ O~O \ O~ 2) NCS
COOMe 3)TBAF
(32)
O O \ NI'H
CI I ~ I / / I / I HzN~SBn
/ O~O \ O~ KZC03, Nal, DMF
COOMe
(40)
_ S .H
N~ N O ~ /
/ / BF Et O, EtSH
3 2
I / O~O W ~ O~ .
COOMe
(42)
S .H
N~N OH
1) LiOH, MeOH
O~O \ I O ~ I 2) Raney Ni, EtOH, NaOH
COOMe 3) HCI
(44)
H
~N~ OH
N ~
HCI I / O~O ~ I O ~ I
COOH
(2)
The trimethylsilyl enol ether of acetophenone (32) is formed
and treated with N-chlorosuccinimide followed by tetra-n-
butylammonium fluoride to provide the chloroketone (40).
Treatment of (40) with 2-benzyl-2-thiopseudourea and base
provides imidazole (42), that is treated with boron
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-38-
trifluoride etherate and ethanethiol to give imidazole (44).
Hydrolysis and protonation provide Example (2) as the
hydrochloride salt.
Scheme 3
The following scheme illustrates a process for making Example
(3), a 4-substituted thiazole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-39-
Scheme 3
0 0
CI I \ / I I thioformamide, MgC03
/ O~O \ O \ dioxane
COOMe
(40)
/= N O
S i ( \ I / / I / I BF3 Et20, EtSH
/ O~O \ O \
COOMe
(46)
/=N OH
S ~
\ / / 1 ) LiOH, MeOH
O~O \ I O \ I 2) HCI
COOMe
(48)
/=N OH
S ~
\ / /
O~\/~O \ I O \
COOH
(3)
Chloroketone (40) is treated with thioformamide and
magnesium carbonate to give thiazole (46), that is
debenzylated with boron trifluoride etherate and ethanethiol
giving thiazole (48). Hydrolysis and protonation provides
Example (3).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-40-
Scheme 4
The following scheme illustrates a process for making Example
(4), a 5(3)-substituted pyrazole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-41-
Scheme 4
OMe
O O \ Me2N
OMe
O~O \ O \ DMF
COOMe
(32)
0 0
MeZN ~ I ~ I I 1) LiOH, MeOH
O~O \ O \ 2) HCI
COOMe 3) NH2NHZ HzO, MeOH
(50)
H
N-N'
BF3 Et20, EtSH
O~O ~ ~ O
COOH
(52)
,H
N'N OH
o
COOH
(4)
Treatment of acetophenone (32) with N,N-dimethylformamide
dimethyl acetal gives enone (50), that may be hydrolyzed,
protonated, and then heated with hydrazine hydrate to
provide pyrazole (52). Debenzylation of the resulting
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-42-
pyrazole with boron trifluoride etherate and ethanethiol
gives Example (4).
Scheme 5
The following scheme illustrates a process for making Example
(5), a 5-substituted isoxazole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-43-
Scheme 5
0 o I \
Me2N \ I \ / / I / I NH20H, MeOH, H20
/ O~O \ O \
COOMe
(50)
N'O O
BF3~Et20, EtSH
\ / / /
I / ono \ I o \ I
COOMe
(54)
N'O OH
\ / / 1 ) LiOH, MeOH
I / O~O \ I O \ I 2) HCI
COOMe
(56)
N'O OH
I /I /I
/ O~O \ O \
COOH
(5)
Treatment of enone (50) with hydroxylamine provides
isoxazole (54), that is debenzylated with boron trifluoride
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-44-
etherate and ethanethiol to give isoxazole (56). Hydrolysis
and protonation provides Example (5).
Scheme 6
The following scheme illustrates a process for making Example
(6), a 5(4)-substituted 1,2,3-triazole LTB4 receptor
antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-45-
Scheme 6
° I ~ ~ I I
gr ~ ~ ~ KZC03, KI, DMSO
HO O
I ~ O~CI + COOMe 2-butanone
(58) (30)
known compounds: RN 152609-60-4 152609-76-2
J. S. Sawyer et al. J. Med. Chem. 1995, 38, 4411
° I ~
Br ~~ / / - SnBu3
O~O \ I O ~ I Pd(PPh3)4, DMF
COOMe
(60)
O I w
i
TMSN3, toluene
I ~ O~O ~ I o ~ I
COOMe
(62)
N NH O
N ~ I ~ I ~ / I / I BF3 Et20, EtSH
O~O \ O
COOMe
(64)
,H
N'N OH
N ~
W / / 1) LiOH, MeOH
I / O~O ~ I O ~ I 2) HCI
COOMe
(66)
,H
N'N OH
N ~
I I I
O~O \ O
COOH
(6)
Known phenol (30) is alkylated with known chloride (58) to
give aryl bromide (60). Treatment of (60) with tri-n-
butylethynyltin and a palladium catalyst gives alkyne (62).
Heating (62) with trimethylsilyl azide provides triazole
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-46-
(64), that is debenzylated with boron trifluoride etherate
and ethanethiol to give triazole (66). Hydrolysis and
protonation provides Example (6).
Scheme 7
The following scheme illustrates a process for making Example
(7), a 1-substituted pyrrole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-47-
Scheme 7
OH _ O
\ N I /
I 1 ) (KS03)2N0, K2P04, Hz0
/ OH I
2) 3-pyrroline, CH3CN / OH
3) BnBr, K2C03, DMF
(68) (70)
1
~N ~ I / 1) Nal, 2-butanone
1-bromo-3-chloropropane I
K2CO3, DMF / O~CI 2) KZC03, DMF
(72) w I w
HO O
COOMe
(30)
0
~N ~ I / / /. BF3 EtZO, EtSH
I / O~O w I O w I
COOMe
(74)
OH
~N ~ / /
I / O~O \ I O w I
COOMe
References for formation of 1-aryl substituted pyrroles: M. Mure and J. P.
Klinman, J. Am. Chem. Soc. 1995, 117(34), 8698;
Y. Lee et al. J. Am. Chem. Soc. 1996, 118(30), 7241
4-Ethylbenzene-1,3-diol (68) is treated with potassium
nitrosodisulfonate followed by 3-pyrroline and benzylbromide
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-48-
and a base to provide pyrrole (70). Alkylation with 1-
bromo-3-chloropropane gives chloride (72), that is used to
alkylate phenol (30) to give pyrrole (74). Debenzylation
with boron trifluoride etherate and ethanethiol provides
Example (7).
Scheme 8
The following scheme illustrates a process for making Example
(8), a 5-substituted 1,2,4-thiadiazole LTB4 receptor
antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-49-
Scheme 8
H
O I ~ O-B~O
Br ~ ~ /
/ O~O / O \ PdClz(dppf)
COOMe
(60)
Br
N~N
/ ~ / S
O CI
/ O~O ~ / O
COOMe PdCl2(dppf), Cs2C03, toluene
(76)
Br
~N O
N I \ ~ / \ / 1 ) BF3~Et20, EtSH
S
/ O~O I / O \ I 2) aq. NaOH
COOMe 3) aq. NCI
Br
N~N OH
.S ( ~ ~ ~ /
/ O~O / O
COOH
The palladium-catalyzed addition of 4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane to bromide (60) gives boronic ester
(76). The palladium-catalyzed addition of 3-bromo-5-chloro-
1,2,4-thiadiazole to (76) gives ester (78).. Debenzylation
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-50-
with boron trifluoride etherate and ethanethiol, followed by
hydrolysis and protonation, gives Example (8).
Scheme 9
The following scheme illustrates a process for making Example
(9), a 2-substituted thiophene LTB4 receptor antagonist:
Scheme 9
0 0 ~ ') s ~
,B I ~ Br
O I \ I I PdCl2(dppf), CszC03, toluene
O~O ~ O
COOMe 2) BF3 Et20, EtSH
(76)
off
I~
O~O ~ O \ 1) aq. LiOH
COOMe 2) NaOH
(80)
OH
i
o I ~ o ~ I
Iw
COONa
(9)
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-51-
The palladium-catalyzed addition of boronic ester (76) to 2-
bromothiophene, followed by debenzylation with boron
trifluoride etherate and ethanethiol, provides thiophene
(80). Hydrolysis and salt formation provides Example (9).
Scheme 10
The following scheme illustrates a process for making Example
(10), a 4-substituted pyrazole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-52-
Scheme 10
I
O O I ~ N-N
Known compound: RN 39806-90-1
~~B I ~ , ~ I ~ I
O~O ~ O
COOMe PdCl2(dppf), Cs2C03, toluene
(76)
N, O
N ~ I ~
( I ~ ) BF3~Et20, EtSH
O~O \ O \ 2) aq. NaOH
COOMe 3) aq. HCI
(82)
N- OH
-N
I~ ~I ~I
O~O \ O
COOH
(10)
The palladium-catalyzed addition of boronic ester (76) to 1-
methyl-4-iodopyrazole provides pyrazole (82). Debenzylation
with boron trifluoride etherate and ethanethiol, followed by
hydrolysis and protonation, provides Example (10).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-53-
Scheme 11
The following scheme illustrates a process for making Example
(11), a 2-substituted thiazole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-54-
Scheme 11
\ ~ N
\ /
I / ~ I ~Br
~O O
COOMe PdCl2(dppf), CszC03, toluene
(76)
o I \
S I \ / I \ I BF3~Et20, EtSH
/ O~O / O \
COOMe
(84)
~N OH
S I \ I I ~ ) aq. LiOH
/ O~O / O \ 2) HCI
COOMe
(86)
~N OH
s I \
~ ono I / o \ I
COOH
(11 )
The palladium-catalyzed addition of boronic ester (76) to 2-
bromothizaole provides thiazole (84). Debenzylation with
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-55-
boron trifluoride etherate and ethanethiol gives thiazole
(86). Hydrolysis and protonation provides Example (11).
Scheme 12
The following scheme illustrates a process for making Example
(12), a 4-substituted isoxazole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-56-
Scheme 12
N~ I
1)
O O~ O
,B
O ~ / ~ ~ / \ ~ PdCl2(dppf), CszC03, toluene
~O O ~O
COOMe
(76)
N, O
1) Me3Sil
i
~ O~O I ~ O \ I 2) aq. NCI
COOMe 3) NaOH
(88)
N- OH
O i ~ ~ ~ ~ i
O~O ~ O
COONa
(12)
The palladium-catalyzed addition of boronic ester (76) to
3,5-dimethyl-4-iodoisoxazole provides oxazole (88).
Debenzylation with trimethylsilyl iodide, followed by
hydrolysis and salt formation, provides Example (12).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-57-
Scheme 13
The following scheme illustrates a process for making Example
(13), a 2-substituted furan LTB4 receptor antagonist:
Scheme 13
o (
Br ~~ / / BBr3, CHzCIz
I ~ O~O w I o w I
COOMe
(60)
OH
TBSCI, imidazole
I I I
/ O~O ~ O
COOMe
(90)
TBS o ~
Br ~ / / B(OH)z
I / O~O ~ I O ~ I Pd(PPh3)4, aq. NazC03, THF
COOMe
(92)
off
O I I I 1) aq. LiOH
/ O~O \ O~ 2) HCI
COOMe 3) NaOH
(94)
off
I ~ I I
/ o'~o ~ o~
COONa
(13)
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-58-
Debenzylation of bromide (60) with boron tribromide provides
phenol (90), that is treated with tert-butyldimethylsilyl
chloride and imidazole to give silyl ether (92). The
palladium-catalyzed addition of (92) to furan-2-boronic acid
provides furan (94). Hydrolysis and salt formation gives
Example (13).
Scheme 14
The following scheme illustrates a process for making Example
(14), a 3-substituted furan LTB4 receptor antagonist:
Scheme 14
TBS
Br ~ / / ~B(OH)2
O~O \ I O \ I Pd(PPh3)4, aq. Na2C03, THF
COOMe
(92)
OH
O~
1 ) aq. LiOH
/ O~O \ O
COOMe 2) HCI
3) NaOH
(96)
OH
O ~
/ o'~o ~ o
COONa
(14)
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-59-
The palladium-catalyzed addition of (92) to furan-3-boronic
acid provides furan (96). Hydrolysis and salt formation
gives Example (14).
Scheme 15
The following scheme illustrates a process for making Example
(15), a 3-substituted tetrahydrofuran LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-60-
Scheme 15
O I w / / B(OH)2
Br I ~ ~ ~ I ~ I o
O~O \ O \ Pd(PPh3)4, aq. Na2C03, THF
COOMe
(60)
o
o ,
H2, Pd(C)
I / O~O ~ I O
COOMe
(98)
OH
O
1 ) aq. LiOH
O~O \ I O \ I 2) HCI
COOMe 3) NaOH
( 100)
OH
O
I ~I ~I
O
COONa
(15)
The palladium-catalyzed addition of bromide (60) to furan-3-
boronic acid provides furan (98). Hydrogenation over a
palladium catalyst gives tetrahydrofuran (100). Hydrolysis
and salt formation gives Example (15).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-61-
Scheme 16
The following scheme illustrates a process for making Example
(16), a 2-substituted pyrrolidine LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-62-
Scheme 16
N
O I W ~O-~ B(OH)z
Br ~ / / / O
I ~ O~O ~ I O ~ I Pd(PPh3)4, aq. NazC03, THF
COOMe
(60)
~I p I~
N I W / / I / I Hz. Pd(C)
~O~O ~ O~O \ O \
COOMe
(102)
OH
aq. LiOH
~' N I I I
~O~O ~ O~O \ O
COOMe
(104)
OH
~' N I I I HCI
~O~O ~ O~O \ O \
COOLi
(106)
OH
N
I ~ pip ~ I p ~ I
HCI
COOH
(16)
The palladium-catalyzed addition of bromide (60) to N-boc
pyrrole-2-boronic acid provides pyrrole (102). Hydrogenation
over a palladium catalyst gives pyrrolidine (104).
Hydrolysis and salt formation gives pyrrolidine (106).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-63-
Treatment with hydrochloric acid provides Example (16) as
the hydrochloride salt.
Scheme 17
The following scheme illustrates a process for making Example
(17), a 3-substituted thiophene LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-64-
Scheme 17
o ~ , o
Br ~ I / ~ g(oH)2 S ~
~ O~CI Pd(PPh3)4, aq. Na2C03, THF I ~ O~CI
(5g) (108)
I I
HO ~ p \ (110)
CN
known compound: RN# 152609-78-4 S ~ 0
J. S. Sawyer et al., J. Med. Chem. 1995, 38, 4411 i ~
KZC03, KI, DMSO, 2-butanone I ~ O~O \ I O
CN
(112)
OH
S ~
BBr3, CHZCIZ I ~ I I 1) NaOH
O~O \ O \ 2) HCI
CN
(114)
OH
S /
O~O \ O
COOH
(17)
The palladium-catalyzed addition of bromide (58) to
thiophene-3-boronic acid provides thiophene (108).
Alkylation of known phenol (110) with (108) catalyzed by
base provides thiophene (112). Debenzylation with boron
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-65-
tribromide gives thiophene (114). Hydrolysis and
protonation provide Example (17).
Scheme 18
The following scheme illustrates a process for making Example
(18), a 5-substituted 1,2,3,4-thiatriazole LTB4 receptor
antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-66-
Scheme 18
/ / / /
\ ~ \ ~ 1-bromo-3-chloropropane ~ ~ 1) KZC03, Nal, 2-butanone
HO O CIO \ O
COOMe K2C03, DMF COOMe O OH
H \
(30) (116) I / off
known compound:
RN 37470-83-0 (118)
2) Cs2C03, BnBr, DMF
O O I \ 1) HS~SH
H \ / / TsOH
O~O I O I 2) NaH, DMF, HMPA
COOMe 3) piperidine
(120)
\
s o ~ \ 1)
\ / / / - +N CI
Me
NHZ I / O~\/~O \ I O \ I 1
COOMe 2) NaN3
(122)
NN-N O
S I \ / / I / I 1) BF3Etz0, CHZCIZ
/ O~O \ O~ 2) aq. NaOH
COOMe 3) aq. HCI
(124)
N'N OH
N I
.S I \ I \ /
/ O~O / O
COOH
(18)
Reference for formation of dithioacids: N. C. Gonnella et al. Syn. Commun.
1979, 17
Reference for formation of 5-substituted 1,2,3,4-thiatriazoles from
dithioacids:
S. 1. Ikeda et al., Synthesis 1990, 415
Phenol (30) is alkylated with 1-bromo-3-chloropropane to
give chloride (116), that is in turn to be treated with
known aldehyde (118) and a base, followed by benzylation
with benzyl bromide and a base, to provide aldehyde (120).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-67-
From aldehyde (120) is made the thioacetal by treatment with
1,2-ethanedithiol. The resulting thioacetal is then to be
treated with base to provide the thioacid. Treatment with
piperidine makes piperidinium salt (122). By the teaching
of Ikeda, infra, (the disclosure of which is incorporated
herein by reference) treatment of (122) with 2-
chloropyridinium methyl iodide followed by azide ion will
give the 1,2,3,4-thiatriazole (124). Debenzylation with
boron trifluoride etherate and ethanethiol, followed by
hydrolysis and protonation, will provide the product of
Example (18).
Scheme 19
The following scheme illustrates a process for making Example
(19), a 4-substituted 1,2,3-thiadiazole LTB4 receptor
antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-68-
Scheme 19
0 0
NH2NHCOOEt
O~O ~ / O
COOMe
(32)
EtO~N.N O
SOCIZ
O~O ~ / O ~
COOMe
( 128)
N_N O
1 ) BF3 Et20, EtSH
~ O~O I ~ O ~ I 2) aq. NaOH
COOMe 3) aq. NCI
( 130)
N=N OH
S ~
o'~O ~
COOH
(19)
Reference for 1,2,3-thiadiazole formation: E. W. Thomas et al., J. Med. Chem.
1985, 28, 442.
Treatment of acetophenone (32) with ethyl carbazate will
give the hydrazone (128). Use of thionyl chloride by the
method of Thomas et. al. (infra., the disclosure of which is
incorporated herein by reference) will give an intermediate
1,2,3-thiadiazole (130), that is to be debenzylated with
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-69-
boron trifluoride etherate and ethanethiol, then hydrolyzed
and protonated to give the product of Example (19).
Scheme 20
The following scheme illustrates a process for making Example
(20), a 3-substituted 1,2,5-thiadiazole LTB4 receptor
antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-70-
Scheme 20
c1
.s,.
O I ~ N N
CI~S.N:S~CI
~ O~O \ I O \ I (trithiazyl trichloride)
COOMe
(62)
S'N O
N ~ I I \ ~ / I I 1) BF3 Et20, EtSH
O~O \ O \ 2) aq. NaOH
COOMe 3) aq. HCI
( 132)
S'N OH
N\ t ~
O
COOH
(20)
Reference for 1,2,5-thiadiazole formation: E. W. Thomas et al., J. Med. Chem.
1985, 28, 442.
Alkyne (62) is to be treated with trithiazyl trichloride by
the method of Thomas et. al. (infra., the disclosure of
which is incorporated herein by reference) to provide
thiadiazole (132). Debenzylation with boron trifluoride
etherate and ethanethiol, followed by hydrolysis and
protonation, will provide the product of Example (20).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-71-
Scheme 21
The following scheme illustrates a process for making Example
(21), a 2-substituted 1,3,4-thiadiazole LTB4 receptor
antagonist:
10
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-72-
Scheme 21
~N,N
S
O O \ Br
,B ~~/ known compound: RN 61929-24-6
O I ~ I ~ / I PCT WO 9730981
/ O~O / O \ PdCl2(dppf), Cs2C03, toluene
COOMe
(76)
N'N O
~~ I ( /
S ~ W I W / I 1 ) BF3 Et20, EtSH
/ .OHO / O \ 2) aq. NaOH
COOMe 3) aq. NCI
(134)
//N'N OH
\S I ~ ( ~ /
/ O'~O / O
COOH
(21 )
The palladium-catalyzed addition of boronic ester (76) to 2-
bromo-1,3,4-thiadiazole will provide ester (134).
Debenzylation with boron trifluoride etherate and
ethanethiol, followed by hydrolysis and protonation, will
provide the product of Example (21).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-73-
Scheme 22
The following scheme illustrates a process for making Example
(22), a 5-substituted isothiazole LTB4 receptor antagonist:
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-74-
Scheme 22
N ~~
S
O~ ~ B(OH)z
gr \ II~/ known compound: RN 216971-00-5
I PCT W O 9855480
O~CI
Pd(PPh3)4, Na2C03, EtOH, H20
(58)
I
HO \ O \
O
N I I , COOMe (30)
.S I w
O~CI
K2C03, KI, DMSO,
( 136)
N~ I ~
~S I ~ I I 1 ) gF3 Et20, EtSH
O~O ~ O \ 2) aq. NaOH
COOMe 3) aq. HCI
( 138)
N~ I OH
I~ I I
o'~o ~ o
COOH
(22)
The palladium-catalyzed addition of bromide (58) to 3-
methylisothiazole-5-boronic acid will provide isothiazole
(136). Alkylation of phenol (30) with (136) catalyzed by
base will provide isothiazole (138). Debenzylation with
boron trifluoride etherate and ethanethiol, followed by
hydrolysis and protonation, will provide the product of
Examp 1 a ( 2 2 ) .
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-75-
Scheme 23
The following scheme illustrates a process for making Example
(23), a 2-substituted oxazole LTB4 receptor antagonist:
Scheme 23
~N
O
Br
O O \ known compound: RN 125533-82-6
' ~~ R. D. Miller et al., Chem. Mater. 1994,
\ ~ I \ ~ I 6(7), 1023.
O~O ~ O \ PdCl2(dppf), Cs2C03, toluene
COOMe
(76)
~N O I \
\ / I 1 ) BF3 EtzO, EtSH
O~O ~ O \ 2) aq. NaOH
COOMe 3) aq. NCI
( 140)
~N OH
O I \ I \
O~O ~ O \
COOH
(23)
The palladium-catalyzed addition of boronic ester (76) to 2-
bromooxazole will provide oxazole (140). Debenzylation with
boron trifluoride etherate and ethanethiol, followed by
hydrolysis and protonation, will provide the product of
Example (23).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-76-
Scheme 24
The following scheme illustrates a process for making Example
(24), a 3-substituted thiophane LTB4 receptor antagonist:
10
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
_77_
Scheme 24
OH
S ~
Et3SiH, TFA, benzene
O~O ~ O
CN
(114)
OH
S
1 ) aq. NaOH
O~O ~ O \ 2) HCI
CN
( 142)
OH
S
o'~o ~ o
COOH
(24)
Reference for formation of tetrahydrothiophenes: D. N. Kursanov et al.
Tetrahedron 1975, 31, 311
Thiophene (114) may be reduced in the presence of
triethylsilane and trifluoroacetic acid by the method of
Kursanov et. al. (infra., the disclosure of which is
incorporated herein by reference) to provide the thiophane
(142). Hydrolysis and protonation will provide the product
of Example (24).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-78-
V. PREPARATIVE EXAMPLES 1 TO 17:
Example 1
Preparation of 2-~3-[3-(2-Ethyl-5-hydroxy-4-oxazol-4-yl-
phenoxy)propoxy]-2-propyl-phenoxy~benzoic acid.
o H o
i
o~ci ~ o'~ci
known compound: RN# 156005-61-7
R. W. Harper et al., J. Med. Chem. 1994, 37(15), 2411-20
A. Preparation of 1-[2-benzyloxy-4-(3-chloropropoxy)-5-
ethylphenyl]ethanone.
A mixture of 1-[2-hydroxy-4-(3-chloropropoxy)-5-
ethylphenyl]ethanone (26.1 g, 102 mmol), cesium carbonate
(33.4 g, 103 mmol), and benzyl bromide (12.2 ml, 103 mmol),
in N,N-dimethylformamide (300 mL) was stirred for 5 h at
room temperature. The mixture was diluted with ethyl
acetate and washed four times with water. The organic layer
was dried (sodium sulfate), filtered, and concentrated in
vacuo. The resulting oil was triturated with ethyl acetate
and hexane, allowed to stand for 18 h, then cooled at 0 °C
for 3 h. The resulting precipitate was collected via vacuum
filtration to provide 24.3 g (69~) of the title compound as
white crystals: mp 60-61 °C. 1H NMR (CDC13) 8 7.68 (s,
1H), 7.40 (m, 5H), 6.48 (s, 1H), 5.17 (s, 2H), 4.13 (t, J =
6 Hz, 2H), 3.75 (t, J = 6 Hz, 2H), 2.56 (s, 3H), 2.55
(q, J = 7 Hz, 2H), 2.26 (quintet, J = 6 Hz, 2H), 1.16 (t, J
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-79-
- 7 Hz, 3H); TOF MS ES exact mass calculated for
C20H24C103 (p+1): m/z = 347.1414. Found: 347.1402; IR
(CHC13,
-1
cm ) 1659, 1602, 1266.
Anal. Calcd for C20H23C103: C, 69.26; H, 6.68. Found: C,
69.30; H, 6.52.
O O
\ I ~ -f- Ho \ I o \
O~C~ COOMe
known compound: RN# 152609-76-2
J. S. Sawyer et al., J. Med. Chem. 1995,
38, 4411
O I \
O~O \ O \
COOMe
B. Preparation of 2-{3-[3-(4-acetyl-5-benzyloxy-2-
ethylphenoxy)propoxy]-2-propyl-phenoxy)benzoic acid methyl
aster.
A mixture of 1-[2-benzyloxy-4-(3-chloropropoxy)-5-
ethylphenyl]ethanone (7.27 g, 21.0 mmol) and sodium iodide
(3.14 g, 23.1 mmol) in 2-butanone (100 mL) was heated at
reflux for 18 h. The mixture was cooled to room
temperature, filtered, and concentrated in vacuo. The
residue was dissolved in N,N-dimethylformamide (100 mL) and
treated with 2-(3-hydroxy-2-propylphenoxy)benzoic acid
methyl ester (6.0 g, 21 mmol) and potassium carbonate (3.2
g, 23 mmol) at room temperature for 15 h. The mixture was
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-80-
diluted with ethyl acetate and washed four times with water
and once with saturated sodium chloride solution. The
organic layer was dried (sodium sulfate), filtered, and
concentrated in vacuo. Chromatography (silica gel, 10~
ethyl acetate/90o hexane) of the residue provided 9.2 g
1
(72~) of the title compound as a colorless oil. H NMR
(CDC13) S 7.88 (d, J = 9 Hz, 1H), 7.69 (s, 1H), 7.38 (m,
6H), 7.12 (d, J = 8 Hz, 1H), 7.07 (d, J = 8 Hz, 1H), 6.80
(d, J = 8 Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.50 (s, 1H),
6.44 (d, J = 9 Hz, 1H), 5.14 (s, 2H), 4.20 (m, 4H), 3.83 (s,
3H), 2.65 (t, J = 7 Hz, 2H), 2.57 (q, J = 7 Hz, 2H), 2.56
(s, 3H), 2.32 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 7
Hz, 2H), 1.15 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); IR
-1
(CHC13, cm ) 2965, 1726, 1602, 1461.
Anal. Calcd for C3~H4~07: C, 74.48; H, 6.76. Found: C,
74.39; H, 6.77.
° Iw
W ~
I ~ O~O ~ I o ~ I
COO Me
O
Ho
~ ono ~ I o ~
COOMe
C. Preparation of 2-(3-(3-[5-benzyloxy-2-ethyl-4-(2-
hydroxyacetyl)phenoxy]propoxy?-2-propylphenoxy)benzoic acid
methyl ester.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-81-
A mixture of 2-{3-[3-(4-acetyl-5-benzyloxy-2-
ethylphenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl
ester (5.31 g, 8.89 mmol) and water (10 mL) in acetonitrile
(50 mL) was treated with trifluoroacetic acid (1.4 mL), 18
mmol) and [bis(trifluoroacetoxy)iodo]benzene (7.65 g, 17.8
mmol). The resulting mixture was heated at reflux for 4 h
then concentrated in vacuo. The residue was dissolved in
methylene chloride and washed once with water. The aqueous
layer was extracted twice with fresh portions of methylene
chloride. The combined organic layers were washed three
times with saturated sodium bicarbonate solution, once with
saturated sodium chloride solution, dried (sodium sulfate),
filtered, and concentrated in vacuo. Chromatography (silica
gel, 20o ethyl acetate/80~ hexane) of the residue provided
1
1.68 g (31~) of the title compound as a brown oil. H NMR
(CDC13) 8 7.92 (s, 1H), 7.88 (d, J = 9 Hz, 1H), 7.40 (m,
6H), 7.12 (d, J = 9 Hz, 1H), 7.05 (d, J = 9 Hz, 1H), 6.79
(d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 6.50 (s, 1H),
6.43 (d, J = 8 Hz, 1H), 5.15 (s, 2H), 4.65 (s, 2H), 4.22 (m,
4H), 3.83 (s, 3H), 2.65 (m, 4H), 2.34 (quintet, J = 6 Hz,
2H), 1.55 (hextet, J = 7 Hz, 2H), 1.17 (t, J = 8 Hz, 3H),
0.89 (t, J = 8 Hz, 3H); TOS MS ES exact mass calculated
for C37H4108 (p+1): m/z = 613.2801. Found: 613.2833.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-82-
O
I
~ ono ~ I o ~
COOMe
O
~I
O \
COOMe
D. Preparation of 2-{3-[3-(5-benzyloxy-2-ethyl-4-oxazol-4-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid methyl
ester.
To a solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(2-
hydroxyacetyl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid
methyl ester (1.39 g, 2.27 mmol) in methylene chloride (20
mL) cooled to -78 °C was added triflic anhydride (0.57 mL,
3.4 mmol) and 2,6-lutidine (0.40 mL, 3.4 mmol). The
resulting mixture was stirred for 1 h then poured into ether
and water. The organic layer was separated and washed once
with saturated sodium chloride solution, dried (sodium
sulfate), filtered, and concentrated in vacuo. The residue
was dissolved in a 2:1 mixture of formamide/N,N-
dimethylformamide (9 mL) and heated at 120 °C in a sealed
tube for 4 h. The mixture was cooled to room temperature
and diluted with ethyl acetate. The mixture was washed four
times with water, once with saturated sodium chloride
solution, dried (sodium sulfate), filtered, and concentrated
in vacuo. Chromatography (silica gel, 10o ethyl acetate/90o
hexane) of the residue provided 89 mg (60) of the title
product as a colorless oil. 1H NMR (CDC13) S 7.92 (s, 1H),
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-83-
7.85 (s, 1H), 7.83 (m, 2H), 7.35 (m, 6H), 7.03 (d, J = 8 Hz,
1H), 7.00 (d, J = 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H), 6.62
(d, J = 8 Hz, 1H), 6.52 (s, 1H), 6.35 (d, J = 8 Hz, 1H),
5.07 (s, 2H), 4.14 (m, 4H), 3.76 (s, 3H), 2.61 (m, 4H), 2.26
(quintet, J = 6 Hz, 2H), 1.48 (hextet, J = 7 Hz, 2H), 1.15
(t, J = 8 Hz, 3H), 0.84 (t, J = 8 Hz, 3H).
/= N O
O~O ~ ~ O
COOMe
/= N H
O ~
O~O ~ ~ O
COOMe
E. Preparation of 2-{3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl aster.
To a solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-oxazol-4-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
(89 mg, 0.14 mmol) in ethanethiol (2 mL) was treated with
boron trifluoride etherate (0.27 mL, 2.2 mmol) at room
temperature for 4 h. The solution was poured into ether and
washed once with water, once with saturated sodium
bicarbonate solution, once with saturated sodium chloride
solution, dried (sodium sulfate), filtered, and concentrated
in vacuo. Chromatography (silica gel, 15o ethyl acetate/85o
hexane) of the residue provided 34 mg (450) of the title
product as a light brown oil. 1H NMR (CDC13) 8 7.99 (d, J =
1 Hz, 1H), 7.90 (d, J = 1 Hz, 1H), 7.88 (dd, J = 8, 2 Hz,
1H), 7.38 (t, J = 7 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J = 9
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-84-
Hz, 1H), 7.06 (d, J = 9 Hz, 1H), 6.81 (d, J = 9 Hz, 1H),
6.70 (d, J = 9 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J = 9 Hz,
1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.65 (t, J = 8 Hz, 2H),
2.58 (q, J = 8 Hz, 2H), 2.33 (quintet, J = 6 Hz, 2H), 1.55
(hextet, J = 7 Hz, 2H), 1.17 (t, J = 8 Hz, 3H), 0.91 (t, J =
8 Hz, 3H); MS ES+ m/e = 532 (p + 1).
/= N H
O~
/ /
O~O \ I O
COOMe
/= N H
O ~
/ /
/ O~O ~ ~ O ~
COOH
F. Preparation of 2-~3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid.
To a solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
(89 mg, 0.14 mmol) in methanol (2 mL) was added 1 M lithium
hydroxide solution (0.28 mL) and the resulting mixture
warmed at 60 °C for 3.5 h. The mixture was cooled to room
temperature and concentrated in vacuo. The aqueous residue
was diluted with water and the pH adjusted to --4. The
mixture was extracted three times with methylene chloride.
The combined organic extracts were dried (sodium sulfate),
filtered, and concentrated in vacuo to provide 27 mg (920)
1
of the title compound as a yellow solid. H NMR (DMSO-d6)
8 12.83 (bs, 1H), 10.12 (bs, 1H), 8.39 (s, 1H), 8.25 (s,
1H), 7.78 (dd, J = 8, 1 Hz, 1H), 7.64 (s, 1H), 7.47 (t, J =
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-85-
8 Hz, 1H), 7.16 (m, 2H), 6.80 (t, J = 8 Hz, 2H), 6.56 (s,
1H) , 6.35 (d, J = 8 Hz, 1H) , 4.20 (t, J = 6 Hz, 2H) , 4.12
(t, J = 6 Hz, 2H); 2.54 (m, 4H), 2.24 (quintet, J = 6 Hz,
2H), 1.43 (hextet, J = 8 Hz, 2H), 1.10 (t, J = 8 Hz, 3H),
0.80 (t, J = 8 Hz, 3H); TOF MS ES exact mass calculated
for C3~H32N07 (p+1): m/z = 518.2179. Found: 518.2206; IR
-1
(KBr, cm ) 2961, 1696, 1460, 1222.
Anal. Calcd for C3pH31N07: C, 69.62; H, 6.04; N, 2.71.
Found: C, 68.71; H, 5.82; N, 2.65.
Example 2
Preparation of 2-(3-~3-[2-Ethyl-5-hydroxy-4-(3H-imidazol-4-
yl)phenoxy]propoxy~-2-propyl-phenoxy)benzoic acid
hydrochloride.
O
W i i
O~O w I O w
COOMe
O O
i
O~O ~ o
COO Me
A. Preparation of 2-(3-~3-[5-benzyloxy-4-(2-chloroacetyl)-
2-ethylphenoxy]propoxy)-2-propylphenoxy)benzoic acid methyl
ester.
To a solution of 2-{3-[3-(4-acetyl-5-benzyloxy-2-
ethylphenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-86-
ester (3.04 g, 5.09 mmol) in tetrahydrofuran (50 mL) cooled
to -78 °C was added a solution of 1 M lithium
hexamethyldisilazide in tetrahydrofuran (11.2 mL, 11.2 mmol)
portion wise. After stirring for 20 min, trimethylsilyl
chloride (2.6 mL, 20 mmol) was added and the mixture warmed
to 0 °C and stirred for 30 min. The mixture was evaporated
in vacuo and the residue dissolved in hexane. The resulting
solution was filtered and concentrated in vacuo. The
residue was dissolved in tetrahydrofuran (50 mL), cooled to
0 °C, and treated with N-chlorosuccinimide (750 mg, 5.6
mmol). The mixture was warmed to room temperature and
stirred for 30 min, then heated at reflux for 2 h. The
mixture was cooled to room temperature and treated with
water (4 mL) and a solution of 1 N tetra-n-butylammonium
fluoride in tetrahydrofuran (6 mL). After stirring for 15
min the mixture was diluted in ether and washed once with
water, once with saturated sodium chloride solution, dried
(sodium sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, 10~ ethyl acetate/90~ hexane) of
the residue provided 1.94 g (60~) of the title compound as a
white solid. 1H NMR (CDC13) S 7.89 (d, J = 8 Hz, 1H), 7.77
(s, 1H), 7.40 (m, 6H), 7.12 (d, J = 9 Hz, 1H), 7.06 (d, J =
8 Hz, 1H), 6.80 (d, J = 8 Hz, 1H), 6.66 (d, J = 8 Hz, 1H),
6.49 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.15 (s, 2H), 4.68 (s,
2H), 4.20 (q, J = 6 Hz, 4H), 3.82 (s, 3H), 2.65 (t, J = 7
Hz, 2H), 2.59 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz,
2H), 1.54 (hextet, J = 8 Hz, 2H), 1.16 (t, J = 8 Hz, 3H),
0.89 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated
for C37H40C107 (p+1): m/z = 631.2463. Found: 631.2470; IR
-1
(CHC13, cm ) 2964, 1720, 1603, 1461.
Anal. Calcd for C37H39C107: C, 70.41; H, 6.23. Found: C,
70.04; H, 5.97.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-87-
O \
CI I / / /
I ~ ono \ I o \ I
COOMe
S H
~N~ \
N' \ I / / /
/ ono \ I o \
COOMe
B. Preparation of 2-(3-~3-[5-benzyloxy-4-(2-benzylsulfanyl-
3X-imidazol-4-yl)-2-ethyl-phenoxy]propoxy~-2-
propylphenoxy)benzoic acid methyl ester.
A mixture of 2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2-
ethylphenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl
ester (800 mg, 1.27 mmol), 2-benzyl-2-thiopseudourea
hydrochloride (313 mg, 1.52 mmol), sodium iodide (77 mg,
0.51 mmol), and potassium carbonate (700 mg, 5.06 mmol) in
N,N-dimethylformamide (20 mL) was treated at 80 °C for 6 h.
The mixture was cooled, diluted with diethyl ether, and
washed once with water. The organic layer was dried (sodium
sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, 30% ethyl acetate/70% hexane) of
the residue provided 376 mg (40%) of the title compound as a
yellow amorphous solid. 1H NMR (CDC13) 8 7.89 (d, J = 8 Hz,
1H), 7.36 (m, 9H), 7.20 (m, 5H), 7.21 (d, = Hz, 1H),
J 9
7.06 (d, = 8 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.67 (d,
J J =
8 Hz, 1H) 6.55 (s, 1H) 6.43 (d, J = 8 Hz, 1H) 5.07 (s,
, , ,
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-88-
2H), 4.21 (t, J = 6 Hz, 2H), 4.18 (t, J = 6 Hz, 2H), 4.10
(s, 2H), 3.83 (s, 3H), 2.63 (m, 4H), 2.31 (quintet, J = 6
Hz, 2H), 1.55 (hextet, J = 7 Hz, 2H), 1.18 (t, J = 8 Hz,
3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass
calculated for C45H47N206S (p+1): m/z = 743.3155. Found:
-1
743.3142; IR (CHC13, cm ) 2963, 1720, 1602, 1453.
Anal. Calcd for C45H46N206S~ C, 72.75; H, 6.24; N, 3.77.
Found: C, 72.69; H, 6.17; N, 3.56.
\ /
H
I~
/ /
/ Ono ~ I o ~ I
COOMe
S H
~N~ H
N ~
I~ /I /I
/ O~O \ O
COOMe
C. Preparation of 2-(3-~3-[4-(2-benzylsulfanyl-3H-imidazol-
4-yl)-2-ethyl-5-hydroxyphenoxy]propoxy)-2-
propylphenoxy)benzoic acid methyl aster.
A solution of 2-(3-{3-[5-benzyloxy-4-(2-benzylsulfanyl-3H-
imidazol-4-yl)-2-ethyl-phenoxy]propoxy}-2-
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-89-
propylphenoxy)benzoic acid methyl ester (360 mg, 0.49 mmol)
in ethanethiol (7 mL) was treated with boron trifluoride
etherate at room temperature for 3.5 h. The mixture was
diluted with diethyl ether and water. The organic layer was
separated and washed with saturated sodium bicarbonate
solution, dried (sodium sulfate), filtered, and concentrated
in vacuo. Chromatography (silica gel, 20~ ethyl acetate/80~
hexane) of the residue provided 154 mg (48~) of the title
compound as an orange oil. 1H NMR (CDC13) 8 7.85 (d, J = 8
Hz, 1H), 7.36 (t, J = 7 Hz, 1H), 7.20 (m, 7H), 7.12 (s, 1H),
7.05 (m, 3H), 6.79 (d, J = 8 Hz, 1H), 6.65 (d, J = 8 Hz,
1H), 6.54 (s, 1H), 6.41 (d, J = 8 Hz, 1H), 4.20 (s, 2H),
4.17 (m, 4H), 3.82 (s, 3H), 2.62 (t, J = 8 Hz, 2H), 2.54 (q,
J = 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.53 (hextet, J
- 8 Hz, 2H), 1.14 (t, J = 7 Hz, 3H), 0.89 (t, J = 8 Hz, 3H);
TOF MS ES exact mass calculated for C38H41N206S (p+1):
m/z = 653.2685. Found: 653.2669.
Anal. Calcd for C38H40N206S: C, 69.92; H, 6.18; N, 4.29.
Found: C, 69.44; H, 6.25; N, 3.99.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-90-
S H
~N~ H
N ~
/ /
/ O~O ~ ~ O ~
COOMe
,,.
~HCI
H
~N~ OH
N ~
/~ /~
/ O~O ~ O
COOH
D. Preparation of 2-(3-{3-[2-ethyl-5-hydroxy-4-(3H-
imidazol-4-yl)phenoxy]propoxy}-2-propyl-phenoxy)benzoic acid
hydrochloride.
A solution of 2-(3-(3-[4-(2-benzylsulfanyl-3H-imidazol-4-
yl)-2-ethyl-5-hydroxyphenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (154 mg, 0.235 mmol)
in methanol (3 mL) was treated with 1 N lithium hydroxide
solution at 60 °C for 3.5 h. The mixture was cooled to room
temperature and concentrated in vacuo. The solution was
diluted with water and adjusted to pH 4. The aqueous
solution was extracted three times with methylene chloride.
The combined organic layers were dried (sodium sulfate),
filtered, and concentrated in vacuo. The residue was
dissolved in ethanol (3 mL) and treated with 0.2 N sodium
hydroxide solution (1 mL) and Raney nickel (75 mg) at 75 °C
for 4 h. The mixture was cooled to room temperature,
TM
filtered through Celite , and the filtrate concentrated in
vacuo. The residue was diluted with water and adjusted to
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-91-
pH 2 with 1 N hydrochloric acid. The resulting precipitate
was collected via vacuum filtration to provide 27 mg (21~)
of the title compound. TOF MS ES exact mass calculated
for C3pH33N206 (p+1): m/z = 517.2339. Found: 517.2340.
Example 3
Preparation of 2-~3-[3-(2-Ethyl-5-hydroxy-4-thiazol-4-yl-
phenoxy)propoxy]-2-propyl-phenoxy)benzoic acid.
O
I~
ono ~ I o ~
COOMe
/= N
s ,
~ ono ~ I o ~
COOMe
A. Preparation of 2-~3-[3-(5-benzyloxy-2-ethyl-4-thiazol-4-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid methyl
ester.
A mixture of 2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2-
ethylphenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl
ester (500 mg, 0.792 mmol), thioformamide (20 mL, 8.0 mmol),
and magnesium carbonate in dioxane (10 mL) was heated at
reflux for 2 h. The mixture was cooled to room temperature
and diluted with diethyl ether and 0.2 M sodium hydroxide
solution. The organic layer was separated, washed with
saturated sodium chloride solution, dried (sodium sulfate),
filtered, and concentrated in vacuo. Chromatography (silica
gel, 10o ethyl acetate/90o hexane) of the residue provided
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-92-
1
254 mg (500) of the title compound as a colorless oil. H
NMR (CDC13) 8.91(s, 1H), (s, 1H), 7.87 (dd, J 8,
S 8.11 = 1
Hz, 1H), 7.84(d, J 1H),7.40 (m, 6H), 7.08 (m, 2H),
=
1
Hz,
6.80 (d, J 8 1H), 6.68 (d, J 8 1H), 6.62 (s,
= Hz, = Hz,
1H), 6.43 (d, J 8 1H), 5.1 6 2H), 4.21 (t, J 6
= Hz, (s, =
Hz, 4H), 3.83(s, 3H), 2.68 (m, 4H), 2.32 (quintet, 6
J
=
Hz, 2H), 1.56(hextet, J = Hz, 2H), 1.21 (t, J = 7
8 Hz,
3H), 0.90 (t, J 7 3H); TOF MS xact mass
= Hz, ES
e
calculated for C38H4~N06S (p+1): m/z = 638.2576. Found:
-1
638.2579. IR (CHC13, cm ) 2964, 1719, 1563, 1461.
/= N
S' I/ / /
/ ono w I o w
COOMe
~N OH
S ~
/ /
I / O~O ~ I O ~ (
COOMe
B. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-thiazol-4-
yl-phenoxy)propoxy]-2-propylphenoxy?benzoic acid methyl
ester.
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-4-yl-
phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl ester
(243 mg, 0.366 mmol) in ethanethiol (7 mL) was treated with
boron trifluoride etherate at room temperature for 4 h. The
mixture was diluted with diethyl ether, washed once with
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-93-
water, once with saturated sodium bicarbonate solution,
dried (sodium sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, 15~ ethyl acetate/85o hexane) of
the residue provided 131 mg (65~) of the title compound as a
colorless oil. 1H NMR (CDC13) 8 8.88 (d, J = 1 Hz, 1H),
7.88 (dd, J = 8, 1 Hz, 1H), 7.44 (d, J = 1 Hz, 1H), 7.38 (m,
2H), 7.08 (m, 2H), 6.81 (d, J = 8 Hz, 1H), 6.68 (d, J = 8
Hz, 1H), 6.55 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 4.21 (t, J =
6 Hz, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J = 6
Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H), 1.19 (t, J = 8 Hz,
3H), 0.91 (t, J = 7 Hz, 3H); TOF MS ES exact mass
calculated for C31H34N06S (p+1): m/z = 548.2107. Found:
548.2085.
/= N H
S ~
/ /
O~O ~ ~ O
COOMe
/= N H
S ~
O~O ~ ~ O
COOH
C. Preparation of 2-~3-[3-(2-ethyl-5-hydroxy-4-thiazol-4-
yl-phenoxy)propoxy]-2-propylphenoxy~benzoic acid.
A solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-thiazol-4-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
(130 mg, 0.236 mmol) in methanol (4 mL) was treated with 1 M
lithium hydroxide solution at 60 °C for 3 h. The mixture
was cooled to room temperature, concentrated in vacuo, and
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-94-
diluted with water. The solution was adjusted to pH ~4 and
extracted three times with methylene chloride. The combined
organic layers were dried (sodium sulfate), filtered, and
concentrated in vacuo. The residue was dissolved in a
minimum of methylene chloride and hexane was added until the
solution became cloudy. The mixture was concentrated slowly
1
in vacuo to give 96 mg (760) of the title compound. H NMR
(CDC13) 8 8.90 (s, 1H), 8.23 (dd, J = 8, 1 Hz, 1H), 7.41 (m,
2H), 7.38 (s, 1H), 7.29 (m, 2H), 6.82 (d, J = 8 Hz, 1H),
6.71 (d, J = 8 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.54 (s,
1H), 4.25 (t, J = 6 Hz, 2H), 4.22 (t, J = 6 Hz, 2H), 2.59
(m, 4H), 2.35 (quintet, J = 6 Hz, 2H), 1.50 (hextet, J = 8
Hz, 2H), 1.19 (t, J = 7 Hz, 3H), 0.88 (t, J = 8 Hz, 3H);
TOF MS ES exact mass calculated for C30H32N06S (p+1): m/z
-1
- 534.1950. Found: 534.1957. IR (CHC13, cm ) 2965, 1738,
1454.
Anal. Calcd for C3~H31N06S: C, 67.52; H, 5.86; N, 2.62.
Found: C, 67.19; H, 5.72; N, 2.53.
Example 4
Preparation of 2-(3-{3-[2-Ethyl-5-hydroxy-4-(2H-pyrazol-3-
yl)phenoxy]propoxy)-2-propyl-phenoxy)benzoic acid.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-95-
° I
i
I ~ O~O ~ ( O ~ I
COOMe
O
I~ i i
I~ ~I ~I
o'~0 0
COOMe
A. Preparation of 2-(3-~3-[5-benzyloxy-4-(3-
dimethylaminoacryloyl)-2-ethyl-phenoxy]propoxy)-2-
propylphenoxy)benzoic acid methyl aster.
A mixture of 2-(3-{3-[4-acetyl-5-benzyloxy-2-
ethylphenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl
ester (3.07 g, 5.04 mmol) and dimethylformamide
dimethylacetal (0.9 mL, 7 mmol) in N,N-dimethylformamide (3
mL) was heated at 110-120 °C for 35 h. The mixture was
cooled to room temperature and diluted with a mixture of
ethyl acetate and 1 N hydrochloric acid. The organic layer
was separated, washed twice with water, once with saturated
sodium chloride solution, dried (sodium sulfate), filtered,
and concentrated in vacuo. Chromatography (silica gel, 300
ethyl acetate/70o hexane to ethyl acetate) of the residue
provided 2.1 g (630) of the title compound as a yellow oil.
TOF MS ES exact mass calculated for C4~H46N07 (p+1): m/z
-1
- 652.3274. Found: 652.3270. IR (CHC13, cm ) 2965, 1720,
1605.
Anal. Calcd for C4~H45N07: C, 73.71; H, 6.96; N, 2.15.
Found: C, 73.72; H, 6.95; N, 2.18.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-96-
O
I/ /
I~ /I
/ o'~o ~ o
COOMe
N-N'H I W
/ /
I / O~O ~ I O ~ I
COOH
B. Preparation of 2-(3-~3-[5-benzyloxy-2-ethyl-4-(2X-
pyrazol-3-yl)phenoxy]propoxy?-2-propylphenoxy)benzoic acid.
A solution of 2-(3-{3-[5-benzyloxy-4-(3-
dimethylaminoacryloyl)-2-ethyl-phenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (550 mg, 0.843 mmol
in methanol (30 mL) was treated with 1 M lithium hydroxide
solution at 60 °C for 3 h. The mixture was cooled to room
temperature and diluted with ethyl acetate and 0.5 M
hydrochloric acid. The organic layer was separated, washed
with saturated sodium chloride solution, dried (sodium
sulfate), filtered, and concentrated in vacuo. The residue
was dissolved in methanol (15 mL) and treated with water (4
mL) and hydrazine monohydrate (0.50 mL, 7.7 mmol) at reflux
for 3 h. The mixture was diluted with ethyl acetate and 1 N
hydrochloric acid. The organic layer was separated, washed
with saturated sodium chloride solution, dried (sodium
sulfate), filtered and concentrated in vacuo.
Chromatography (30% ethyl acetate/69% hexane/1% acetic acid)
of the residue provided 350 mg (65%) of the title compound
as the acetate salt. A portion of this material was free-
based with sodium bicarbonate to provide an analytical
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-97-
sample. 1H NMR (CDC13) b 8.20 (dd, J = 8, 2 Hz, 1H), 7.55
(s, 1H), 7.44 (s, 1H), 7.38 (m, 5H), 7.15 (m, 2H), 6.78 (d,
J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.61 (d, J = 8 Hz,
1H), 6.58 (s, 1H), 6.55 (bs, 1H), 5.18 (s, 2H), 4.22 (t, J =
6 Hz, 2H), 4.17 (t, J = 6 Hz, 2H), 2.58 (m, 4H), 2.30
(quintet, J = 6 Hz, 2H), 1.47 (hextet, J = 8 Hz, 2H), 1.18
(t, J = 7 Hz, 3H), 0.88 (t, J = 8 Hz, 3H); TOF MS ES exact
mass calculated for C37H39N206 (p+1): m/z = 607.2808.
-1
Found: 607.2831. IR (CHC13, cm ) 2965, 1739 ,1604, 1454.
Anal. Calcd for C37H38N206: C, 73.25; H, 6.31; N, 4.62.
Found: C, 73.31; H, 6.30; N, 4.62.
N-N'H
O~\/~O \
COOH
,H
N-N H
/) /I
/ o~0 \ O \
COOH
C. Preparation of 2-(3-~3-[2-ethyl-5-hydroxy-4-(2H-pyrazol-
3-yl)phenoxy~propoxy~-2-propylphenoxy)benzoic acid.
A solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(2H-pyrazol-3-
yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid (300 mg,
0.490 mmol) in ethanethiol (2.5 mL) was treated with boron
trifluoride etherate (2 mL) at room temperature for 3 h, at
which time an additional portion of boron trifluoride
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-98-
etherate (1 mL) was added and stirring resumed for an
additional 1 h. The mixture was diluted with diethyl ether
and water. The organic layer was separated, washed with
water, dried (sodium sulfate), filtered, and concentrated in
vacuo. Chromatography (silica gel, 15o ethyl acetate/85~
hexane to 60o ethyl acetate/40~ hexane) of the residue
provided 60 mg (24~) of the title compound as a white solid.
1H NMR (CDC13) 8 8.23 (d, J = 8 Hz, 1H), 7.61 (s, 1H), 7.42
(t, J = 7 Hz, 1H), 7.30 (s, 1H), 7.19 (d, J = 8 Hz, 1H),
7 . 15 (d, J = 8 Hz, 1H) , 6. 81 (d, J = 8 Hz, 1H) , 6. 69 (d, J =
8 Hz, 1H), 6.61 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 6.54 (s,
1H), 4.20 (m, 4H), 2.58 (m, 4H), 2.33 (quintet, J = 6 Hz,
2H), 1.48 (hextet, J = 8 Hz, 2H), 1.17 (t, J = 8 Hz, 3H),
0.86 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated
for C30H33N2~6 (p+1): m/z = 517.2339. Found: 517.2334.
-1
IR (CHC13, cm ) 2965, 1738, 1454.
Anal. Calcd for C30H32N2~6= C~ 69.75; H, 6.24; N, 5.42.
Found: C, 69.73; H, 6.33; N, 5.25.
Example 5
Preparation of 2-(3-[3-(2-Ethyl-5-hydroxy-4-isoxazol-5-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-99-
O
/ /
N W
O~O O
COOMe
N_O
/ /I /I
/ O~O ~ O
COOMe
A. Preparation of 2-~3-[3-(5-benzyloxy-2-ethyl-4-isoxazol-
5-yl-phenoxy)propoxy]-2-propylphenoxy~benzoic acid methyl
ester.
A mixture of 2-(3-{3-[5-benzyloxy-4-(3-
dimethylaminoacryloyl)-2-ethylphenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (280 mg, 0.43 mmol),
hydroxylamine hydrochloride (75 mg, 1.1 mmol), and water (1
mL) in methanol (4 mL) was heated at reflux for 2 h. The
mixture was cooled to room temperature and diluted with
diethyl ether and water. The organic layer was separated,
washed with saturated sodium chloride solution, dried
(sodium sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, 10~ ethyl acetate/90o hexane) of
the residue provided 202 mg (76~) of the title compound as a
white solid. 1H NMR (CDC13) 8 8.20 (d, J = 2 Hz, 1H), 7.88
(dd, J = 9, 2 Hz, 1H), 7.79 (s, 1H), 7.40 (m, 7H), 7.08 (m,
2H), 6.68 (d, J = 8 Hz, 1H), 6.59 (s, 1H), 6.58 (s, 1H),
6.43 (d, J = 8 Hz, 1H), 5.15 (s, 2H), 4.21 (t, J = 6 Hz,
4H), 3.82 (s, 3H), 2.65 (m, 4H), 2.33 (quintet, J = 6 Hz,
2H), 1.56 (hextet, J = 8 Hz, 2H), 1.20 (t, J = 7 Hz, 3H),
0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-100-
for C38H40N07 (p+1): m/z = 622.2805. Found: 622.2817. IR
-1
(CHC13, cm ) 2964, 1720, 1461.
Anal. Calcd for C3gH39N07: C, 73.41; H, 6.32; N, 2.25.
Found: C, 73.20; H, 6.34; N, 2.27.
N-p
i i ~
o'~O ~ o
COOMe
N'O OH
o'~O ~ o
COOMe
B. Preparation of 2-~3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid methyl
ester.
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-isoxazol-5-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
(180 mg, 0.289 mmol) in ethanethiol (5 mL) was treated with
boron trifluoride etherate (1.5 mL) at room temperature for
2 h, at which time an additional portion of boron
trifluoride etherate (0.5 mL) was added and stirring resumed
for an additional 1 h. The mixture was diluted with diethyl
ether and water. The organic layer was separated, washed
once with saturated sodium bicarbonate solution, once with
saturated sodium chloride solution, dried (sodium sulfate),
filtered, and concentrated in vacuo. Chromatography (silica
gel, 15% ethyl acetate/85% hexane) of the residue provided
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-101-
1
94 mg (61~) of the title compound as a colorless oil. H
NMR (CDC13) S 8.28 (d, J = 1 Hz, 1H), 7.88 (dd, J = 8, 2 Hz,
1H), 7.38 (t, J = 8 Hz,lH), 7.36 (s, 1H), 7.08 (t, J = 8 Hz,
1H), 7.05 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 6.67
(d, J = 8 Hz, 1H), 6.50 (s, 1H), 6.45 (s, 1H), 6.43 (d, J =
8 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.62 (m, 4H), 2.34
(quintet, J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.18
(t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact
mass calculated for C31H34N07 (p+1): m/z = 532.2335.
-1
Found: 532.2335. IR (CHC13, cm ) 2964, 1715, 1601, 1461.
Anal. Calcd for C31H33N07: C, 70.04; H, 6.26; N, 2.63.
Found: C, 70.13; H, 6.35; N, 2.63.
N'0 H
I / O~O ~ I O
COOMe
N'O OH
~ ono w I o w
COOH
C. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid.
To a solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-isoxazol-5-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
(94 mg, 0.18 mmol) in methanol (3 mL) was added 1 M lithium
hydroxide solution (1 mL) and the resulting mixture warmed
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-102-
at 60 °C for 3 h. The mixture was cooled to room
temperature and concentrated in vacuo. The aqueous residue
was diluted with water and the pH adjusted to ~4. The
mixture was extracted three times with methylene chloride.
The combined organic extracts were dried (sodium sulfate),
filtered, and concentrated in vacuo to provide 12 mg (13~)
1
of the title compound as an off-white amorphous solid. H
NMR (CDC13) 8 8.26 (s, 1H), 8.20 (dd, J = 8, 1 Hz, 1H), 7.49
(t, J = 6 Hz, 1H), 7.36 (s, 1H), 7.18 (d, J = 8 Hz, 1H),
7.15 (d, J = 8 Hz, 1H), 7.02 (bs, 1H), 6.80 (d, J = 8 Hz,
1H), 6.69 (d, J = 8 Hz, 1H), 6.60 (d, J = 8 Hz, 1H), 6.50
(s, 1H), 6.46 (s, 1H), 4.22 (t, J = 6 Hz, 2H), 4.19 (t, J =
6 Hz, 2H); 2.57 (m, 4H), 2.34 (quintet, J = 6 Hz, 2H), 1.47
(hextet, J = 8 Hz, 2H), 1.16 (t, J = 8 Hz, 3H), 0.85 (t, J =
7 Hz, 3H); TOS MS ES exact mass calculated for C30H32N07
(p+1): m/z = 518.2179. Found: 518.2175.
Anal. Calcd for C30H31N07: C, 69.62; H, 6.04; N, 2.71.
Found: C, 69.57; H, 6.15; N, 2.74.
Example 6
Preparation of 2-(3-~3-[2-Ethyl-5-hydroxy-4-(3H-
[1,2,3]triazol-4-yl)phenoxy]propoxy)-2-propyl-
phenoxy)benzoic acid.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-103-
Br I ~ ~ I ~
I ~ + HO ~ O
O~CI . COOMe
Br I ~
~ ono w I o w
COOMe
A. Preparation of 2-~3-[3-(5-benzyloxy-4-bromo-2-
ethylphenoxy)propoxy]-2-propylphenoxy)-benzoic acid methyl
ester.
A mixture of 5-benzyloxy-4-bromo-1-(3-chloropropoxy)-2-
ethylbenzene (1.19 g, 3.11 mmol), 2-(3-hydroxy-2-
propylphenoxy)benzoic acid methyl ester (0.89 g, 3.1 mmol),
potassium carbonate (1.29 g, 9.34 mmol), potassium iodide
(0.52 g, 3.1 mmol), and methyl sulfoxide (2 mL) in 2-
butanone (20 mL) was heated at reflux for 48 h. The mixture
was cooled to room temperature, diluted with diethyl ether,
and washed once with water. The organic layer was dried
(sodium sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, 6o ethyl acetate/94o hexane) of
the residue provided 1.34 g (680) of the title compound as a
1
colorless oil. H NMR (CDC13) 8 7.91 (dd, J = 8, 2 Hz, 1H),
7.50 (d, J = 7 Hz, 2H), 7.38 (m, 5H), 7.15 (d, J = 8 Hz,
1H), 7.10 (d, J = 8 Hz, 1H), 6.83 (d, J = 8 Hz, 1H), 6.71
(d, J = 8 Hz, 1H), 6.55 (s, 1H), 6.48 (, J = 8 Hz, 1H), 5.16
(s, 2H), 4.21 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H),
3.83 (s, 3H), 2.68 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz,
2H), 2.31 (quintet, J = 6 Hz, 2H), 1.58 (hextet, J = 6 Hz,
2H), 1.17 (t, J = 7 Hz, 3H), 0.93 (t, J = 7 Hz, 3H).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-104-
O
Br ( i , i
~ ono ~ I o ~
COOMe
o I ~
w i i
~ ono w I o w
COOMe
B. Preparation of 2-~3-[3-(5-benzyloxy-2-ethyl-4-
ethynylphenoxy)propoxy]-2-propyl-phenoxy~benzoic acid methyl
ester.
A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2-
ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl
ester (1.50 g, 2.37 mmol), tri-n-butylethynyltin (0.82 mL,
2.8 mmol), and tetrakis(triphenylphosphine)palladium (0)
(1.0 g, 0.95 mmol) in N,N-dimethylformamide (25 mL) was
purged with argon and heated in a sealed tube at 120 °C for
24 h. The mixture was cooled to room temperature and
filtered. The filtrate was diluted with ethyl acetate,
washed four times with water, once with saturated sodium
chloride solution, dried (sodium sulfate), filtered, and
concentrated in vacuo. Chromatography (silica gel, 10~
ethyl acetate/90~ hexane) of the residue provided 532 mg
1
(390) of the title compound as a brown oil. H NMR (CDC13)
8 = 2 Hz, 1H), 7.79 (s, 1H), 7.20-7.50 (m,
7.88 8,
(dd,
J
6H), 7.10 (d, J 8 Hz, 1H), 7.05 (d, J Hz, 1H), 6.80
= =
8
(d, J = 8 1H), 6.66 (d, J = 8 Hz, 1H), 6.43 (m, 2H),
Hz,
5.16 (s, 2H), 4.17 (t, = 6 Hz, 2H), 4.11 (t, J = 6 Hz,
J
2H), 3.83 (s, 3H), 3.23 (s, 1H), 2.64 (t, = 8 Hz, 2H),
J
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-105-
2.53 (q, J = 7 Hz, 2H), 2.27 (quintet, J = 6 Hz, 2H), 1.53
(m, 2H), 1.13 (t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); TOF
MS ES exact mass calculated for C37H3906 (p+1): m/z =
579.2747. Found: 579.2739.
I/
/ /
I / O~O ~ I O ~ I
COOMe
NN_N.H
I / O~O ~ I O w I
COOMe
C. Preparation of 2-(3-~3-[5-benzyloxy-2-ethyl-4-(3H-
[1,2,3]triazol-4-yl)phenoxy]-propoxy~-2-
propylphenoxy)benzoic acid methyl aster.
A mixture of 2-{3-[3-(5-benzyloxy-2-ethyl-4-
ethynylphenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl
ester (517 mg, 0.893 mmol) and trimethylsilyl azide (3.0 mL,
18 mmol) was heated in toluene (20 mL) in a sealed tube at
130 °C for 120 h. The mixture was cooled to room
temperature and concentrated in vacuo. Chromatography
(silica gel, 10o ethyl acetate/90~ hexane to 50o ethyl
acetate/50o hexane) of the residue provided 347 mg (88~
based upon recovered starting material) of the title
compound as a brown solid. 1H NMR (CDC13) b 8.10 (bs, 1H),
7.89 (dd, J = 8, 2 Hz, 1H), 7.76 (s, 1H), 7.40 (m, 7H), 7.10
(d, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 6.79 (d, J = 8
Hz, 1H), 6.67 (d, J = 8 Hz, 1H), 6.62 (s, 1H), 6.43 (d, J =
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-106-
8 Hz, 1H), 5.18 (s, 2H), 4.21 (m, 4H), 3.82 (s, 3H), 2.65
(m, 4H), 2.32 (quintet, J = 6 Hz, 2H), 1.56 (hextet, J = 8
Hz, 2H), 1.21 (t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF
MS ES exact mass calculated for C37H40N306 (p+1): m/z =
-1
622.2917. Found: 622.2946. IR (CHC13, cm ) 3400, 1721,
1602, 1453.
Anal. Calcd for C37H39N306: C, 71.48; H, 6.32; N, 6.76.
Found: C, 70.28; H, 6.07; N, 6.54.
NN-N'H O
\~
O~O \ I O
COOMe
H
,N'N~ OH
N ~
\ / /
O~\/~O \ I O \
COOMe
D. Preparation of 2-(3-~3-[2-ethyl-5-hydroxy-4-(3H-
[1,2,3]triazol-4-yl)phenoxy]-propoxy}-2-propyl-
phenoxy)benzoic acid methyl ester.
A solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(3H-
[1,2,3]triazol-4-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic
acid methyl ester (330 mg, 0.531 mmol) in ethanethiol (9 mL)
was treated with boron trifluoride etherate (2.0 mL,l6 mmol)
for 1 h at room temperature and then with an additional
portion of boron trifluoride etherate (1.0 mL) for 1 h. The
mixture was diluted with diethyl ether and water. The
organic layer was washed once with saturated sodium
bicarbonate solution, once with saturated sodium chloride
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-107-
solution, dried (sodium sulfate), filtered, and concentrated
in vacuo. Chromatography (silica gel, 30~ ethyl acetate/70o
hexane to 50o ethyl acetate/50~ hexane) of the residue
provided 180 mg (630) of the title compound as a brown
solid. 1H NMR (CDC13) 8 7.97 (s, 1H), 7.88 (dd, J = 8, 2
Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J =
8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H),
6.67 (d, J = 8 Hz, 1H), 6.59 (s, 1H), 6.43 (d, J = 8 Hz,
1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.34
(quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.19
(t, J = 8 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact
mass calculated for C3~H34N306 (p+1): m/z = 532.2447.
-1
Found: 532.2466. IR (CHC13, cm ) 2964, 1718, 1453.
Anal. Calcd for C3~H33N306: C. 67.78; H, 6.26; N, 7.90.
Found: C, 66.80; H, 6.02; N, 7.53.
,H
,N'N H
N ~
/ I /
/ O~O \ O
COOMe
H
,N_N. H
N ~
/ /
/ O~O ~ ~ O ~
COOH
E. Preparation of 2-(3-~3-[2-ethyl-5-hydroxy-4-(313-
[1,2,3]triazol-4-yl)phenoxy]-propoxy)-2-
propylphenoxy)benzoic acid.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-108-
A solution of 2-(3-{3-[2-ethyl-5-hydroxy-4-(3H-
[1,2,3]triazol-4-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic
acid methyl ester (160 mg, 0.30 mmol) in methanol (5 mL) was
treated 1 N lithium hydroxide solution (1.5 mL) at 60 °C for
3.5 h. The mixture was cooled to room temperature, diluted
with water, and adjusted to ~pH 4. The resulting mixture
was extracted three times with methylene chloride. The
combined organic extracts were dried (sodium sulfate),
filtered, and concentrated in vacuo to provide 134 mg (860)
1
of the title compound as a tan solid. H NMR (DMSO-d)
8 14.98 (bs, 1H), 12.80 (bs, 1H), 10.02 (bs, 1H), 8.17 (bs,
1H), 7.77 (dd, J = 7, 2 Hz, 1H), 7.60 (bs, 1H), 7.47 (t, J =
8 Hz, 1H), 7.18 (t, J = 8 Hz, 1H), 7.14 (t, J = 8 Hz, 1H),
6.82 (d, J = 8 Hz, 1H) , 6. 68 (d, J = 8 Hz, 1H) , 6.57 (s,
1H), 6.35 (d, J = 8 Hz, 1H), 4.22 (t, J = 6 Hz, 2H), 4.15
(t, J = 6 Hz, 2H), 2.54 (m, 4H), 2.25 (quintet, J = 6 Hz,
2H), 1.45 (hextet, J = 8 Hz, 2H), 1.11 (t, J = 7 Hz, 3H),
0.81 (t, J = 7 Hz, 3H); TOF MS ES exact mass calculated
for C29H32N306 (p+1): m/z = 518.2291. Found: 518.2302.
-1
IR (CHC13, cm ) 2965, 1738, 1454.
Anal. Calcd for C29H31N306: C, 67.30; H, 6.04; N, 8.12.
Found: C, 67.15; H, 5.98; N, 7.93.
Example 7
Preparation of 2-~3-[3-(2-Ethyl-5-hydroxy-4-pyrrol-1-yl-
phenoxy)propoxy]-2-propyl-phenoxy~benzoic acid methyl ester.
OH
O
CN I /
-OH /
~OH
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-109-
A. Preparation of 5-benzyloxy-2-ethyl-4-pyrrol-1-yl-phenol.
To a mixture of potassium nitrosodisulfonate (40.0 g, 149
mmol) and potassium hydrogen phosphate (10 g) in water (1.2
L) at room temperature was added a solution of 4-
ethylbenzene-1,3-diol (10.0 g, 2.37 mmol) and potassium
hydrogen phosphate (10.5 g) in water (150 mL). The mixture
was stirred for 15 min and adjusted to pH ~3. The solution
was extracted three times with diethyl ether. The organic
layer was dried (sodium sulfate), filtered, and concentrated
in vacuo. The residue was dissolved in acetonitrile (70 mL)
and treated at room temperature with 65~ 3-pyrroline (12
mL). The resulting mixture was stirred for 1 h and
concentrated in vacuo, dissolved in ethyl acetate and
hexane, and filtered down a short column of silica gel. The
resulting solution was concentrated in vacuo. The residue
was dissolved in N,N-dimethylformamide (10 mL) and treated
with benzyl bromide (0.85 mL, 7.1 mmol) and potassium
carbonate (960 mg, 6.9 mmol) at room temperature for 15 h.
The mixture was diluted with ethyl acetate, washed four
times with water, once with saturated sodium chloride
solution, dried (sodium sulfate), filtered, and concentrated
in vacuo. Chromatography (silica gel, ethyl acetate/hexane
gradient) of the residue provided 316 mg (20) of the title
compound. TOF MS ES exact mass calculated for C19H20N02
(p+1): m/z = 294.1494. Found: 294.1471.
B. Preparation of 1-[2-benzyloxy-4-(3-chloropropoxy)-5-
ethylphenyl]-1H-pyrrole.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-110-
O ~ 1 O
CN I / CN
I / OH ( / O~CI
A mixture of 5-benzyloxy-2-ethyl-4-pyrrol-1-yl-phenol (316
mg, 1.08 mmol), potassium carbonate (223 mg, 1.62 mmol), and
1-bromo-3-chloropropane (0.16 mL, 1.6 mmol) in N,N-
dimethylformamide (5 mL) was stirred at room temperature for
18 h. The mixture was diluted with ethyl acetate and water,
washed four times with water, once with saturated sodium
chloride solution, dried (sodium sulfate), filtered, and
concentrated in vacuo. Chromatography (silica gel, 5o ethyl
acetate/95o hexane) of the residue provided 314 mg (79~) of
the title compound as a colorless oil. TOF MS ES exact
mass calculated for C22H25NC102 (p+1): m/z = 370.1574.
Found: 370.1548.
w
~N I / I ~ /
HO / O
/ O~CI + COOMe
~N I / / /
~ ono ~ I o ~
COOMe
C. Preparation of 2-~3-[3-(5-benzyloxy-2-ethyl-4-pyrrol-1-
yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl
aster.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-111-
A mixture of 1-[2-benzyloxy-4-(3-chloropropoxy)-5-
ethylphenyl]-1H-pyrrole (310 mg, 0.85 mmol) and sodium
iodide (140 mg, 0.94 mol) in 2-butanone (5 mL) was heated at
reflux for 6 h. The mixture was cooled to room temperature,
filtered, and concentrated in vacuo. The residue was
dissolved in N,N-dimethylformamide (7 mL) and treated with
2-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester (242
mg, 0.85 mmol) and potassium carbonate (129 g, 93 mmol) at
room temperature for 15 h. The mixture was diluted with
ethyl acetate and water, washed four times with water, once
with saturated sodium chloride solution, dried (sodium
sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, 5~ ethyl acetate/95~ hexane) of
the residue provided 196 mg (37~) of the title compound as a
colorless oil. 1H NMR (CDC13) 8 7.86 (dd, J = 8, 2 Hz, 1H),
7.37 (dt, J = 8, 2 Hz, 1H), 7.30 (m, 5H), 7.07 (m, 3H), 6.84
(m, 2H), 6.79 (d, J = 8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H),
6.58 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 6.29 (m, 2H), 4.92 (s,
2H), 4.17 (t, J = 6 Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 3.83
(s, 3H), 2.65 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz, 2H),
2.30 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H),
1.16 (t, J = 7 Hz, 3H), 0.80 (t, J = 7 Hz, 3H); TOF MS ES
exact mass calculated for C39H42N06 (p+1): m/z = 620.3012.
Found: 620.3021.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-112-
CN
O~O ~ I O
COOMe
\ N
COOMe
D. Preparation of 2-~3-[3-(2-ethyl-5-hydroxy-4-pyrrol-1-yl-
phenoxy)propoxy]-2-propyl-phenoxy)benzoic acid methyl aster.
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-pyrrol-1-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
(195 mg, 0.315 mmol) in ethanethiol (5 mL) was treated with
boron trifluoride etherate (1.3 mL, 9.5 mmol) at room
temperature for 2.5 h. The mixture was diluted with diethyl
ether and water. The organic layer was washed with
saturated sodium bicarbonate solution, dried (sodium
sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, 10~ ethyl acetate/90~ hexane) of
the residue provided 39 mg (230) of the title compound as a
colorless oil. 1H NMR (CDC13) ~ 7.89 (d, J = 8 Hz, 1H),
7.37 (t, J 8 Hz, 1H), 7.07(m, 2H), 6.98 (s, 1H), 6.68
= (m,
3H) , 6.65 (d, J = 8 Hz, 1H) 6.57 (s, 1H) 6.42(d, J = 8
, ,
Hz, 1H), 6.35(m, 2H), (bs, 1H), 4.19 (m, 2H), 3.83
5.04 (s,
3H), 2.64 (t, J = 8 Hz, 2H),2.58 (q, J Hz, 2H), 2.32
=
7
(quintet, J 6 Hz, 2H), 1.5 5 2H), 1.14 (t, J 7 Hz,
= (m, =
3H), 0.90 (t, J = 7 Hz, 3H);TOF MS exact mass
ES
calculated for C32H36N~6 (p+1): m/z = 530.2543. Found:
530.2516.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-113-
Example 8
Preparation of 2-(3-~3-[4-(3-Bromo-[1,2,4]thiadiazol-5-yl)-
2-ethyl-5-hydroxyphenoxy]-propoxy)-2-propylphenoxy)benzoic
acid.
Br I i
~ ono ~ I o ~
COOMe
O
,B I ~ ~ /
o I ~ ono ~ I o ~ I
COOMe
A. Preparation of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy~-2-
propylphenoxy)benzoic acid methyl aster.
A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2-
ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl
ester (8.30 g, 13.1 mmol), triethylamine (5.2 mL, 39 mmol),
and PdCl2(dppf) (320 mg, 0.39 mmol) in de-oxygenated toluene
(80 mL) was treated with a 1 M solution of 4,4,5,5-
tetramethyl-[1,3,2]dioxaborolane in tetrahydrofuran (20 mL,
mmol) and heated at reflux for 6 h. The mixture was
filtered down a short column of silica gel and the filtrate
concentrated in vacuo. Chromatography (silica gel, 35~
20 ethyl acetate/65o hexane) of the residue provided a dark oil
that was subjected to further chromatography (silica gel,
hexane to 30o ethyl acetate/70~ hexane) to give 7.70 g (84~)
of the title compound. 1H NMR (CDC13) 8 7.86 (dd, J = 8, 2
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-114-
Hz, 1H), 7.60 (d, J = 8 Hz, 2H), 7.47 (s, 1H), 7.34 (m, 3H),
7.24 (t, J = 8 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J =
9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.66 (d, J = 9 Hz, 1H),
6.47 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.07 (s, 2H), 4.18 (m,
4H), 3.81 (s, 3H), 2.64 (t, J = 8 Hz, 2H), 2.56 (q, J = 7
Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.53 (hextet, J = 8
Hz, 2H), 1.34 (s, 12H),1.14 (t, J = 7 Hz, 3H), 0.89 (t, J =
7 Hz, 3H); TOF MS ES exact mass calculated for C41H53NB08
(p + NH4): m/z = 698.3864. Found: 698.3889. IR (CHC13,
-1
cm ) 2964, 1720, 1604, 1453.
Anal. Calcd for C41H49B08~ C, 72.35; H, 7.26. Found: C,
72.30; H, 7.12.
O O
o~B ~/ \ I ~ i i
~ ono w I o w
COOMe
Br
N~N O I
I ~ ono ~ I o ~ I
COOMe
B. Preparation of 2-(3-(3-[5-benzyloxy-4-(3-bromo-
[1,2,4]thiadiazol-5-yl)-2-ethyl-phenoxy]propoxy~-2-
propylphenoxy)benzoic acid methyl ester.
A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-
tetramethyl-[1,3,2]dioxaboro.lan-2-yl)phenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (310 mg, 0.46 mmol),
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-115-
3-bromo-5-chloro-1,2,4-thiadiazole (120 mg, 0.60 mmol),
cesium carbonate (300 mg, 0.92 mmol), and PdCl2(dppf) (20
mg, 0.024 mmol) in de-oxygenated toluene (10 mL) was heated
at 100 °C for 15 h. The mixture was diluted with a solution
of 35o ethyl acetate/65~ hexane and filtered down a short
column of silica gel. The filtrate was concentrated in
vacuo. Chromatography (silica gel, hexane to 30o ethyl
acetate/70~ hexane) of the residue provided 232 mg (70~) of
the title compound. 1H NMR (CDC13) 8 8.13 (s, 1H), 7.87
(dd, J = 8, 2 Hz, 1H), 7.44 (m, 2H), 7.37 (m,-4H), 7.08 (t,
dJ = 8, 1 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.78 (d, J = 9
Hz, 1H), 6.66 (d, J = 9 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J =
8 Hz, 1H), 5.28 (s, 2H), 4.21 (t, J = 6 Hz, 2H), 4.19 (t, J
- 6 Hz, 2H), 3.81 (s, 3H), 2.62 (m, 4H), 2.34 (quintet, J =
6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.17 (t, J = 7 Hz,
3H), 0.88 (t, J = 7 Hz, 3H); MS ES m/e 717, 719.
Br
/ O
COOMe
Br
N~ N H
_S ~ ~ / ~ /
/ O~O ~ O
COOH
C. Preparation of 2-(3-~3-[4-(3-bromo-[1,2,4]thiadiazol-5-
yl)-2-ethyl-5-hydroxyphenoxy]propoxy~-2-
propylphenoxy)benzoic acid.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-116-
A solution of 2-(3-{3-[5-benzyloxy-4-(3-bromo-
[1,2,4]thiadiazol-5-yl)-2-ethyl-phenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (230 mg, 0.31 mmol)
in ethanethiol (4 mL) was treated with boron trifluoride
etherate (0.32 mL, 2.5 mmol) at room temperature for 6 h, at
which time an additional portion of boron trifluoride
etherate was added and stirring continued for 7 h. The
reaction mixture was diluted with water, concentrated in
vacuo, and extracted with diethyl ether. The residue was
dissolved in methanol (5 mL) and treated with 1 N lithium
hydroxide solution (2 mL) at 65 °C for 1 h. The mixture was
concentrated in vacuo and the residue diluted with water and
adjusted to ~pH 3 with 1 N hydrochloric acid. The resulting
precipitate was collected via vacuum filtration and
dissolved in dilute aqueous base. Reverse phase
chromatography (1:1 acetonitrile/water) provided 43 mg (230)
of the title compound as a yellow solid. 1H NMR (DMSO-d6) S
7.85 (s, 1H), 7.80 (dd, J = 8, 2 Hz, 1H), 7.45 (m, 2H), 7.15
(m, 3H), 6.83 (d, J = 9 Hz, 1H), 6.80 (d, J = 9 Hz, 1H),
6.62 (s, 1H), 6.35 (d, J = 9 Hz, 1H), 4.20 (m, 4H), 2.55 (m,
4H), 2.27 (quintet, J = 5 Hz, 2H), 1.44 (hextet, J = 8 Hz,
2H), 1.13 (t, J = 7 Hz, 3H), 0.81 (t, J = 7 Hz, 3H); MS ES
+ -1
m/e 551 (p+NH4 -Br); IR (KBr, cm ) 2900, 1696, 1603, 1461.
Anal. Calcd for C29H29BrN206S: C, 56.77; H, 4.76; N, 4.56.
Found: C, 56.63; H, 4.72; N, 3.98.
Example 9
Preparation of 2-{3-[3-(2-Ethyl-5-hydroxy-4-thiophen-2-yl-
phenoxy)propoxy]-2-propyl-phenoxy~benzoic acid sodium salt.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-117-
A. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-thiophen-2-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid methyl
ester.
A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (300 mg, 0.44 mmol),
2-bromothiophene (110 mg, 0.66 mmol), cesium carbonate (300
mg, 2.17 mmol), and PdCl2(dppf) (20 mg, 0.024 mmol) in de
oxygenated toluene (10 mL) was heated at 105 °C for 66 h.
The mixture was cooled to room temperature and concentrated
in vacuo. The residue was dissolved in methylene chloride
and filtered down a short column of silica gel. The
filtrate was concentrated in vacuo. Chromatography (silica
gel, 30o ethyl acetate/70o hexane) of the residue provided
an oil that was dissolved in ethanethiol (4 mL) and treated
with boron trifluoride etherate (0.44 mL, 3.4 mmol) at room
temperature for 3 h. The mixture was diluted with water and
extracted with diethyl ether. The organic layer was dried
(sodium sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, hexane to 30~ ethyl acetate/70~
hexane) of the residue provided 120 mg (500) of the title
compound as a yellow film. 1H NMR (CDC13) S 7.85 (dd, J =
8, 2 Hz, 1H), 7.35 (t, J = 8 Hz, 1H), 7.15 (d, J = 7 Hz,
1H), 7.03-7.15 (m, 5H), 6.80 (d, J = 9 Hz, 1H), 6.66 (d, J =
9 Hz, 1H), 6.51 (s, 1H), 6.42 (d, J = 8 Hz, 1H), 5.44 (bs,
1H), 4.18 (m, 4H), 3.82 (s, 3H), 2.62 (t, J = 8 Hz, 2H),
2.58 (q, J = 7 Hz, 2H), 2.54 (quintet, J = 6 Hz, 2H), 1.52
(hextet, J = 8 Hz, 2H), 1.16 (t, J = 7 Hz, 3H), 0.90 (t, J =
7 Hz, 3H); MS ES m/e 545 (p - 1).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-118-
B. Preparation of 2-~3-[3-(2-ethyl-5-hydroxy-4-thiophen-2-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid sodium
salt.
OH
I~ ~I ~I
O'~o ~ o
COOMe
OH
s I ~ / I / I
O~O ~ O
COONa
A solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-thiophen-2-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
(120 mg, 0.22 mmol) in methanol (3 mL) was treated with 1 N
lithium hydroxide solution (0.5 mL) at room temperature for
1 h and then with an additional portion of 1 N lithium
hydroxide solution (0.75 mL) for 18 h. The mixture was
heated at 50 °C then concentrated in vacuo. The residue was
acidified with dilute hydrochloric acid and extracted with
diethyl ether. The organic layer was washed once with water
and concentrated in vacuo. The residue was diluted with 1 N
sodium hydroxide solution (0.22 mL), diethyl ether, and
toluene. The mixture was concentrated in vacuo, dissolved
in methylene chloride, and concentrated in vacuo to provide
1
120 mg (980) of the title compound as a green film.- H NMR
(DMSO-d6) 8 7.71 (d, J = 8 Hz, 1H), 7.42 (m, 2H), 7.31 (m,
2H), 7.10 (m, 2H), 6.99 (m, 1H), 6.76(t, J = 7 Hz, 2H),
6.52 (s, 1H), 6.30 (d, J = 8 Hz, 1H),4.16 (t, J 7 Hz,
=
2H), 4.07 (t, J = Hz, 2H), 2.50 (m, 4H), 2.20 (m, 2H),
7
1.40 (m, 2H), 1.06 (t, J = 8 Hz, 3H),0.77 (t, J 7 Hz,
=
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-119-
+ + -1
3H); MS ES m/e 533 (p + 1 - Na ). IR (CHC13, cm ) 2900,
1738, 1604, 1454.
Example 10
Preparation of 2-(3-~3-[2-Ethyl-5-hydroxy-4-(1-methyl-1H-
pyrazol-4-yl)-phenoxy]propoxy)-2-propylphenoxy)benzoic acid.
I I
\ \ \ \
N-N N-N
~H
A. Preparation of 4-iodo-1-methylpyrazole (Known compound:
RN 39806-90-1).
To a solution of 4-iodopyrazole (1.3 g, 6.8 mmol) in dioxane
(10 mL) was added iodomethane (0.42 mL, 6.8 mmol) and the
resulting mixture stirred at room temperature for 96 h. The
mixture was concentrated in vacuo and the residue mixed with
methylene chloride and filtered. The filtrate was
concentrated in vacuo to provide 1.35 g (950) of the title
compound as a colorless oil. 1H NMR (CDC13) 8 7.47 (s, 1H),
7.38 (s, 1H), 3.90 (s, 3H).
B. Preparation of 2-(3-(3-[5-benzyloxy-2-ethyl-4-(1-methyl-
1H-pyrazol-4-yl)phenoxy]-propoxy~-2-propylphenoxy)benzoic
acid methyl ester.
A mixture of 2-(3-~3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (1.00 g, 1.47 mmol),
4-iodo-1-methylpyrazole (450 mg, 2.16 mmol), cesium
carbonate (1.20 g, 3.62 mmol), and PdCl2(dppf) (72 mg, 0.088
mmol) in de-oxygenated toluene (35 mL) was heated at 100 °C
for 24 h. Additional portions of 4-iodo-1-methylpyrazole
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-120-
(~30 mg) and PdCl2(dppf) (~30 mg) were added and heating
continued at 100 °C for 40 h. The mixture was cooled to
room temperature, concentrated in vacuo, diluted with
methylene chloride, and filtered down a short plug of silica
gel. The filtrate was concentrated in vacuo.
Chromatography (silica gel, 35~ ethyl acetate/65~ hexane to
65o ethyl acetate/35~ hexane) of the residue provided 710 mg
1
(760) of the title compound. H NMR (CDC13) 8 7.86 (dd, J =
8, 2 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.37 (m, 6H), 7.28
(s, 1H), 7.09 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H),
6.78 (d, J = 9 Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.56 (s,
1H), 6.42 (d, J = 8 Hz, 1H), 5.08 (s, 2H), 4.18 (t, J = 6
Hz, 2H), 4.15 (t, J = 6 Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H),
2.63 (t, J = 8 Hz, 2H), 2.59 (q, J = 7 Hz, 2H), 2.30
(quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.23
(t, J = 7 Hz, 3H) , 0.89 (t, J = 7 Hz, 3H) .
N,
I~
~ ono ~ I o ~
COOMe
N- H
-N ~
I / O~O ~ I O ~ I
COOH
C. Preparation of 2-(3-(3-[2-ethyl-5-hydroxy-4-(1-methyl-
1H-pyrazol-4-yl)-phenoxy]propoxy)-2-propylphenoxy)benzoic
acid.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-121-
A solution of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(1-methyl-1H-
pyrazol-4-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid
methyl ester (710 mg, 1.12 mmol) in ethanethiol (5 mL) was
treated with boron trifluoride etherate (1.42 mL, 11.2 mmol)
at room temperature for 20 h. The reaction mixture was
diluted with water, concentrated in vacuo, and extracted
with diethyl ether. The organic layer was dried (magnesium
sulfate), filtered, and concentrated in vacuo. The residue
was triturated twice with hexane and the residue dissolved
in methanol (5 mL). This solution was treated with 1 N
lithium hydroxide solution (5 mL) at ~95 °C for 2 h. The
mixture was concentrated in vacuo and the residue diluted
with water, washed twice with diethyl ether, and the aqueous
layer acidified with 1 N hydrochloric acid. The resulting
solution was extracted with diethyl ether. The organic
layer was dried (magnesium sulfate), filtered, and
concentrated in vacuo. Chromatography (silica gel, 10~
methanol/90o methylene chloride) provided 338 mg (570) of
the title compound as a tan foam. 1H NMR (DMSO-d6) 8 12.85
(bs, 1H), 9.50 (bs, 1H), 7.98 (s, 1H), 7.78 (m, 2H), 7.48
(dt, J = 8, 2 Hz, 1H), 7.44 (s, 1H), 7.18 (t, J = 8 Hz, 1H),
7.13 (t, J = 9 Hz, 1H) , 6.79 (d, J = 9 Hz, 1H) , 6.77 (d, J =
9 Hz, 1H), 6.53 (s, 1H), 6.35 (d, J = 9 Hz, 1H), 4.20 (t, J
- 6 Hz, 2H), 4.08 (t, J = 6 Hz, 2H), 3.85 (s, 3H), 2.50 (m,
4H), 2.24 (quintet, J = 5 Hz, 2H), 1.45 (hextet, J = 8 Hz,
2H), 1.09 (t, J = 7 Hz, 3H), 0.82 (t, J = 7 Hz, 3H); MS ES
-1
m/e 531 (p+1); IR (KBr, cm ) 2961, 1697, 1602, 1460, 1222.
Anal. Calcd for C31H34N2O6: C, 70.17; H, 6.46; N, 5.28.
Found: C, 69.27; H, 6.08; N, 4.63.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-122-
Example 11
Preparation of 2-~3-[3-(2-Ethyl-5-hydroxy-4-thiazol-2-yl-
phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid.
O O
0
I
~ w I o w I -1- ~~Br -
'o o ~'
COOMe
I
s I ~ ~ ~ I ~
o'n'o ~ o
COOMe
A. Preparation of 2-~3-[3-(5-benzyloxy-2-ethyl-4-thiazol-2-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid methyl
ester.
A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (960 mg, 1.41 mmol),
2-bromothiazole (0.25 mL, 2.8 mmol), cesium carbonate (1.15
g, 3.52 mmol), and PdCl2(dppf) (35 mg, 0.040 mmol) in de-
oxygenated toluene (35 mL) was heated at 60 °C for 16 h then
at 100 °C for 7 h. Additional portions of 2-bromothiazole
(0.13 mL) and PdCl2(dppf) (~30 mg) were added and heating
continued at 100 °C for 72 h. The mixture was cooled to
room temperature, concentrated in vacuo, diluted with
methylene chloride, and filtered down a short plug of silica
gel. The filtrate was concentrated in vacuo.
Chromatography (silica gel, hexane to 35o ethyl acetate/65~
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-123-
hexane) of the residue provided 282 mg (310) of the title
compound. 1H NMR (CDC13) 8 8.20 (s, 1H), 7.86 (dd, J = 8, 1
Hz, 1H), 7.82 (d, J = 3 Hz, 1H), 7.49 (d, J = 7 Hz, 2H),
7.35 (m, 4H), 7.23 (d, J = 3 Hz, 1H), 7.09 (d, J = 9 Hz,
1H), 7.04 (d, J = 9 Hz, 1H), 6.78 (d, J = 9 Hz, 1H), 6.65
(d, J = 9 Hz, 1H), 6.57 (s, 1H), 6.42 (d, J = 8 Hz, 1H),
5.24 (s, 2H), 4.17 (m, 4H), 3.81 (s, 3H), 2.63 (m, 4H), 2.33
(quintet, J = 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.19
(t, J = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H).
I~
I~ ~I ~I
o'~' o ~ o
COOMe
~N H
s I ~ ~ I ~ I
O~O ~ O
COOMe
B. Preparation of 2-~3-[3-(2-ethyl-5-hydroxy-4-thiazol-2-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid methyl
ester.
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-2-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
(282 mg, 0.442 mmol) in ethanethiol (3 mL) was treated with
boron trifluoride etherate (0.56 mL, 4.4 mmol) at room
temperature for 3 h. The reaction mixture was diluted with
water, concentrated in vacuo, and extracted with diethyl
ether. The organic layer was dried (magnesium sulfate),
filtered, and concentrated in vacuo. Chromatography (silica
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-124-
gel, ethyl acetate/hexane) provided 107 mg (44~) of the
title compound. 1H NMR (CDC13) b 7.88 (dd, J = 8, 2 Hz,
1H), 7.80 (d, J = 4 Hz, 1H), 7.35 (dt, J = 8, 2 Hz, 1H),
7.28 (d, J = 4 Hz, 1H), 7.24 (s, 1H), 7.09 (dt, J = 9, 2 Hz,
1H), 7.05 (t, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.66
(d, J = 9 Hz, 1H), 6.61 (s, 1H), 6.42 (d, J = 9 Hz, 1H),
4.24 (t, J = 6 Hz, 2H), 4.18 (t, J = 6 Hz, 2H), 3.81 (s,
3H), 2.63 (t, J = 7 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.34
(quintet, J = 6 Hz, 2H), 1.52 (hextet, J = 8 Hz, 2H), 1.17
(t, J = 7 Hz, 3H), 0.88 (t, J = 7 Hz, 3H); MS ES m/e 548
(p+1) .
CN OH
g I ~ i I i
OHO \ O
COOMe
~N OH
O~O \ O \
COOH
C. Preparation of 2-~3-[3-(2-ethyl-5-hydroxy-4-thiazol-2-
yl-phenoxy)propoxy]-2-propylphenoxy~benzoic acid.
2-{3-[3-(2-Ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy)propoxy]-
2-propylphenoxy}benzoic acid methyl ester (107 mg, 0.196
mmol) was dissolved in a 1:1 solution of methanol/dioxane (3
mL) and.treated with 1 N lithium hydroxide solution (1 mL)
at 60 °C for 2 h. The mixture was concentrated in vacuo and
the residue diluted with water, washed twice with diethyl
ether, and the aqueous layer acidified with 1 N hydrochloric
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-125-
acid. The resulting solution was extracted twice with
methylene chloride and the combined organic layers dried
(magnesium sulfate), filtered, and concentrated in vacuo.
Trituration (hexane) of the residue provided 72 mg (69~) of
the title compound as a tan powder. 1H NMR (CDC13) 8 8.22
(dd, J = 8, 2 Hz, 1H), 7.70 (d, J = 4 Hz, 1H), 7.41 (dt, J =
8, 2 Hz, 1H), 7.35 (s, 1H), 7.18 (m, 3H), 6.82 (d, J = 9 Hz,
1H), 6.69 (d, J = 9 Hz, 1H), 6.62 (d, J = 9 Hz, 1H), 6.55
(s, 1H) , 4.22 (t, J = 6 Hz, 2H) , 4.21 (t, J = 6 Hz, 2H) ,
2.57 (m, 4H), 2.35 (quintet, J = 6 Hz, 2H), 1.49 (hextet, J
- 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.86 (t, J = 7 Hz, 3H);
+ -1
MS ES m/e 534 (p+1); IR (KBr, cm ) 2957, 1695, 1599, 1457.
Anal. Calcd for C30H31N~6S: C, 67.52; H, 5.86; N, 2.62.
Found: C, 67.44; H, 5.95; N, 2.55.
Example 12
Preparation of 2-(3-{3-[4-(3,5-Dimethylisoxazol-4-yl)-2-
ethyl-5-hydroxyphenoxy]propoxy~-2-propylphenoxy)benzoic acid
sodium salt.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-126-
O O
O' B \ II / / / ~ ~ N
/ \I \I +
O'~o O
COOMe
NO I O ~ \
\ /
/ O~O \ O \
COOMe
O OH
N~ I
I\ /I /I
/ O'~O \ O \
COONa
A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (305 mg, 0.448
mmol), 3,5-dimethyl-4-iodoisoxazole (110 mg, 0.493 mmol),
cesium carbonate (293 mg, 0.899 mmol), and PdCl2(dppf) (15
mg, 0.018 mmol) in de-oxygenated toluene (10 mL) was heated
at 95 °C for 10 h. Additional portions of 3,5-dimethyl-4
iodoisoxazole (110 mg), cesium carbonate (260 mg), and
PdCl2(dppf) (~15 mg) were added and heating continued at 110
°C for 20 h. The mixture was cooled to room temperature,
concentrated in vacuo, diluted with methylene chloride, and
filtered down a short plug of silica gel with 20% ethyl
acetate/80% hexane. The filtrate was concentrated in vacuo.
The resulting colorless oil was dissolved in methylene
chloride (4 mL), cooled to 0 °C, and treated with
iodotrimethylsilane (0.40 mL, 2.7 mmol). The resulting
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-127-
mixture was allowed to warm to room temperature and stirred
for 18 h. An additional portion of iodotrimethylsilane
(0.70 mL) was added and stirring continued for 72 h. The
mixture was poured into dilute sodium thiosulfate solution.
The organic layer was separated, washed with water, dried
(sodium sulfate), filtered, and concentrated in vacuo. The
resulting foam was dissolved in a 1:1 mixture of
tetrahydrofuran/1 N hydrochloric acid (5 mL) and stirred at
room temperature for 18 h. The mixture was concentrated in
vacuo and treated with 1 equivalent 1 N sodium hydroxide
solution in ether. The resulting mixture was concentrated
in vacuo to provide 59 mg (230) of the title compound as an
off-white solid. 1H NMR (DMSO-d6) b 7.40 (dd, J = 9, 2 Hz,
1H), 7.13 (dt, J = 8, 2 Hz, 1H), 6.97 (m, 2H), 6.79 (s, 1H),
6.68 (d, J = 9 Hz, 1H), 6.65 (d, J = 9 Hz, 1H), 6.60 (s,
1H), 6.21 (d, J = 8 Hz, 1H), 4.19 (t, J = 6 Hz, 2H), 4.01
(t, J = 6 Hz, 2H) , 2.66 (t, J = 8 Hz, 2H) , 2.48 (q, J = 8
Hz, 2H), 2.24 (s, 3H), 2.17 (quintet, J = 6 Hz, 2H), 2.07
(s, 3 H), 1.49 (hextet, J = 8 Hz, 2H), 1.07 (t, J = 7 Hz,
3H), 0.85 (t, J = 7 Hz, 3H); TOF MS ES exact mass
calculated for C32H36N07 (p+1): m/z = 546.2492. Found:
-1
546.2514; IR (KBr, cm ) 3400, 1605, 1460.
Example 13
Preparation of 2-(3-[3-(2-Ethyl-4-furan-2-yl-5-
hydroxyphenoxy)propoxy]-2-propylphenoxy)-benzoic acid sodium
salt.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-128-
Br ( ~
~ ono ~ I o ~
COOMe
H
sr I ~ ~ I ~ I
oho \ O
COOMe
A. Preparation of 2-~3-[3-(4-bromo-2-ethyl-5-
hydroxyphenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl
ester.
A solution of 2-{3-[3-(5-benzyloxy-4-bromo-2-
ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl
ester (2.50 g, 3.95 mmol) in methylene chloride (40 mL) was
cooled to -70 °C and treated with boron tribromide (0.25 mL,
2.6 mmol). After 25 min the mixture was poured into cold
water and the resulting mixture extracted with methylene
chloride. The combined organic extracts were washed once
with water, once with saturated sodium chloride solution,
dried (sodium sulfate), filtered, and concentrated in vacuo
to provide 1.1 g (52~) of the title compound as a pale
yellow oil. 1H NMR (CDC13) 8 7.89 (d, J = 9 Hz, 1H), 7.38
(t, J = 8 Hz, 1H), 7.18 (s 1H), 7.12 (d, J = 9 Hz, 1H), 7.08
(d, J = 2 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.68 (d, J = 9
Hz, 1H), 6.56 (s, 1H), 6.46 (d, J = 9 Hz, 1H), 5.40 (s, 1H),
4.18 (t, J = 6 Hz, 2H), 4.11 (t, J = 6 Hz, 2H), 3.84 (s,
3H), 2.65 (t, J = 8 Hz, 2H), 2.54 (q, J = 7 Hz, 2H), 2.32
(quintet, J = 6 Hz, 2H), 1.54 (hextet, J = 8 Hz, 2H), 1.13
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-129-
(t, J = 7 Hz, 3H), 0.89 (t, J = 7 Hz, 3H); MS ES m/z = 541
(M - H) , 543 (M - H + 2 ) .
H
Br ~ / /
/ O~O \ I O ~
COOMe
Br /
O
COOMe
B. Preparation of 2-(3-~3-[4-bromo-5-(tert-
butyldimethylsilanyloxy)-2-ethylphenoxy]-propoxy)-2-
propylphenoxy)benzoic acid methyl aster.
A solution of 2-{3-[3-(4-bromo-2-ethyl-5-
hydroxyphenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl
ester (1.00 g, 1.84 mmol) in methylene chloride (20 mL) was
treated with imidazole (0.19 g, 2.8 mmol) and tert-
butyldimethylsilyl chloride (0.388 g, 2.57 mmol) at room
temperature for 2 h. The mixture was poured into water and
the organic layer separated, washed once with water, once
with saturated sodium chloride solution, filtered through a
short pad of silica gel, and concentrated in vacuo to
provide 1.1 g (910) of the title compound as a colorless
oil. 1H NMR (CDC13) b 7.88 (d, J = 9 Hz, 1H), 7.38 (t, J =
8 Hz, 1H), 7.22 (s 1H), 7.12 (d, J = 9 Hz, 1H), 7.08 (d, J =
2 Hz, 1H), 6.80 (d, J = 9 Hz, 1H), 6.69 (d, J = 9 Hz, 1H),
6.45 (d, J = 9 Hz, 1H), 6.40 (s, 1H), 4.20 (t, J = 6 Hz,
2H), 4.11 (t, J = 6 Hz, 2H), 3.83 (s, 3H), 2.64 (t, J = 8
Hz, 2H), 2.54 (q, J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz,
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-130-
2H), 1.54 (hextet, J = 8 Hz, 2H), 1.13 (t, J = 7 Hz, 3H),
1.03 (s, 9H), 0.89 (t, J = 7 Hz, 3H), 0.23 (s, 6H).
OTBS ,
Br ~
~ O~O \ I O ~
COOMe
OH
o I ~ i ~ i
OHO \ O
COOMe
C. Preparation of 2-(3-[3-(2-ethyl-4-furan-2-yl-5-
hydroxyphenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl
ester.
A mixture of 2-(3-{3-[4-bromo-5-(tert-
butyldimethylsilanyloxy)-2-ethylphenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (1.05 g, 1.60 mmol),
furan-2-boronic acid (0.358 g, 3.20 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.160
mmol), and 2 M aqueous sodium carbonate solution (8 mL) in
tetrahydrofuran (20 mL) was heated at reflux for 18 h. The
mixture was cooled to room temperature, diluted with water,
and extracted with ethyl acetate. The organic layer was
separated, washed once with water, once with saturated
sodium chloride solution, dried (sodium sulfate), filtered,
and concentrated in vacuo. Chromatography (silica gel, 100
ethyl acetate/90o hexane) of the residue provided 0.8 g
1
(940) of the title compound as a colorless oil. H NMR
(CDC13) 8 7.90 (d, J = 9 Hz, 1H), 7.48 (s, 1H), 7.38 (t, J =
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-131-
8 Hz, 1H), 7.21 (s 1H), 7.13 (s, 1H), 7.10 (d, J = 9 Hz,
1H), 7.07 (d, J = 2 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.69
(d, J = 9 Hz, 1H), 6.52 (m, 3H), 6.44 (d, J = 9 Hz, 1H),
4.20 (m, 4H), 3.83 (s, 3H), 2.67 (t, J = 8 Hz, 2H), 2.59 (q,
J = 7 Hz, 2H), 2.32 (quintet, J = 6 Hz, 2H), 1.55 (hextet, J
- 8 Hz, 2H), 1.18 (t, J = 7 Hz, 3H), 0.91 (t, J = 7 Hz,
3H); MS ES m/z = 589 (p + Ac0 ).
Anal. Calcd for C32H34~7= C~ 72.43; H, 6.46. Found: C,
72.21; H, 6.15.
OH
O, ~ W
/ O~O \ O
COOMe
H
O, ~ ~ /
/ O~O ~ O \
COONa
D. Preparation of 2-~3-[3-(2-ethyl-4-furan-2-yl-5-
hydroxyphenoxy)propoxy]-2-propylphenoxybenzoic acid sodium
salt.
2-{3-[3-(2-Ethyl-4-furan-2-yl-5-hydroxyphenoxy)propoxy]-2-
propylphenoxy)benzoic acid methyl ester (250 mg, 0.47 mmol)
was dissolved in tetrahydrofuran (4 mL) and treated with 1 N
lithium hydroxide solution (2 mL) at 50 °C for 16 h. The
mixture was concentrated in vacuo and the residue diluted
with water and extracted twice with ethyl acetate. The
combined organic extracts were washed once with water, once
with saturated sodium chloride solution, dried (sodium
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-132-
sulfate), filtered, and concentrated in vacuo. The residue
was dissolved in ethyl acetate and shaken with 1 N
hydrochloric acid. The organic layer was dried (sodium
sulfate), filtered, and concentrated in vacuo. The residue
was dissolved in diethyl ether and treated with 1 N aqueous
sodium hydroxide solution (0.32 mL). The mixture was
concentrated in vacuo and azeotroped successively with
diethyl ether, chloroform, and diethyl ether and dried to
provide 168 mg (660) of the title product as a cream solid.
1H NMR (DMSO-d6) 8 7.56 (s, 1H), 7.44 (d, J = 8 Hz, 1H),
7.35 (s, 1H), 7.13 (m, 1H), 6.97 (m, 2H), 6.77 (d, J = 2 Hz,
1H), 6.65 (m, 4H), 6.48 (d, J = 2 Hz, 1H), 6.24 (d, J = 9
Hz, 1H), 4.15 (t, J = 6 Hz, 2H), 3.96 (t, J = 6 Hz, 2H),
2.66 (t, J = 8 Hz, 2H), 2.42 (q, J = 7 Hz, 2H), 2.13
(quintet, J = 6 Hz, 2H), 1.48 (hextet, J = 8 Hz, 2H), 1.09
(t, J = 7 Hz, 3H), 0.84 (t, J = 7 Hz, 3H); TOF MS ES
exact mass calculated for C31H3307 (p+1): m/z = 517.2226.
-1
Found: 517.2230. IR (KBr, cm ) 3400, 2961, 1599, 1460.
Example 14
Preparation of 2-(3-~3-[2-Ethyl-5-hydroxy-4-furan-3-
yl]phenoxy]propoxy)-2-propylphenoxy)benzoic acid.
OTBS
Br I ~ ~ ~
O~O \ O \
COOMe
OH
O~O \ O
COOMe
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-133-
A. Preparation of 2-~3-[3-(2-ethyl-4-furan-3-yl-5-
hydroxyphenoxy)propoxy]-2-propyl-phenoxy?benzoic acid methyl
ester.
A mixture of 2-(3-{3-[4-bromo-5-(tert-
butyldimethylsilanyloxy)-2-ethylphenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester (2.10 g, 3.19 mmol),
furan-3-boronic acid (0.722 g, 6.45 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32
mmol), and 2 M aqueous sodium carbonate solution (16 mL) in
tetrahydrofuran (30 mL) was heated at reflux for 48 h. The
mixture was cooled to room temperature, diluted with water,
and extracted with ethyl acetate. The organic layer was
separated, washed once with water, once with saturated
sodium chloride solution, dried (sodium sulfate), filtered,
and concentrated in vacuo. Chromatography (silica gel, 150
ethyl acetate/85~ hexane) of the residue provided 0.29 g
(170) of the title compound as a yellow oil. TOF MS ES
exact mass calculated for C32H35~7 (p+1): m/z = 531.2383.
Found: 531.2396.
H
O ~
/ /
O~O ~ ~ O
COOMe
OH
O ~
/ /
/ O~O ~ ~ O ~
COOH
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-134-
B. Preparation of 2-~3-[3-(2-ethyl-4-furan-3-yl-5-
hydroxyphenoxy)propoxy]-2-propylphenoxy~benzoic acid sodium
salt.
2-{3-[3-(2-Ethyl-4-furan-3-yl-5-hydroxyphenoxy)propoxy]-2-
propylphenoxy}benzoic acid methyl ester (170 mg, 0.32 mmol)
was dissolved in tetrahydrofuran (4 mL) and methanol (1 mL)
and treated with 1 N lithium hydroxide solution (4 mL) at 50
°C for 2 h. The mixture was concentrated in vacuo and the
residue acidified with hydrochloric acid and the resulting
mixture extracted twice with ethyl acetate. The combined
organic extracts were washed once with water, once with
saturated sodium chloride solution, dried (sodium sulfate),
filtered, and concentrated in vacuo. Chromatography (silica
gel, 2o methanol/98~ chloroform) of the residue gave 45 mg
of material that was again submitted to chromatography
(silica gel, 1~ methanol/99o chloroform) to provide 25 mg
(15~) of the title compound as an oil.
TOF MS ES exact mass calculated for C31H33~7 (p+1): m/z =
517.226. Found: 517.2230.
Example 15
Preparation of .2-(3-(3-[2-Ethyl-5-hydroxy-4-
(tetrahydrofuran-3-yl)phenoxy]propoxy)-2-
propylphenoxy)benzoic acid sodium salt hemihydrate.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-135-
Br I ~
~ ono w I o w
COOMe
i i
~ ono ~ ( o ~
COOMe
A. Preparation of 2-~3-(3-(5-benzyloxy-2-ethyl-4-furan-3-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid methyl
ester.
A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2-
ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl
ester (3.00 g, 4.73 mmol), furan-3-boronic acid (1.06 g,
9.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.54
g, 0.47 mmol), and 2 M aqueous sodium carbonate solution (20
mL) in tetrahydrofuran (40 mL) was heated at 100 °C for 48
h. The mixture was cooled to room temperature, diluted with
water, and extracted with ethyl acetate. The organic layer
was separated, washed once with water, once with saturated
sodium chloride solution, dried (sodium sulfate), filtered,
and concentrated in vacuo. Chromatography (silica gel, 10~
ethyl acetate/90~ hexane) of the residue provided 1.9 g
1
(65~) of the title compound as a yellow oil. H NMR (CDC13)
8 7.88 (dd, J = 8, 2 Hz, 1H), 7.87 (s, 1H), 7.40 (m, 7H),
7.26 (s 1H), 7.05 (m, 2H), 6.80 (d, J = 9 Hz, 1H), 6.76 (d,
J = 2 Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.60 (s, 1H), 6.43
(d, J = 9 Hz, 1H), 5.11 (s, 2H), 4.18 (m, 4H), 3.83 (s, 3H),
2.66 (t, J = 8 Hz, 2H), 2.62 (q, J = 7 Hz, 2H), 2.30
(quintet, J = 6 Hz, 2H), 1.57 (hextet, J = 8 Hz, 2H), 1.20
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-136-
(t, J = 7 Hz, 3H), 0.92 (t, J = 7 Hz, 3H); MS ES m/z = 621
-1
(p + 1); IR (CHC13, cm ) 3000, 1727, 1603, 1461.
O
/ ~
/ o'~O ~ o
COOMe
O H
/ /
O~O \ ~ O w
COOMe
B. Preparation of 2-(3-~3-[2-ethyl-5-hydroxy-4-
(tetrahydrofuran-3-yl)phenoxy~-propoxy)-2-
propylphenoxy)benzoic acid methyl aster.
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-furan-3-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
(1.8 g, 2.9 mmol) in ethyl acetate (40 mL) was treated with
10~ palladium-on-carbon (0.39 g) and hydrogenated at 48 psi
and 45 °C for 72 h. The mixture was cooled to room
TM
temperature, filtered through Celite , and the filtrate
concentrated in vacuo to provide 1.2 g (770) of the title
compound as a colorless oil. 1H NMR (CDC13) 8 7.88 (dd, J =
8, 2 Hz, 1H), 7.57 (dt, J = 8, 2 Hz, 1H), 7.09 (d, J = 9 Hz,
1H), 7.04 (d, J = 9 Hz, 1H), 6.81 (d, J = 9 Hz, 1H), 6.80
(s, 1H), 6.67 (d, J = 9 Hz, 1H), 6.44 (d, J = 9 Hz, 1H),
6.43 (s, 1H), 4.19 (m, 3H), 4.10 (m, 2H), 4.02 (dd, J = 12,
3 Hz, 1H), 3.88 (dd, J = 12, 8 Hz, 1H), 3.84 (s, 3H), 3.73
(q, J = 9 Hz, 1H), 3.45 (m, 1H), 2.64 (t, J = 8 Hz, 2H),
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-137-
2.53 (q, J = 7 Hz, 2H), 2.38 (m, 1H), 2.28 (quintet, J = 6
Hz, 2H), 1.99 (m, 1H), 1.55 (hextet, J = 8 Hz, 2H), 1.15 (t,
J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H); MS ES m/z = 593 (p +
- -1
CH3C00 ); IR (CHC13, cm ) 2963, 1719, 1589, 1461.
Anal. Calcd for C32H3807: C, 71.89; H, 7.16. Found: C,
71.41; H, 7.06.
O H
O~O ~ ~ O
COOMe
O H
/I /I
/ O'~O
COONa
C. Preparation of 2-(3-~3-[2-ethyl-5-hydroxy-4-
(tetrahydrofuran-3-yl)phenoxy]-propoxy~-2-
propylphenoxy)benzoic acid sodium salt hemihydrate.
A solution of 2-(3-{3-[2-ethyl-5-hydroxy-4-(tetrahydrofuran-
3-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl
ester (0.92 g, 1.7 mmol) in tetrahydrofuran (10 mL) and
methanol (5 mL) was treated with 1 M aqueous lithium
hydroxide solution (10 mL) at 55 °C for 2 h. The mixture
was allowed to cool to room temperature and stirred for an
additional 18 h. The mixture was concentrated in vacuo and
the remaining aqueous mixture was washed once with diethyl
ether. The aqueous layer was acidified with concentrated
hydrochloric acid and the resulting solution extracted with
ethyl acetate. The ethyl acetate layer was washed once with
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-138-
water, once with saturated sodium chloride solution, dried
(sodium sulfate), filtered, and concentrated in vacuo. The
resulting colorless oil was dissolved in diethyl ether and
treated with 1 N aqueous sodium hydroxide solution (1.72
mL). The resulting biphasic mixture was diluted with
chloroform and concentrated in vacuo. Diethyl ether was
added and the mixture concentrated in vacuo. The resulting
white foam was dried in vacuo at room temperature for 60 h
to provide 0.78 g (84~) of the title compound: mp 67-71 °C.
1H NMR (DMSO-d6) 8 7.62 (dd, J = 8, 2 Hz, 1H), 7.30 (dt, J =
8, 2 Hz, 1H), 7.05 (m, 2H), 6.85 (s, 1H), 6.73 (d, J = 9 Hz,
1H), 6.70 (d, J = 9 Hz, 1H), 6.53 (s, 1H), 6.34 (d, J = 9
Hz, 1H), 4.15 (t, J = 6 Hz, 2H), 4.04 (t, J = 6 Hz, 2H),
3.95 (m, 1H), 3.88 (m, 1H), 3.75 (q, J = 9 Hz, 1H), 3.49 (m
2H), 2.60 (t, J = 8 Hz, 2H), 2.45 (q, J = 7 Hz, 2H), 2.15
(m, 3H), 1.90 (m, 1H), 1.48 (hextet, J = 8 Hz, 2H), 1.06 (t,
J = 7 Hz, 3H), 0.83 (t, J = 7 Hz, 3H); MS ES m/z = 519 (p -
+ -1
Na ); IR (CHC13, cm ) 2964, 1783, 1604, 1461.
Anal. Calcd for C31H35Na07 . 0.5 H20: C, 67.50; H, 6.58.
Found: C, 67.76; H, 6.68.
Example 16
Preparation of 2-~3-[3-(2-Ethyl-5-hydroxy-4-pyrrolidin-2-yl
phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid hydrochloride
hydrate.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-139-
O
Br I
~ ono ~ I o ~
COOMe
o I
I~ ~ ~I ~I
O O ~ 0~0 ~ O
COOMe
A. Preparation of 2-(2-benzyloxy-5-ethyl-4-(3-[3-(2-
methoxycarbonylphenoxy)-2-
propylphenoxy]propoxy}phenyl)pyrrole-1-carboxylic acid tert-
butyl ester.
A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2-
ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl
ester (3.00 g, 4.73 mmol), N-boc pyrrole-2-boronic acid
(1.99 g, 9.43 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.54 g, 0.47
mmol), and 2 M aqueous sodium carbonate solution (25 mL) in
tetrahydrofuran (60 mL) was heated at reflux for 40 h. The
mixture was cooled to room temperature, diluted with water,
and extracted with ethyl acetate. The organic layer was
separated, washed once with water, once with saturated
sodium chloride solution, dried (sodium sulfate), filtered,
and concentrated in vacuo. Chromatography (silica gel, 10~
ethyl acetate/90o hexane) of the residue provided 2.6 g
(760) of the title compound as a solid. 1H NMR (CDC13) 8
7.88 (dd, J = 8, 2 Hz, 1H), 7.15-7.40 (m, 7H), 7.08 (m, 3H),
6.82 (d, J = 9 Hz, 1H), 6.68 (d, J = 9 Hz, 1H), 6.52 (s,
1H), 6.44 (d, J = 9 Hz, 1H), 6.23 (t, J = 4 Hz, 1H), 6.12
(m, 1H), 4.95 (s, 2H), 4.20 (t, J = 6 Hz, 2H); 4.15 (t, J =
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-140-
6 Hz, 2H), 3.84 (s, 3H), 2.66 (t, J = 8 Hz, 2H), 2.60 (q, J
- 7 Hz, 2H), 2.30 (quintet, J = 6 Hz, 2H), 1.57 (hextet, J =
8 Hz, 2H), 1.28 (s, 9H), 1.18 (t, J = 7 Hz, 3H), 0.93 (t, J
- 7 Hz, 3H); TOS MS ES exact mass calculated for
C44H53N208 (p + NH4 ): m/z = 737.3802. Found: 737.3804;
-1
IR (CHC13, cm ) 2964, 1730, 1461.
Anal. Calcd for C44H49N08: C, 73.41; H, 6.86; N, 1.94.
Found: C, 73.76; H, 6.76; N, 2.04.
O O ~ o~o ~ O
COOMe
H
il il
O 0 ~ O'~o ~ O
COOMe
B. Preparation of 2-(5-ethyl-2-hydroxy-4-~3-[3-(2-
methoxycarbonylphenoxy)-2-propylphenoxy]propoxy)phenyl)-
pyrrolidine-1-carboxylic acid tert-butyl ester.
A solution of 2-(2-benzyloxy-5-ethyl-4-{3-[3-(2-
methoxycarbonylphenoxy)-2-
propylphenoxy]propoxy}phenyl)pyrrole-1-carboxylic acid tert-
butyl ester (0.98 g, 1.4 mmol) in ethyl acetate (40 mL) was
treated with 10o palladium-on-carbon (0.98 g) and
hydrogenated at 45 psi and 45 °C for 25 h, at room
temperature for 20 h, then at 45 °C for 19 h. The mixture
TM
was cooled to room temperature, filtered through Celite ,
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-141-
and the filtrate concentrated in vacuo to provide 0.76 g
1
(88~) of the title compound as a colorless oil. H NMR
(CDC13) 8 7.87 (dd, J = 8, 2 Hz, 1H), 7.37 (dt, J = 8, 2 Hz,
1H), 7.10 (d, J = 9 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.91
(s, 1H), 6.81 (d, J = 9 Hz, 1H), 6.67 (d, J = 9 Hz, 1H),
6.47 (s, 1H), 6.44 (d, J = 9 Hz, 1H), 5.09 (m, 1H), 4.18 (d,
J = 6 Hz, 2H), 4.14 (t, J = 6 Hz, 2H), 3.84 (s, 3H), 3.45
(m, 2H), 2.64 (t, J = 8 Hz, 2H), 2.54 (m, 3H), 2.25 (m, 5H),
2.06 (m, 1H), 1.54 (hextet, J = 8 Hz, 2H), 1.43 (s, 9H),
1.15 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H).
OH
O O ~ O~O \ O
COOMe
OH
il il
O O ~ O~O ~ O
COOLi
C. Preparation of 2-(4-i3-.[3-(2-carboxyphenoxy)-2-
propylphenoxy]propoxy~-5-ethyl-2-hydroxyphenyl)pyrrolidine-
1-carboxylic acid tart-butyl ester lithium salt hydrate.
A solution of 2-(5-ethyl-2-hydroxy-4-{3-[3-(2-
methoxycarbonylphenoxy)-2-
propylphenoxy]propoxy}phenyl)pyrrolidine-1-carboxylic acid
tert-butyl ester (0.114 g, 0.18 mmol) in a 1:1 mixture of
methanol/tetrahydrofuran (4 mL) was treated with solution of
1 M lithium hydroxide (4 mL) at room temperature for 18 h.
The mixture was concentrated in vacuo and the residue
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-142-
dissolved in water. The resulting mixure was extracted with
ethyl acetate. The organic extract was dried (sodium
sulfate), filtered, and concentrated in vacuo. The residue
was diluted with diethyl ether, concentrated in vacuo, and
dried to provide 90 mg (78~) of the title compound. MS ES
+ -1
m/z = 620 (p + 1 - Li ); IR (KBr, cm ) 2964, 1672, 1603,
1416.
Anal. Calcd for C36H44NO8Li . H20: C, 67.17; H, 7.20; N,
2.18. Found: C, 66.72; H, 6.99; N, 2.27.
H
O O ~ O~O ~ O
COOLi
OH
N
H
O~O ~ O
COOH
D. Preparation of 2-t3-[3-(2-ethyl-5-hydroxy-4-pyrrolidin-
2-yl-phenoxy)propoxy]-2-propylphenoxy]benzoic acid
hydrochloride hydrate.
Into a solution of 2-(4-{3-[3-(2-carboxyphenoxy)-2-
propylphenoxy]propoxy}-5-ethyl-2-hydroxyphenyl)pyrrolidine-
1-carboxylic acid tert-butyl ester lithium salt hydrate
(0.100 g, 0.16 mmol) in anhydrous diethyl ether (5 mL) was
bubbled gaseous HC1. The resulting mixture was allowed to
stir for 1 h. The mixture was concentrated in vacuo.
Chromatography (SCX cation exchange resin, 1:1
tetrahydrofuran/methanol to dilute ammonia/methanol) of the
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-143-
residue provided a tan solid. This material was dissolved
in ether and treated with gaseous HCl. This mixture was
concentrated in vacuo to provide 48 mg (52~) of the title
compound. 1H NMR (DMSO-d6) S 12.80 (bs, 1H), 10.12 (s, 1H),
9.34 (bs, 1H), 8.36 (bs, 1H), 7.79 (dd, J = 9, 2 Hz, 1H),
7.47 (dt, J = 8, 2 Hz, 1H), 7.17 (t, J = 8 Hz, 1H), 7.12 (d,
J = 9 Hz, 1H), 7.07 (s, 1H), 6.80 (d, J = 9 Hz, 1H), 6.78
(d, J = 9 Hz, 1H), 6.58 (s, 1H), 6.35 (d, J = 9 Hz, 1H),
4.56 (m, 1H), 4.20 (t, J = 6 Hz, 2H); 4.11 (t, J = 6 Hz,
2H), 3.25 (m, 2H), 2.50 (m, 5H), 1.90-2.60 (m, 5H), 1.44
(hextet, J = 8 Hz, 2H), 1.08 (t, J = 7 Hz, 3H), 0.82 (t, J =
7 Hz, 3H); TOS MS ES exact mass calculated for C31H38N06
(p + 1): m/z = 520.2699. Found: 520.2672.
Example 17
Preparation of 2-~3-[3-(2-Ethyl-5-hydroxy-4-thiophen-3-yl-
phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid hydrate.
Br O I ~ ~ ~ ~ I i
~ o~ci I ~ o'~ci
Known compound:
Sawyer et al., J. Med. Chem. 1995, 38, 4411.
A. Preparation of 3-[2-benzyloxy-4-(3-chloropropoxy)-5-
ethylphenyl]thiophene. A mixture of 4-(benzyloxy)-5-bromo-
2-(3-chloropropoxy)ethylbenzene (1.90 g, 5.30 mmol), 3-
thiopheneboronic acid (2.00 g, 15.9 mmol),
tetrakis(triphenylphosphine)palladium(0) (312 mg, 0.270
mmol), 2 M aqueous sodium carbonate solution (4 mL), and n-
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-144-
propanol (4 mL) in toluene (16 mL) was refluxed for 4 h.
The mixture was cooled to room temperature, diluted with
diethyl ether, washed once with water and once with ,
saturated sodium chloride solution. The organic layer was
dried (magnesium sulfate), filtered, and concentrated in
vacuo. Chromatography (silica gel, 5~ ethyl acetate/95~
hexane) of the residue provided 1.54 g (800) of the title
product as a white solid: mp 65-67 °C. 1H NMR (CDC13) 8
7.58 (d, J = 2.8 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.45-
7.30 (m, 7H), 6.62 (s, 1H), 5.13 (s, 2H), 4.14 (t, J = 5.8
Hz, 2H), 3.81 (t, J = 6.3 Hz, 2H), 2.66 (q, J = 7.5 Hz, 2H),
2.29 (quintet, J = 6.0 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); MS
-1
FD m/e 386 (p); IR (CHC13, cm ) 2969, 1613, 1501, 1138.
Anal. Calcd for C22H23~2C1S: C, 68.29; H, 5.99. Found: C,
68.53; H, 6.00.
\ I \ I / -~ I w
HO ~ O
O~CI CN
Known compound:
Sawyer et al.,
J. Med. Chem. 1995, 38, 4411.
\ I O I i
I I I
oho \ O
CN
B. Preparation of 2-[2-propyl-3-I3-[5-(benzyloxy)-2-ethyl-
4-(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile.
A mixture of 4-(benzyloxy)-2-(3-chloropropoxy)-5-(thiophen-
3-yl)ethylbenzene (1.25 g, 3.23 mmol), 3-(2-cyanophenoxy)-2-
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-145-
propylphenol (0.82 g, 3.2 mmol), potassium iodide (0.21 g,
1.3 mmol), potassium carbonate (1.12 g, 8.08 mmol), and
methyl sulfoxide (2 mL) in 2-butanone (10 mL) was refluxed
for 60 h. The mixture was cooled to room temperature,
diluted with ether, and washed with water. The organic
layer was dried (magnesium sulfate), filtered, and
concentrated in vacuo. Chromatography (silica gel, 5~ ethyl
acetate/95~ hexane) of the residue provided 1.31 g (67~) of
the title product as a colorless oil. 1H NMR (CDC13) 8 7.66
(d, J = 7.8_ Hz, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.48 (d, J =
5.2 Hz, 1H), 7.45-7.25 (m, 8H), 7.20 (t, J = 8.2 Hz, 1H),
7.10 (t, J = 8.1 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.77 (d,
J = 8.6 Hz, 1H), 6.64 (s, 1H), 6.63 (d, J = 6.4 Hz, 1H),
5.11 (s, 2H), 4.26 (t, J = 6.0 Hz, 2H), 4.22 (t, J = 6.0 Hz,
2H), 2.65 (m, 4H), 2.36 (quintet, J = 5.9 Hz, 2H), 1.58
(hextet, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H), 0.95 (t,
-1
J = 7.3 Hz, 3H); MS FD m/e 603 (p); IR (CHC13, cm ) 2967,
2250, 1613, 1501. Anal. Calcd for C38H37N04S: C, 75.59; H,
6.18; N, 2.32. Found: C, 74.65; H, 6.21; N, 2.57.
C. Preparation of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-
(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-146-
O I i
I ~ O~O w I o w I
CN
OH
\ I \ ~ I ~
o'~o ~ o
CN
To a solution of 2-[2-propyl-3-[3-[5-(benzyloxy)-2-ethyl-4-
(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile (900 mg,
1.49 mmol) in methylene chloride (25 mL) cooled to -78 °C
was added 1 M boron tribromide solution in methylene
chloride (2.99 mL, 2.99 mmol) over 2 min. The resulting
deep violet solution was stirred for 30 min and allowed to
warm to room temperature. The mixture was diluted with
water and shaken. The organic layer was separated, dried
(magnesium sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, 25~ ethyl acetate, 75~ hexane)
provided 400 mg (520) of the title product as a colorless
oil. 1H NMR (CDC13) 8 7.84 (d, J = 4.8 Hz, 1H), 7.71 (d, J =
4.9 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.42
(t, J = 7.1 Hz, 1H), 7.27 (t, J = 6.6 Hz, 1H), 7.20 (s, 1H),
7.08 (t, J = 6.9 Hz, 1H), 6.85 (s, 1H), 6.89 (d, J = 8.1 Hz,
1H), 6.74 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H),
4.71 (s, 1H, -OH), 4.26 (t, J = 6.0 Hz, 4H), 2.72 (q, J =
7.4 dHz, 2H), 2.59 (t, J = 7.3 Hz, 2H), 2.39 (quintet, J =
6.1 Hz, 2H), 1.54 (hextet, J = 7.7 Hz, 2H), 1.25 (t, J = 7.5
Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H).
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-147-
D. Preparation of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-
(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzoic acid hydrate.
OH
o'~o ~ o
CN
I OH
I~ ~I ~I
O~O ~ O
COOH
A solution of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-
(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile (400 mg,
0.780 mmol) in 2:1 methanol/water (6 mL) was treated with
12.5 M aqueous sodium hydroxide (4.0 mL) at reflux for 36 h.
The mixture was cooled to room temperature, diluted with
water, and extracted once with diethyl ether. The aqueous
layer was acidified with concentrated hydrochloric acid and
extracted twice with methylene chloride. The combined
methylene chloride layers were dried (magnesium sulfate),
filtered, and concentrated in vacuo to provide a tan solid:
1
mp 90-95 °C (dec). H NMR (CDC13) 8 8.24 (d, J = 7.8 Hz,
1H), 7.47 (d, J = 5.0 Hz, 1H), 7.44 (t, J = 8.6 Hz, 1H),
7.36 (d, J = 3 Hz, 1H), 7.24 (d, J = 4.9 Hz, 1H), 7.19 (m,
2H), 7.09 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.73 (d, J =
8.3 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 5.38
(bs, 1H, -OH), 4.26 (t, J = 6.2 Hz, 2H), 4.21 (t, J = 7.1
Hz, 2H), 2.60 (m, 4H), 2.36 (quintet, J = 5.8 Hz, 2H), 1.51
(hextet, J = 7.1 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H), 0.90 (t,
-1
J = 7.4 Hz, 3H); MS FD m/e 532 (p); IR (KBr, cm ) 3200
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-148-
(br), 2961, 1697, 1457, 1110. Anal. Calcd for C31H32~6S '
H20: C, 67.62; H, 6.22. Found: C, 67.34; H, 5.87.
vI. Pharmaceutical Compositions of the Invention
Preferably compounds of the invention (per Formulae I
or II) or pharmaceutical formulations containing these
compounds are in unit dosage form for administration to a
mammal. The unit dosage form can be a capsule, an IV bag, a
tablet, or a vial. The quantity of Active Ingredient in a
unit dose of composition is a therapeutically effective
amount and may be varied according to the particular
treatment involved. It may be appreciated that it may be
necessary to make routine variations to the dosage depending
on the age and condition of the patient. The dosage will
also depend on the route of administration.
The compound can be administered by a variety of
routes including oral, aerosol, rectal, transdermal,
subcutaneous, intravenous, intramuscular, and intranasal.
Pharmaceutical formulations of the invention are
prepared by combining (e. g., mixing) a therapeutically
effective amount of the compounds of the invention (e. g.,
compounds of Formula I, II) together with a
pharmaceutically acceptable carrier or diluent therefor.
The present pharmaceutical formulations are prepared by
known procedures using well known and readily available
ingredients.
In making the compositions of the present invention,
the Active Ingredient will usually be admixed with a
carrier, or diluted by a carrier, or enclosed within a
carrier which may be in the form of a capsule, sachet,
paper or other container. ln~hen the carrier serves as a
diluent, it may be a solid, lyophilzed solid or paste,
semi-solid, or liquid material which acts as a vehicle, or
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-149-
can be in the form of tablets, pills, powders, lozenges,
elixirs, suspensions, emulsions, solutions, syrups,
aerosols (as a solid or in a liquid medium), or ointment,
containing, for example, up to 10~ by weight of the active
compound. The compounds of the present invention are
preferably formulated prior to administration.
For the pharmaceutical formulations any suitable
carrier known in the art can be used. In such a
formulation, the carrier may be a solid, liquid, or mixture
of a solid and a liquid. For example, for intravenous
injection the compounds of the invention may be dissolved in
at a concentration of about 0.05 to about 5.0 mg/ml in a 4~
dextrose/0.5o Na citrate aqueous solution.
Solid form formulations include powders, tablets and
capsules. A solid carrier can be one or more substances
which may also act as flavoring agents, lubricants,
solubilisers, suspending agents, binders, tablet
disintegrating agents and encapsulating material.
Tablets for oral administration may contain suitable
excipients such as calcium carbonate, sodium carbonate,
lactose, calcium phosphate, together with disintegrating
agents, such as maize, starch, or alginic acid, and/or
binding agents, for example, gelatin or acacia, and
lubricating agents such as magnesium stearate, stearic
acid, or talc.
In powders the carrier is a finely divided solid which
is in admixture with the finely divided Active Ingredient.
In tablets the Active Ingredient is mixed with a carrier
having the necessary binding properties in suitable
proportions and compacted in the shape and size desired.
Advantageously, compositions containing the compound of
Formula (I) may be provided in dosage unit form, preferably
each dosage unit containing from about 5 to about 500 mg
(from about 5 to 50 mg in the case of parenteral or
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-150-
inhalation administration, and from about 25 to 500 mg in
the case of oral or rectal administration. Dosages from
about 0.5 to about 300 mg/kg per day, preferably 0.5 to 20
mg/kg, of Active Ingredient may be administered although it
will, of course, readily be understood that the amount of
the compound or compounds of Formula I actually to be
administered will be determined by a physician, in the light
of all the relevant circumstances.
Powders and tablets preferably contain from about 1 to
about 99 weight percent of the Active Ingredient which is
the novel compound of this invention. Suitable solid
carriers are magnesium carbonate, magnesium stearate, talc,
sugar lactose, pectin, dextrin, starch, gelatin, tragacanth,
methyl cellulose, sodium carboxymethyl cellulose, low
melting waxes, and cocoa butter.
Sterile liquid form formulations include suspensions,
emulsions, syrups and elixirs.
The Active Ingredient can be dissolved or suspended
in a pharmaceutically acceptable carrier, such as sterile
water, sterile organic solvent or a mixture of both. By
"pharmaceutically acceptable" it is meant the carrier,
diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the
recipient thereof.
The Active Ingredient can also be dissolved in a
suitable organic solvent, for instance aqueous propylene
glycol. Other compositions can be made by dispersing the
finely divided Active Ingredient in aqueous starch or
sodium carboxymethyl cellulose solution or in a suitable
oil.
The following pharmaceutical formulations 1 to 8 are
illustrative only and are not intended to limit the scope of
the invention in any way. "Active Ingredient", refers to a
compound according to Formula (I) or (II) or a
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-151-
pharmaceutically acceptable salt, solvate, or prodrug
thereof.
Formulation 1
Hard gelatin capsules are prepared using the following
ingredients:
Quantity
(mg/capsule)
Active Ingredient 250
Starch, dried 200
Magnesium stearate 10
Total 460 mg
Formulation 2
A tablet is prepared using the ingredients below:
Quantity
(mg/tablet)
Active Ingredient 250
Cellulose, microcrystalline 400
Silicon dioxide, fumed 10
Stearic acid 5
Total 665 mg
The components are blended and compressed to form tablets
each weighing 665 mg
Formulation 3
An aerosol solution is prepared containing the following
components:
Weight
Active Ingredient 0.25
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-152-
Ethanol 25.75
Propellant 22 (Chlorodifluoromethane) 74.00
Total 100.00
The Active Ingredient is mixed with ethanol and the mixture
added to a portion of the propellant 22, cooled to -30°C and
transferred to a filling device. The required amount is
then fed to a stainless steel container and diluted with the
remainder of the propellant. The valve units are then fitted
to the container.
Formulation 4
Tablets, each containing 60 mg of Active Ingredient, are
made as follows:
Active Ingredient 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone (as 10~ solution in water) 4 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1 mg
Total 150 mg
The Active Ingredient, starch and cellulose are passed
through a No. 45 mesh U.S. sieve (355 ).~,m) and mixed
thoroughly. The aqueous solution containing
polyvinylpyrrolidone is mixed with the resultant powder, and
the mixture then is passed through a No. 14 mesh U.S. sieve
(l.4mm). The granules so produced are dried at 50°C and
passed through a No. 18 mesh U.S. sieve (l.OOmm). The
sodium carboxymethyl starch, magnesium stearate and talc,
previously passed through a No. 60 mesh U.S. sieve (250 Vim),
are then added to the granules which, after mixing, are
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-153-
compressed on a tablet machine to yield tablets each
weighing 150 mg.
Formulation 5
Capsules, each containing 80 mg of Active Ingredient, are
made as follows:
Active Ingredient 80 mg
Starch 59 mg
Microcrystalline cellulose 59 mg
Magnesium stearate 2 mg
Total 200 mg
The Active Ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 45 U.S. sieve
(355~m), and filled into hard gelatin capsules in 200 mg
quantities.
Formulation 6
Suppositories, each containing 225 mg of Active Ingredient,
are made as follows:
Active Ingredient 225 mg
Saturated fatty acid glycerides 2,000 mg
Total 2,225 mg
The Active Ingredient is passed through a No. 60 U.S.
sieve (250 ~m)and suspended in the saturated fatty acid
glycerides previously melted using the minimum heat
necessary. The mixture is then poured into a suppository
mold of nominal 2g capacity and allowed to cool.
Formulation 7
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-154-
Suspensions, each containing 50 mg of Active Ingredient per
ml dose, are made as follows:
Active Ingredient 50 mg
Sodium carboxymethyl cellulose 50 mg
Syrup 1.25 ml
Benzoic acid solution 0.10 ml
Flavor q.v.
Color q.v.
Purified water to total 5 ml
5 The Active Ingredient is passed through a No. 45 mesh U.S.
sieve (355 Win) and mixed with the sodium carboxymethyl
cellulose and syrup to form a smooth paste. The benzoic acid
solution, flavor and color are diluted with a portion of the
water and added, with stirring. Sufficient water is then
added to produce the required volume.
Formulation 8
An intravenous formulation may be prepared as follows:
Active Ingredient 100 mg
Isotonic saline 1,000 ml
The solution of the above materials generally is
administered intravenously to a subject at a rate of 1 ml
per minute.
All of the products of the Examples described below as
well as intermediates used in the following procedures
showed satisfactory nmr and it spectra. They also had the
correct mass spectral values.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-155-
vII. Method of Using the Compounds of the Invention
This invention is a method for preventing or treating
LTB4 induced inflammation in a mammal by contacting the
LTB4 in a mammal with an LTB4 antagonizing amount of the
heterocyclic substituted diphenyl compounds of the
invention (as per formula I or II) or a salt, solvate or
prodrug of said compounds.
Another aspect of this invention is a method for
preventing or treating Inflammatory Diseases such as
inflammatory bowel disease, septic shock, adult
respiratory distress syndrome, panceatitis, trauma,
bronchial asthma, allergic rhinitis, rheumatoid arthritis,
osteoarthritis, and related diseases which comprises
administering to a mammal (including a human) a
therapeutically effective dose of heterocyclic substituted
diphenyl compounds of the invention (as per formula I or
II) or a salt, solvate or prodrug of said compounds.
The specific dose of a compound administered according
to this invention to obtain therapeutic or prophylactic
effects will, of course, be determined by the particular
circumstances surrounding the case, including, for example,
the compound administered, the route of administration and
the condition being treated. Typical daily doses will
contain a non-toxic dosage level of the compound of formulae
(I). When route of administration is parenteral the dose is
about 0.1 to about 100 milligrams per day. Intravenous
administration can include a continuous drip. When the
route is oral the dose is about 1 to about 1000 milligrams
per day. Preferred dosages are from about 0.5 to about 300
mg/kg per day, most preferably 0.5 to 20 mg/kg, of Active
Ingredient may be administered although it will, of course,
readily be understood that the amount of the compound or
compounds of Formula I actually to be administered will be
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-156-
determined by a physician, in the light of all the relevant
circumstances.
VIII. Assay Method
The following Assay method was used to evaluate the
effects of 3 compounds for LTB4-mediated CDllb upregulation
on human neutrophils:
Note: The Assay procedure described herein was modeled
after a previously published method(viz., Prostaglandins,
Leukot, Essent. Fatty Acids. 46:265-270. 1992, Biochem.
Pharmacol. 49:1683-1690. 1995), the disclosure of which is
incorporated herein by reference.
The compound C (within the scope of the invention) was
evaluated for LTB4 antagonist efficacy. Compounds A and B
were control compounds. Compound A is a leukotriene B4
antagonist known to be effective, but belonging to a
different class of compounds than represented by formulae I
or II, supra. Comparison compound B is structurally similar
to the compounds of the invention, but lacks certain
essential functional groups necessary for an effective LTB4
antagonist.
Approximately 1-2 mg of each compound was weighed and
diluted to 1 mM in neat dimethyl sulphoxide (DMSO). These
stocks were then diluted (using "doubling" dilutions) in
assay buffer.
The assay buffer used throughout the studies consisted
of Hanks Balanced Salts Solution (HBSS) with added 0.5~
bovine serum albumin, low endotoxin (ICN Biomedicals Catalog
# 16-980-49). After dissolving the BSA in the HBSS, the
buffer was membrane-filtered (0.2~,) before use.
Human blood was drawn into 3 x 10 ml EDTA-K3 Vacutainer
tubes, which were pooled and mixed in a 50 ml, blue cap
polypropylene tube. Three ml portions of Mono-Poly
Resolving medium (MPRM; ICN #16-980-49) were dispensed into
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-157-
4 separate 13 x 100 glass disposable tubes. An additional
0.3 ml of PBS (phosphate buffered saline) was added to each
tube and mixed with the MPRM by vigorous vortexing. Exactly
3.5 ml of the blood was carefully layered on top of the four
MPRM-water mixtures. The tubes were gradually accelerated
to 400 x g and spun at this speed for 30 min at room
temperature. Tubes were removed from the centrifuge and
both the plasma and top cell (mononuclear) layers were
removed and discarded. The second layer of cells was
carefully collected, pooled and washed with assay buffer.
The collected neutrophil cell preparation was then spun at
400 x g for 5 min and re-washed once again. The cells were
resuspended in assay buffer and counted using a Cell-Dyn
1600 cell counter (Abbott Diagnostics Co.). They were then
resuspended in buffer at 9 x 106 cells/ml and held briefly
for addition in a later step of the assay.
LTB4, (Biomol ; ETOH stock @ 148.5 ~,M) was diluted to a
3.9 ~.M stock in assay buffer by dilution of 10 ~,l ETOH stock
+ 371 ~1 assay buffer, mixed well and further diluted 1:100
(100 ~,1 + 9.9 ml buffer) to make a use stock of 39 nM in
buffer for later use. The final concentration of LTB4 (3
nM) was determined after several experimental runs.
Exactly 10 ~.1 of each putative compound/dilution and 10
~,l of anti-CDllb-FITC (FITC = Fluorescein Isothiocyanate;
Biosource Intl., # AHS1148) was carefully added to the
bottom of 12 x 75 mm polypropylene tubes (Falcon # 2063) as
determined by the experimental design. Following this, 100
~,1 of the human neutrophil preparation (9E6/ml) was added
and mixed well by vortexing. The compound/cell mixtures
were incubated together for 15 minutes at room temperature.
Following this incubation, 10 ~.1 of diluted LTB4 stock was
added (to make 3 nM final LTB4 concentration), mixed by
vortexing and incubated in a 37°C shaking water bath for 30
min. Following this the tubes were immediately placed on
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-158-
ice for 10 minutes. Following this 1 ml of diluted BD FAGS
Lyse (Becton Dickinson Fluorescense Activated Cell Sorting
Lyse) was added to the tubes and vortexed. 10 minutes later
the tubes were spun at 400 x g at room temperature. After
centrifugation, the tubes were aspirated and re-suspended in
1.0 ml of 1~ paraformaldehyde solution.
The samples were then analyzed for fluorescence
intensity (linear scale) using an EPICS XL flow cytometer
and the "Mo-1 Isolated Neutrophil" protocol.
The mean fluorescence intensity (MFI) for each sample
was computed using WinList software and expressed as
percentage of maximum MFI.Microsoft Excel and further
graphed and analyzed using linear regression.
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-159-
Table 1
Assay Results
Compounds of the Invention
Example No. CDllb/CD18 IC50(nM)
1 480
2 5880
3 353;339
4 74;117
175;223
6 260
7 2020;3790
8 >50000
9 23;20
14;4.4;8.3
11 620;2560;1010
12 10000;5700
13 39;54
14 31;30
27
16 1080;837
17 11;5.6;8
5 * note - semicolons separate individual
assay determinations
Table 2
Assay Results for Comparison
10 Compounds
Compound IC-50(nM) SEM
A* 1.7 0.25
B not active
* = average of 3 tests
CA 02391230 2002-05-10
WO 01/34580 PCT/US00/30942
-160-
Compound A - a known LTB4 antagonist (see, Example 66 of
U.S. Patent No. 5,462,954) which is not heterocycle
substituted and is not an aspect of this invention:
F
H
~I I~ ~I
O~~O / O
HO O
Compound B - a control compound related to Compound A and
not an aspect of this invention, represented by the formula:
F
