Note: Descriptions are shown in the official language in which they were submitted.
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ONCOLYTIC COMBINATIONS FOR THE TREATMENT OF CANCER
CROSS REFERENCE TO RELATED APPLICATION
This application claims priority from United States
Provisional Patent Application No. 60/164,786 filed 11
November 1999; the entire disclosure of which is
incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to a method of treating cancer
with anti-cancer agents. More specifically, it relates to
the use of 2',2'-difluoronucleoside anti-cancer agents, in
conjunction with leukotriene (LTB4) antagonists which
enhance the effectiveness of the anti-cancer agent.
BACKGROUND OF THE INVENTION
Leukotriene B4 (LTB4) is a proinflammatory lipid
which has been implicated in the pathogenesis of
psoriasis, arthritis, chronic lung diseases, acute
respiratory distress syndrome, shock, asthma, inflammatory
bone diseases and other inflammatory states characterized
by the infiltration and activation of polymorphonuclear
leukocytes and other proinflammatory cells. Thus
activated, the polymorphonuclear leukocytes liberate
tissue-degrading enzymes and reactive chemicals causing
the inflammation. US Patent 5,462,954 discloses
phenylphenol leukotriene antagonists that are useful in
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the treatment of psoriasis, arthritis, chronic lung
diseases, acute respiratory distress syndrome, shock,
asthma, inflammatory bone diseases and other inflammatory
states characterized by the infiltration and activation of
polymorphonuclear leukocytes and other proinflammatory
cells. US Patent 5,910,505 discloses that certain
phenylphenol leukotriene B4 (LTB4) antagonists are useful
as agents for the treatment of oral squamous cell
carcinoma. US Patent 5,543,428 discloses a group of
phenylphenol leukotriene antagonists which have the
property of reversing multi drug resistance in tumor
cells. The use of the leukotriene antagonist will reverse
the drug resistance of resistant tumor cells to
vinblasine, vincristine, vindesine, navelbine,
daunorubicin, doxorubicin, mitoxantrone, etoposide,
teniposide, mitomycin C, actinomycin, taxol, topotecan,
mithramycin, colchicine, puromycin, podophylotoxin,
emetine, gramicidin, and valinomycin.
2 0 BRIEF SUN~A,RY OF THE INVENTION
This invention provides compositions and methods useful
for treating cancers, in particular, cancers that are not
multi drug resistant. The methods of the present invention
include the 2',2'-difluoronucleoside anti-cancer agents
described in US Patent 5,464,826 in combination with
leukotriene (LTB4) antagonists of formula A, formula I and
formula II, described below.
Surprisingly, we have found that the combination of
2',2'-difluoro nucleoside anti-cancer agents with
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leukotriene (LTB4) antagonists act synergistically against
cancers which are not multi-drug resistant.
The types of cancers that may be treated with the
compositions of the present invention include: Breast
Carcinoma, Bladder Carcinoma, Colorectal Carcinoma,
Esophageal Carcinoma, Gastric Carcinoma, Germ Cell Carcinoma
e.g. Testicular Cancer, Gynecologic Carcinoma, Lymphoma
Hodgkin's, Lymphoma - Non-Hodgkin's, Malignant Melanoma,
Multiple Myeloma, Neurologic Carcinoma, Brain Cancer,
Pancreatic Carcinoma, Prostate Carcinoma, Ewings Sarcoma,
Osteosarcoma, Soft Tissue Sarcoma, Non-Small Cell Lung
Cancer, Pediatric Malignancies and the like.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1 through 6 are horizontal bar graphs
displaying the data of Tables 1 through 6 provided in the
"ASSAY EXAMPLE 1", infra. The vertical axis of the graph in
each Figure forms the origin of the numbered horizontal
bars, wherein each bar is a separate Treatment as set out in
the Tables. The horizontal axis is tumor growth delay (TGD)
in days.
DETAILED DESCRIPTION OF THE INVENTION
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.
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The term, "Active Ingredient" refers both to certain
2', 2'-difluoronucleoside compounds and also leukotriene B4
antagonist compounds generically described by formula A as
well as diphenyl leukotriene Bg antagonist compounds
generically described by formula I and formula II or the
list of specific diphenyl compounds disclosed, infra., as
well as a combination of a 2', 2'-difluoronucleoside and a
leukotriene B4 antagonist described by formula A or formulas
I and/or II, and 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
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.
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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).
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 terms, "mammal" and "mammalian" include human.
The term, "N-sulfonamidyl" means the radical:
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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).
The term, "tetrazolyl" refers to an acidic group
represented by either of the formulae:
N N HN N
N~ NH N~ N
The term "therapeutically effective interval" is a
period of time beginning when one of either (a) the 2', 2'-
difluoronuceoside anti-cancer agent or (b) the LTBg
antagonist is administered to a mammal and ending at the
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limit of the anti-cancer beneficial effect in treating
cancer of (a) or (b). Typically, the anti-cancer agents and
the leukotriene (LTB4) antagonist are administered within 24
hours of each other, more preferably within 4 hours and most
preferably within 1 hour.
The phrase "therapeutically effective combination",
used in the practice of this invention, means administration
of both (a) the 2', 2'-difluoronuceoside anti-cancer agent
and (b) the LTB4 antagonist, either simultaneously or
separately, in any order.
The anti cancer agents which may be used are 2',2'-
difluoronucleoside compounds of the formula:
R'O -H2C O
R2
F
OH F
wherein:
R2 is hydrogen or
0
~C-Rs
R2 is a base defined by one of the formulae
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NHRg
N~X H N N
R3 HN~ N N
~J
H
V
HN /\
HN X
O~N~\N~ ~ N
H I
/NHR3 N
N I
X is N or C-R4
R3 is hydrogen, C1-Cg alkyl or
0
~C-Rs
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R4 is hydrogen, C1-Cg alkyl, amino, bromo, fluoro,
chloro or iodo;
Each R5 independently is hydrogen or C1-C4 alkyl; and
the pharmaceutically-acceptable salts thereof.
The following compounds may also be used
R6OH2
R'
F
OH F
wherein:
R6 is hydrogen, C1-C4 alkyl;
R~ is a base of one of the formulae
NHRB O
N~X H N ~
RB HN~N N/
I
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H RB
J ~ ~N>
N I R N I N
X is N or C-R4;
R8 is hydrogen or C1-C4 alkyl;
R4 is hydrogen, C1-C4 alkyl; amino, bromo, fluoro, chloro
and iodo; and the pharmaceutically-acceptable salts thereof;
with the proviso that R6 and R8 may both be hydrogen only
when x is N and
R6 O _ H2C O
R9
F
OH F
wherein:
R6 is hydrogen or C1-C4 alkyl;
O
R9is HN
N /I N
H I
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These compounds are disclosed in US Patent 5,464,826
which is incorporated by reference herein for its disclosure
of the methods of preparing these compounds, formulating
these compounds, and the treatment of cancer using these
compounds.
Alternatively, preferred 2'2'-difluoronucleoside compounds
are compounds represented by the formula:
R, O R2
F
where:
R1 is hydrogen;
Rz is a base defined by one of the formulae:
NHR3 O
N ~~X HN
N
O N ~ R3HN N
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O NHR3
HN N ~ N
N
O N N .
R4
X is C-R4;
R3 is hydrogen;
R4 is hydrogen, C1-C4 alkyl, bromo, fluoro, chloro or
iodo;
and pharmaceutically acceptable salts thereof.
More preferably the compounds are whereRz is the base
defined by the formula:
NHR3
N ~\X
~N
O
Even more preferred are anti-cancer agents are selected from
the group consisting of the following compounds or a
pharmaceutically acceptable salt thereof:
(i) 1-(4-amino-2-oxo-1H-pyrimidin-1-yl)-2-desoxy-2',2'-
difluororibose,
(ii) 1-(4-amino-2-oxo-1H-pyrimidin-1-yl)-2-desoxy-
2',2'-difluoroxylose,
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(iii) 1-(2,4-dioxo-1H,3H-pyrimidin-1-yl)-2-desoxy-
2',2'-difluororibose, and
(iv) 1-(4-amino-5-methyl-2-oxo-1H-pyrimidin-1-yl)-2-
desoxy-2',2'-difluororibose.
The most preferred compound is gemcitabine HC1 which is
a nucleoside analogue that exhibits antitumor activity.
Gemcitabine HC1 is 2'-deoxy-2',2'-difluorocytidine
monohydrochloride ((3-isomer), also known as 2',2'-difluoro-
2'-deoxycytidine monohydrochloride, or also as 1-(4-amino-2-
oxo-1H-pyrimidin-1-yl)-2-desoxy-2',2'-difluororibose.
The structural formula is as follows:
NHZ HCI
~~ N
HO
,O_
H
~H
The anti-cancer agents are generally mixed with a
carrier which may act as a diluent, or excipient the anti-
cancer agents may be administered in the form of tablets,
pills, powders lozenges, sachets, cachets, elixirs,
suspensions, emulsion, solution, syrups or aerosols.
Sterile injectable solutions may also be used.
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The leukotriene (LTB4) antagonists useful in the
present invention include those given in formula A.
X'-Y'-Z'-A'-RQ'
R3.
R1~
Formula A
or a pharmaceutically acceptable base addition salt
thereof, wherein:
R1' is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C4
alkoxy, (C1-C4 alkyl)thio, halo, or R2'-substituted phenyl;
each R2' and R3' are each independently hydrogen, halo,
hydroxy, C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyl)-(0)q S-,
trifluoromethyl, or di-(C1-C3 alkyl)amino;
X' is -O-, -S-, -C(=O), or -CH2-;
Y' is -O- or -CH2-;
or when taken together, -X'-Y'- is -CH=CH- or -C=C-;
Z' is a straight or branched chain C1-C1p alkylidenyl;
A' is a bond, -0-, -S-, -CH=CH-, or -CRaRy~-, where Ra
and Rb are each independently hydrogen, C1-C5 alkyl, or R~~-
substituted phenyl, or when taken together with the carbon
atom to which they are attached form a C4-Cg cycloalkyl
ring;
R4' is R6
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R~
R~
I OGRs
-O
R
(K)P'W'Rs (CH2)t
c
R» ,
R~
W'Rs
T
R~
Rg
UV-Rs
T
R~
W_Rs
R~
where
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each R6 is independently -COON, 5-tetrazolyl,
CON(R9)2, or -CONHS02R10%
each R~ is hydrogen, C1-C4 alkyl, C2-C5 alkenyl, C2-C5
alkynyl, benzyl, methoxy, -W-R6, -T-G-R6, (C1-C4 alkyl)-T-
(C1-Cg alkylidenyl)-O-, or hydroxy;
Rg is hydrogen or halo;
each R9 is independently hydrogen, phenyl, or C1-C4
alkyl, or when taken together with the nitrogen atom form a
morpholino, piperidino, piperazino, or pyrrolidino group;
R10 is C1-C4 alkyl or phenyl;
R11 is R2, -W-R6, or -T-G-R(;
each W is a bond or a straight or branched chain
divalent hydrocarbyl radical of one to eight carbon atoms;
each G is a straight or branched chain divalent
hydrocarbyl radical of one to eight carbon atoms;
each T is a bond, -CH2-, -0-, -NH-, -NHCO-, -C(=O)-, or
(O) q S-;
K is -C(=0)- or -CH(OH)-;
each q is independently 0, 1, or 2;
p is 0 or 1; and
t is 0 or 1;
provided when X is -O- or -S-, Y is not -O-;
provided when A is -O- or -S-, R4' is not R6;
and provided W is not a bond when p is 0.
Preferred LTB4 antagonists of Formula A are those
compounds wherein R4' is selected from the following
formulae:
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R~~
R~
or
- Rs
An even more preferred LTBg antagonist of Formula A are
those compounds-wherein R4' is:
- Rs
Some of these preferred LTBg antagonist compounds or
pharmaceutically acceptable acid or salt derivatives thereof
are listed herein from the group (A) to (KKKK) consisting
of
A) 2-Methyl-2-(1H-tetrazol-5-yl)-7-(2-ethyl-4-
(4-fluorophenyl)-5-hydroxyphenoxy)heptane;
B) 2-Methyl-2-(1H-tetrazol-5-yl)-7-(2-ethyl-4-
(3-fluorophenyl)-5-hydroxyphenoxy)heptane;
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C) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-(4-
dimethylaminocarbonylbutyloxy)phenyl)propion
is acid;
D) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propionic
acid;
E) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-(4-
carboxybutyloxy)phenyl)propionic acid;
F) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-
methoxyphenyl)propionic acid;
G) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-(4-(1H-tetrazol-5-
yl)butyloxy)phenyl)propionic acid;
H) Methyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl)-
5-hydroxyphenoxy)-(1-
butenyl))phenyl)propionate;
I) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)-(1-butenyl))phenyl)propionic
acid;
J) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)butyl)phenyl)propionic acid;
K) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)butyl)-6-
methoxyphenyl)propionic acid;
L) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-
5-hydroxyphenoxy)propoxy)-6-
hydroxyphenyl)propionate;
M) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-
hydroxyphenyl)propionic acid;
N) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-(4-
butyloxy)phenyl)propionic acid;
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O) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-(4-
methylthiobutyloxy)phenyl)propionic acid;
P) 3-(2-(3-(2,4-Di(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-(4-
carboxybutoxy)phenyl)propionic acid;
Q) 6-Methyl-6-(1H-tetrazol-5-yl)-11-(2-ethyl-4-
(4-fluorophenyl)-5-hydroxyphenoxy)undecane;
R) N,N-Dimethyl-3-(2-(3-(2-ethyl-4-(4-
fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propionamide;
S) N-Methanesulfonyl-3-(2-(3-(2-ethyl-4-(4-
fluorophenyl)-5-
hydroxyphenoxy)propoxy).phenyl)propionamide;
T) N-Phenylsulfonyl-3-(2-(3-(2-ethyl-4-(4-
fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propionamide;
U) 3-(2-(3-(2-Butyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propionic
acid;
V) Ethyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)butyloxy)phenyl)propionate;
W) 3-(2-(4-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)butyloxy)phenyl)propionic
acid;
X) Methyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-
5-hydroxyphenoxy)propoxy)-6-(4-
(methoxycarbonyl)phenoxy)phenyl)propionate;
Y) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-(4-
carboxyphenoxy)phenyl)propionic acid;
z) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-4-(4-
carboxyphenoxy)phenyl)propionic acid;
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AA) 3,3-Dimethyl-3-(2-(3-(2-ethyl-4-(4-
fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propionic
acid;
BB) 2-Methyl-2-(1H-tetrazol-5-yl)-3-(2-(3-(2-
ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propane;
CC) 2-Methyl-2-(1H-tetrazol-5-yl)-3-hydroxy-3-
(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propane;
DD) 3-(2-(3-(2-Bromo-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propionic
acid;
EE) 3-(2-(3-(2-Ethylthio-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propionic
acid;
FF) Methyl 3-(2-hydroxy-3-(4-
methoxycarbonylbutyl)-6-(3-(2-ethyl-4-(4-
fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)propionate;
GG) 5-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-8-(4-carboxybuty
1)dihydrocoumarin;
HH) 2-Phenyl-4-ethyl-5-[6-(2H-tetrazol-5-yl)-6-
methylheptyloxy]phenol sodium salt;
II) 2-(4-Methylphenyl)-4-ethyl-5-[6-methyl-6-
(2H-tetrazol-5-yl)heptyloxy]phenol disodium
salt;
JJ) 2-(3-Methylphenyl)-4-ethyl-5-[6-methyl-6
(2H-tetrazol-5-yl)heptyloxy]phenol sodium
salt;
KK) 2-(2-Methylphenyl)-4-ethyl-5-[6-methyl-6-
(2H-tetrazol-5-yl)heptyloxy]phenol disodium
salt;
LL) 2-(4-Methoxyphenyl)-4-ethyl-5-[6-methyl-6-
(2H-tetrazol-5-yl)heptyloxy]phenol sodium
salt;
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MM) 2-(3-Methoxyphenyl)-4-ethyl-5-[6-methyl-6-
(2H-tetrazol-5-yl)heptyloxy]phenol sodium
salt;
NN) 2-(4-Trifluoromethylphenyl)-4-ethyl-5-[6-
methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol
disodium salt;
00) 2-(3-Dimethylaminophenyl)-4-ethyl-5-[6-
methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol
disodium salt;
PP) 3-(5-(6-(4-Phenyl-5-hydroxy-2-
ethylphenoxy)propoxy)-2-carboxymethyl-
1,2,3,4 -tetrahydronaphthalen-1(2H)-
one)propanoic acid;
QQ) 3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2-
ethylphenoxy)propoxy)-2-carboxymeth yl-
1,2,3,4-tetrahydronaphthalen-1(2H)-
one)propanoic acid;
RR) 3-(4-(5-(4-(4-Fluorophenyl)-5-hydroxy-2-
ethylphenoxy)propoxy)-2-carboxymeth yl-2,3-
dihydroinden-1(2H)-one)propanoic acid;
SS) 3,3-Dimethyl-5-(3-(2-carboxyethyl)-4-(3-(4-
fluorophenyl)-5-hydroxy-2-
ethylphenoxy)propoxy)phenyl)-5-oxopentanoic
acid;
TT) 7-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl]-4
yl)oxy]propoxy]-3,4-dihydro-8-propyl-2H-1
benzopyran-2-carboxylic acid;
UU) 8-Propyl-7-[3-[4-(4-fluorophenyl)-2-ethyl-5-
hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1-
benzopyran-2-carboxylic acid;
W) 2-[3-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl]-
4-yl)oxy]propoxy]-2-propylphenoxy]propanoic
acid;
WW) 2-(4-Chlorophenyl)-4-ethyl-5-[6-methyl-6-
(2H-tetrazol-5-yl)heptyloxy]phenol
monosodium salt;
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XX) 2-(3,5-Dichlorophenyl)-4-ethyl-5-[6-methyl-
6-(2H-tetrazol-5-yl)heptyloxy]phenol
monosodium salt;
YY) 3-[2-[3-[(5-Ethyl-2-hydroxy[1,1'-biphenyl]-
4-yl)oxy]propoxy]-1-dibenzofuran]propanoic
acid disodium salt;
ZZ) 7-Carboxy-9-oxo-3-[3-(2-ethyl-5-hydroxy-4-
phenylphenoxy)propoxy]-9H-xanthene-4-
propanoic acid disodium salt monohydrate;
AA.A) 2-[2-Propyl-3-[3-(2-ethyl-5-hydroxy-4-
phenylphenoxy)propoxy]phenoxy]benzoic acid
sodium salt hemihydrate;
BBB) 3-[3-(2-Ethyl-5-hydroxy-4-
phenylphenoxy)propoxy][1,1'-biphenyl]-4-
propanoic acid disodium salt monohydrate;
CCC) 5-Ethyl-4-[3-[2-propyl-3-[2-(2H-tetrazol-5-
yl)phenoxy]phenoxy]propoxy][1,1'-biphenyl]-
2-0l disodium salt sesquihydrate;
DDD) 3-[4-[3-[ 3-(2-Ethyl-5-hydroxy-4-
phenylphenoxy)propoxy]-9-oxo-9H-
xanthene]]propanoic acid sodium salt
hemihydrate;
EEE) 2-Fluoro-6-[2-propyl-3-[3-(2-ethyl-5-
hydroxy-4-
phenylphenoxy)propoxy]phenoxy]benzoic acid
disodium salt;
FFF) 2-[2-Propyl-3-[3-[2-ethyl-4-(4-
fluorophenyl)-5-
hydroxyphenoxy]propoxy]phenoxy]benzoic acid
sodium salt;
GGG) 3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4-(4-
fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H-
xanthene]] propanoic acid disodium salt
trihydrate;
HHH) 3-[4-[9-Oxo-3-[3-[2-ethyl-4-(4-
fluorophenyl)-5-hydroxyphenoxy]propoxy]-9H-
xanthene]]propanoic acid;
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III) 3-[2-[1-[2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy]propoxy]-4-(5-oxo-5-
morpholinopentanamido)phenyl]propanoic acid;
JJJ) 2-Fluoro-6-[2-propyl-3-[3-[2-ethyl-5-
hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]benzoic
acid disodium salt hydrate;
KKK) 4-Fluoro-2-[2-propyl-3-[3-[2-ethyl-5-
hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]benzoic
acid;
LLL) 2-[2-Propyl-3-[5-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]pentoxy]phenoxy]benzoic
acid;
MMM) 2-[2-Propyl-3-[4-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]butoxy]phenoxy]benzoic
acid sesquihydrate;
NNN) 2-[2-(2-Methylpropyl)-3-[3-[2-ethyl-5-
hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]benzoic
acid;
000) 2-[2-Butyl-3-[3-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]benzoic
acid hydrate;
PPP) 2-[2-(Phenylmethyl)-3-[3-[2-ethyl-5-hydroxy-
4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]benzoic
acid;
QQQ) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]phenyla
cetic acid;
RRR) 2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]benzoyl]benzoic
acid;
SSS) 2-[[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenyl]methyl]b
enzoic acid;
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10
20
TTT) 2-[2-Propyl-3-[3-[2-ethyl-4-(4-
fluorophenyl)-5-
hydroxyphenoxy]propoxy]thiophenoxy]benzoic
acid;
UUU) 2-[2-Propyl-3-[3-[2-ethyl-4-(4-
fluorophenyl)-5-
hydroxyphenoxy]propoxy]phenylsulfinyl]benzoi
c acid;
VW) 2-[2-Propyl-3-[3-[2-ethyl-4-(4-
fluorophenyl)-5-
hydroxyphenoxy]propoxy]phenylsulfonyl]benzoi
c acid hydrate;
WWW) 5-[3-[2-(1-Carboxy)ethyl]-4-[3-[2-ethyl-4-
(4-fluorophenyl)-5-
hydroxyphenoxy]propoxy]phenyl]-4-pentynoic
acid disodium salt 0.4 hydrate;
XXX) 1-Phenyl-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-
(4-fluorophenyl)-5-hydroxyphenoxy)hexane;
YYY) 1-(4-(Carboxymethoxy)phenyl)-1-(1H-tetrazol-
5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)hexane;
ZZZ) 1-(4-(Dimethylaminocarbonylmethoxy)phenyl)
1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4
fluorophenyl)-5-hydroxyphenoxy)hexane;
AAAA) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)-E-propenoic
acid;
BBBB) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)-2-methyl-E-
propenoic acid;
CCCC) 5-(2-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)phenyl)ethyl)-1H-
tetrazole;
DDDD) 3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-4-(4-
carboxybutyloxy)phenyl)propionic acid;
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EEEE) 5-[3-[4-(4-Fluorophenyl)-2-ethyl-5-
hydroxyphenoxy]propoxy]-3,4-dihydro-2H-1-
benzopyran-2-one;
FFFF) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenyloxy]propoxy}phenyl)propanoic
acid;
GGGG) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenyloxy]propoxy}-4-
propylphenyl)propanoic acid sodium salt;
HHHH) 3-(4-{3-[2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenyloxy]propoxy}-3-
propylphenyl)propanoic acid;
IIII) 3-(3-{3-[2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenyloxy]propoxy}-2-
propylphenyl)propanoic acid;
25
JJJJ) 3-{3-[3-(2-Ethyl-5-
hydroxyphenyloxy)propoxy]-2-
propylphenyl}propanoic acid disodium salt;
and
KKKK) 2-[3-[3-[2-Ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]benzoyl]benzoic
acid disodium salt hemihydrate.
These leukotriene (LTB4) antagonists are well known in
the art, and are fully described in U.S. Patent 5,462,954,
which is hereby specifically incorporated by reference for
its disclosure of the methods of preparation of specific
leukotriene B4 antagonists and compounds or formulations of
the leukotriene antagonists which may be administered to
patients. A preferred compound is 2-[2-propyl-3-[3-[2-
ethyl-5-hydroxy-4-(4-flourophenyl)phenoxy]propoxy]phenoxy
benzoic acid which can also be named 2-[3-[3-(5-ethyl-4'-
flouro-2-hydroxybiphen-4-yloxy)propoxy-2-
propylphenoxy]benzoic acid, described in U.S. Patent
5,462,954 as example 66 and also shown below as Compound A
(Formula B):
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A second class of LTB4 antagonists to use as the
essential co-agent in the compositions and practice of the
method of this invention are those disclosed in copending
provisional patent application, titled, "Heterocycle
Substituted biphenyl Leukotriene Antagonists" (inventor,
Jason Scott Sawyer) containing 97 pages and identified as
Eli Lilly and Company Docket No. B-13240), filed on November
11, 1999, and now Provisional patent Application Serial
Number 60/164,786. This second class of heterocycle
substituted diphenyl leukotriene antagonists are described
in more detail below:
II. Additional LTB4 Antagonists:
Additional LTB4 antagonists are described below which
are novel heterocyclic substituted Biphenyl compounds of
formula (I)
Compound A (Formula B)
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X "
R2
Y~H
2 n Yz Y~
R4 R1
(I~
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;
Y2 and Y3 are divalent linking groups independently selected
from -CH2-, -0-, 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-C10 haloalkyl, C6-C20 aryloxy, or C1-C10 alkoxy;
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R2 is hydrogen, halogen, C1-Clp haloalkyl, C1-Clp alkoxy,
C1-C1p alkyl, C3-Cg cycloalkyl, Acidic Group, or
-(CH2)1_~(Acidic Group);
R3 is hydrogen, halogen, C1-C1p alkyl, aryl, C1-C10
haloalkyl, C1-Clp alkoxy, C1-C1p aryloxy, C3-Cg cycloalkyl;
R4 is C1-Cg alkyl, C3-Cg cycloalkyl,
-(CH2)1-~(cycloalkyl), C2-C4 alkenyl, C2-C4 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 LTBg Antagonists include the following:
III A. Preferred X substituents:
A "substituted heterocyclic radical" is preferably
substituted with from 1 to 3 groups independently selected
from hydrogen, halo, C1-C1p alkyl, C1-C1p haloalkyl, C1-C10
alkoxy, aryl, or C6-C2p aryloxy.
Preferred Group 1 of X substituent (symbol, "PG1-X")
Preferred LTBg antagonist compounds used in the
composition of the invention are those wherein X is a
heterocyclic radical selected from the group consisting of
substituents represented by the following structural
formulae:
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R11 ~ R11 ~ R11
O ~ S ~ N
R10
N R11 ~ N R11 R11
~N
O ~ S ~ O/
R11 ~ R11 ~-N R11
N N ,
S/ ~ N/ ~ O/
R10
N R11 ~R11 N
N ~ N
S ~ N/ ~ N/
R10 R10
N R11 ~~R11 ~~R11
N/ , N/N ' N 1\S/N
R10 R10
~R11 N
N N N ~ N
> >
S/ \O/ O/
~R11 ~R11 N~R11
N ~ N ~ N
S/ O~ S/
> >
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R10
N N N/
\ ~ \\
N~S/N ~ N\O/N ~ N R11
O/ ' S/ ' N/
H
R10
R11
J
N
and ~ .
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
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atom or any nitrogen atom which has less than three bonds in
the heterocyclic ring;
Location of attachment bond for pyrrole,
I
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;
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N S
CH3 N O
or
_~
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 LTB4 compounds included in the composition of
the invention are those wherein Y1 is a divalent linking
group selected from the group consisting of substituents
represented by the following formulae:
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O , S ,
S02 ,
2
O
S S N-
1 13
O ~ O
N C
R13 ' O '
C C
H2 H2 '
O~
H2 '
z
N C ,
Hz
R13
O
C
Hz
O and
C C
II H2
O
where R13 is hydrogen, methyl, or ethyl;
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The above divalent groups may be used in their forward
or reversed positions. For example, the group;
C C
'
H2
O
may be positioned as either,
R2
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 Yz 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 -O-.
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III G. Preferred Group 2 of YZ substituent (symbol, "PG2-
YZ") and Preferred Group 2 of Y3 substituent (symbol, "PG2-
Y3" )
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
O O
tetrazolyl,
-S03H,
O
OH
P ,
OH
O
1
OH
O P
OH
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0
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:
/ CH3 /
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")
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The most preferred integer values for the divalent
linking group, -(CH2)n- , are n=1, n=2, and n=3.
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
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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
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).
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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
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
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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:
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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
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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
XZnl5 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
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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 composition and method of invention.
III Q. Additional preferred LTB4 antagonists are
described by formula (II):
X2
R22
O
Z2
(II~
wherein;
25
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X2 is a heterocyclic radical selected from,
N S
CH3 N O
or
s~
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 antagonist
component of the composition and method of the invention
are represented by the following structural formulae:
(C1)
/=N OH
O ~
O~O ~ ~ O
COOH
(C2):
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~HCI
H
~N~ OH
N ~
O ~\/~ O \
COOH
(C3)
/=N OH
S ~
/
/ O~O \ O
COOH
(C4)
N'N~~ ~ OH
/
/ O~O \ O \
COOH
(C5)
N'O OH
\ / /
/ O~O \ I O \
COOH
(C6)
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~N~N.H OH
N ~
\ / /
I / O~O \ I O \ I
COOH
(C7):
OH
~N \ / /
/ o~O \ I O \
COOMe
(C8):
OH
g I \ / I / I
/ O~O \ O \
COOH
(C9):
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N- OH
-N
\ / /
/ ono \ I o \
COOH
(C10):
~N OH
s I \ / I /
/ o'~o ~ o
COOH
(C11):
O OH
N~ I
I \ / I / I
/ O~O \ O
COONa
(C12):
off
O I \ /
/ O~O \ O \
COOH
(C13):
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OH
O ~
\ / /
O~\/~O \
COOH
(C14):
O OH
\ / /
O~O \ ~ O \
COONa
(C15):
OH
N \ / /
CI / O~O \ O \
COOH
(C16)
OH
O~O \ ~ O
COOH
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(C17):
N-N OH
N
I~ ~I ~I
O~O \ O
COOH
(C18)
N=N OH
S ,
i i
~ ono w I o w
COOH
(C19)
S-N OH
N~ ~
o'~o ~ o
COOH
15 (C20)
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~N-N OH
s I ~ ~ I
oho \ O
COOH
(C21)
Ni I off
I~ ~I ~I
o'~o ~ o
COOH
(C22):
~N OH
I
p I ~ ~ I ~ I
O~O \ O
COOH
(C23):
OH
S
I / O~O w I O w I
COOH
and all acid, salt, solvate and prodrug derivatives thereof.
III S. Highly Preferred LTB4 Antagonists are as follows:
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OH
/ I /
o'~o ~ o
COOH
O OH
I / O~O ~ I O
COONa
OH
s, I ~ / I / I
/ O~O \ O
COOH
N- OH
-N ~
/ /
/ OHO ~ I o ~
COOH
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OH
0, I ~ / I / I
/ O'~O ~ O
COOH
OH
O ~
/ /
/ O~o ~ I o ~
COOH
and all acid, salt, solvate and prodrug derivatives thereof.
IV. Method of Making the LTBg Antagonist Compounds of the
Composition and Method 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 LTB4 ANTAGONIST
COMPOUNDS USED IN THE COMPOSITIONS AND METHOD
OF THE INVENTION
The following scheme illustrates a process for making Example
(1), a 4-substituted oxazole LTBg receptor antagonist:
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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
I
HO ~ O ~ (30)
0 0
COOMe
i
O~CI
known compound: RN 152609-76-2
J. S. Sawyer et al., J. Med. Chem. 1995, 38, 4411
(28) K2C03, Nal, 2-butanone
OI'
O O ~ O~CF3
i r ~ i
~O
I I ~ o~'cF
-O O -O '~'
COOMe TFA, H20, CH3CN
(32)
0 0
HO ~ ~ / / 1) Tf20, 2,6-lutidine
O~O \ I O \ I 2) formamide
COOMe
(34)
/= N O
I ~ ~ BF3 Et20, EtSH
O~O \ O
COOMe
(36)
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/= N H
O~
~ ) 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:
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Scheme 2
p I
/ / 1) LiHMDS, TMSCI, THF
I / O~O \ I O~ 2) NCS
COOMe 3) TBAF
(32)
O O ~ NI'H
CI ~ I / / / H2N~SBn
I / p~0 \ I O \ I K2C03, Nal, DMF
COOMe
(40)
S H
N~N~ O
/ / BF Et O, EtSH
3 2
I / O~O ~ I o ~ I
COOMe
(42)
S .H
N~N OH
I I I 1) LiOH, MeOH
/ O~O \ O~ 2) Raney Ni, EtOH, NaOH
COOMe 3) HCI
(44)
H
~N~ OH
N ~
/ /
HCI I / O
COOH
(2)
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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
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:
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Scheme 3
0 0
CI ~ / , , thioformamide, MgC03
O~O \ I O \ I dioxane
COOMe
(40)
!= N O
S i 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 ~ o
COOH
(3)
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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).
Scheme 4
The following scheme illustrates a process for making Example
(4), a 5(3)-substituted pyrazole LTBg receptor antagonist:
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Scheme 4
OMe
O O \ Me2N-
I I ~ I oMe
/ O~O \ O \ DMF
COOMe
(32)
0 o I \
MeZN \ I \ / / I / I 1 ) LiOH, MeOH
/ O~O \ O \ 2) HCI
COOMe 3) NH2NHZ H20, MeOH
(50)
N_N.n O I \
I BF3 Et20, EtSH
/ O~O \ O \
COOH
(52)
,H
N'N OH
O~\/~O \ I O \ I
COOH
(4)
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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
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 LTBg receptor antagonist:
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Scheme 5
0 0
Me2N ~ I ~ / / I / I NH20H, MeOH, H20
/ O~O \ O
COOMe
(50)
N' O O
BF3~EtZ0, EtSH
/
I / O~O ~ I o w I
COOMe
(54)
N'O OH
/ / 1 ) LiOH, MeOH
I / O~O ~ I O ~ I 2) HCI
COOMe
(56)
N'O OH
I / O~O ~ I o ~ I
COOH
(5)
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Treatment of enone (50) with hydroxylamine provides
isoxazole (54), that is debenzylated with boron trifluoride
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:
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Scheme 6
I ~ ~ I I
Br ~ i ~ ~ 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
i
TMSN3, toluene
I ~ O~O ~ I o ~ I
COOMe
(62)
N NH O
N ~ I ~ ( ~ / I / I BF3 Et20, EtSH
O~O ~ O
COOMe
(64)
,H
N'N OH
N ~
1) LiOH, MeOH
I , pip ~ I O ~ I 2) HCI
COOMe
(66)
_H
N'N OH
N ~
I I I
COOH
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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
(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:
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Scheme 7
OH _ O
1) (KS03)2N0, K2P04, H20 ~N ~ I /
I / OH 2) 3-pyrroline, CH3CN I / OH
3) BnBr, KZC03, DMF
(68) (70)
o
~N ~ I / 1 ) Nal, 2-butanone
1-bromo-3-chloropropane I
KzC03, DMF / O~CI 2) K2C03, DMF
(72) / I /
HO \ O \
COOMe
(30)
O
~N ~ I / / / BF3 Et20, EtSH
I / O~O w I O w I
COOMe
(74)
OH
~N w / /
I / O~O w 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
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4-Ethylbenzene-1,3-diol (68) is treated with potassium
nitrosodisulfonate followed by 3-pyrroline and benzylbromide
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:
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Scheme 8
H
O I ~ O,B~O
Br ~~ ~ /
/ O~O / O \ PdCl2(dppf)
COOMe
(60)
Br
N~N
O O
.B ~~ ~ / S
O CI
~ O~O I, / 0
COOMe PdCl2(dppf), CszC03, toluene
(76)
Br
~N O
N I \ ~ / \ / 1) BF3~Et20, EtSH
S
/ O~O I / 0 ~ I 2) aq. NaOH
COOMe 3) aq. NCI
(78)
Br
~N OH
N
,S ~ ~ ~ ~ /
/ O~O / O \
COOH
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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
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:
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Scheme 9
0 0 ~ 1) s ~
,B I , Br
O I \ I I PdCl2(dppf), Cs2C03, toluene
O~O ~ O
COOMe 2) BF3 Et20, EtSH
(76)
off
s I ~
O~O ~ O ~ 1 ) aq. LiOH
COOMe 2) NaOH
(80)
off
s I ~
~ o'n'o ~ o
COONa
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).
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Scheme 10
The following scheme illustrates a process for making Example
(10), a 4-substituted pyrazole LTB4 receptor antagonist:
10
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Scheme 10
I
N-N
I\
I Known compound: RN 39806-90-1
O~O O
COOMe PdCl2(dppf), Cs2C03, toluene
(76)
N, O w
-N i
/ I / I ~ ) BFa Et20, EtSH
O~O \ O \ 2) aq. NaOH
COOMe 3) aq. HCI
(82)
N- OH
-N ~
I~ ~I ~I
O~O \ O
COOH
(10)
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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).
Scheme 11
The following scheme illustrates a process for making Example
(11), a 2-substituted thiazole LTBg receptor antagonist:
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Scheme 11
O B O~ ~ ~ S /N
I ~ ~ I ~ ~ I ~Br
~O O ~O
COOMe PdCl2(dppf), CszC03, toluene
(76)
0
S I \ I I BFs~Et20, EtSH
O~O ~ O
COOMe
(84)
~N OH
S I \ I I 1 ) aq. LiOH
O~O ~ O \ 2) HCI
COOMe
(86)
~N OH
i
S I w
~ o~p I ~ p ~ I
COOH
(11 )
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The palladium-catalyzed addition of boronic ester (76) to 2-
bromothizaole provides thiazole (84). Debenzylation with
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:
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Scheme 12
i I
\ 1) N
O O~ p
O'B \ / \ /
PdCl2(dppf), Cs2C03, toluene
/ O ~\/~ O I / O \
COOMe
(76)
N, O \
O i I / 1) Me3Sil
\ \ /
/ O~O I / O \ I 2) aq. HCI
COOMe 3) NaOH
(88)
N- OH
O ~
\ \ /
O~O ~ / O
COONa
(12)
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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).
Scheme 13
The following scheme illustrates a process for making Example
(13), a 2-substituted furan LTB4 receptor antagonist:
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Scheme 13
o ~
B ~ ~ ~ BBr , CH CI
3 2 2
~ O~O W I O w
COOMe
(60)
OH
TBSCI, imidazole
O~O \ O
COOMe
(90)
oTBs
0
Br ~ / / B(OH)Z
~ O~O ~ I O ~ I Pd(PPh3)4, aq. Na2C03, THF
COOMe
(92)
OH
O I ~ ~ I ~ I 1) aq. LiOH
O~O \ O~ 2 HCI
COOMe 3) NaOH
(94)
off
i~ il
o'~o ~ o~
COONa
(13)
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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:
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Scheme 14
TBS
Br ~ / / ~B(OH)z
O~O \ I O \ I Pd(PPh3)a, aq. NazC03, THF
COOMe
(92)
OH
O ~
/ /
1) aq. LiOH
O~O O
COOMe 2) HCI
3) NaOH
(96)
OH
O ~
/ o'~o ~ o
COONa
(14)
The palladium-catalyzed addition of (92) to furan-3-boronic
acid provides furan (96). Hydrolysis and salt formation
gives Example (14).
10
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Scheme 15
The following scheme illustrates a process for making Example
(15), a 3-substituted tetrahydrofuran LTB4 receptor antagonist:
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Scheme 15
O I ~ / / B(OH)z
Br I ~ ~ , I ~ I o
O~O \ O \ Pd(PPh3)4, aq. Na2C03, THF
COOMe
(60)
o
o,
H2, Pd(C)
~ ono w I o w I
COOMe
(98)
OH
O
I / I / I 1 ) aq. LiOH
O~O \ O \ 2) HCI
COOMe 3) NaOH
( 100)
OH
O
I ~~ ~I
O~O \ O
COONa
(15)
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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).
Scheme 16
The following scheme illustrates a process for making Example
(16), a 2-substituted pyrrolidine LTB4 receptor antagonist:
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Scheme 16
N
O I w ~O-~ B(OH)2
Br ~ i / / O
I ~ O~O ~ I O ~ I Pd(PPh3)4, aq. Na2C03, THF
COOMe
(60)
p I
H2, Pd(C)
~' I
' 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)
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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).
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:
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Scheme 17
o w
o ~
Br ~ I ~ ~ B(oH)2
I ~ O~CI Pd(PPh3)4, aq. NaZC03, THF I ~ O~CI
(5g) (108)
I I
HO ~ ~ \ (110)
CN
known compound: RN# 152609-78-4 S ~ O
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, CH2C12 I \ I I 1) NaOH
O~O ~ O \ 2) HCI
CN
(114)
OH
S ~
I I I
o'~o ~ o
COOH
(y 7)
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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
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:
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Scheme 18
/
\ ~ \ ~ t-bromo-3-chloropropane ~ / ~ 1) KZCO3, Nal, 2-butanone
HO O CIO \ O
COOMe KZC03, DMF COOMe O OH
H I \
(30) (116) / OH
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 I \ 1)
\ / / / -+N CI
NHZS I / O~\/~O \ I O \ I I Me
COOMe 2) NaN3
(122)
NN-N O
S I I I 1) BF3EtZ0, CHZCIZ
/ O~O \ O~ 2) aq. NaOH
COOMe 3) aq. NCI
(124)
N~N OH
N I
S 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. I. Ikeda et al., Synthesis 1990, 415
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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).
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:
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Scheme 19
0 0 ~ ~
NHzNHCOOEt
O~O I ~ O
COOMe
(32)
EtO~N.N O
/ SOCI2
O~O ~ / O ~
COOMe
( 128)
N;N O
~ / I 1) BF3Et20, EtSH
O~O ~ O ~ 2) aq. NaOH
COOMe 3) aq. NCI
( 130)
N=N OH
S ~
O~O ~ O \
COOH
(19)
Reference for 1,2,3-thiadiazole formation: E. W. Thomas et al., J. Med. Chem.
1985, 28, 442.
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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
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:
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Scheme 20
c1
.s,.
\ N N
\ / / / CI~S.N:S~CI
/ O~O \ I O \ I (trithiazyl trichloride)
COOMe
(62)
S'N O
N ~ I I \ I / / I / I 1 ) BF3 EtzO, EtSH
/ O~O \ O \ 2) aq. NaOH
COOMe 3) aq. HCI
( 132)
S'N OH
N~ I
/ O'~O / 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).
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Scheme 21
The following scheme illustrates a process for making Example
(21), a 2-substituted 1,3,4-thiadiazole LTB4 receptor
antagonist:
Scheme 21
CN.N
S
O O \ Br
,B ~~/ known compound: RN 61929-24-6
O ~ \ I \ / I PCT W O 9730981
/ O~O / O \ PdCl2(dppf), Cs2C03, toluene
COOMe
(76)
//N'N O I \
\S ~ \ / I \ / I 1) BF3Et20, EtSH
/ O~O / O \ 2) aq. NaOH
COOMe 3) aq. HCI
(134)
//N'N OH
\
/ O~O ~ O \
COOH
(21 )
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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).
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Scheme 22
The following scheme illustrates a process for making Example
(22), a 5-substituted isothiazole LTB4 receptor antagonist:
Scheme 22
N ~~
S
O~ ~ B(OH)z
gr ~ ~' //\ known compound: RN 216971-00-5
I PCT W O 9855480
O~CI
Pd(PPh3)4, NazC03, EtOH, H20
(58)
HO \ O \
O
N ~ I , COOMe (30)
.S
O~CI
K2C03, KI, DMSO,
(136)
N/ I
'S I \ I I 1 ) BF3 EtzO, EtSH
O~O ~ O ~ 2) aq. NaOH
COOMe 3) aq. NCI
(138)
N~ I OH
I~ I I
o'~O
COOH
(22)
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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
Example (22).
Scheme 23
The following scheme illustrates a process for making Example
(23), a 2-substituted oxazole LTB4 receptor antagonist:
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Scheme 23
~N
O
Br
O O \ known compound: RN 125533-82-6
,B I~/ R. D. Miller et al., Chem. Mater. 1994,
O I \ I \ / I 6(7), 1023.
O~O ~ O \ PdCl2(dppf), Cs2C03, toluene
COOMe
(76)
N o I ~
O I \ I I 1) BF3~Et20, EtSH
O~O ~ O \ 2) aq. NaOH
COOMe 3) aq. HCI
( 140)
~N OH
o I ~ 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).
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Scheme 24
The following scheme illustrates a process for making Example
(24), a 3-substituted thiophane LTB4 receptor antagonist:
10
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Scheme 24
OH
S
I I ~ Et3SiH, TFA, benzene
O~O ~ O
CN
(114)
OH
S
1 ) aq. NaOH
2) HCI
CN
( 142)
OH
S
I I
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).
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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 I ~ 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 (690) 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 =
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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
- 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- Ho 0
/ O~CI COOMe
known compound: RN# 152609-76-2
J. S. Sawyer et al., J. Med. Chem. 1995,
38, 4411
O O
/ /
O~O ~ ~ O
COOMe
B. Preparation of 2-~3-[3-(4-acetyl-5-benzyloxy-2-
ethylphenoxy)propoxy]-2-propyl-phenoxy)benzoic acid methyl
ester.
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
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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
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, 100
ethyl acetate/90o hexane) of the residue provided 9.2 g
1
(720) of the title compound as a colorless oil. H NMR
(CDC13) 8 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 C37H4007: C, 74.48; H, 6.76. Found: C,
74.39; H, 6.77.
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O
O~O ~ ~ O ~
COOMe
O
HO ~~
O~O ~ ~ O
COO Me
C. Preparation of 2-(3-~3-[5-benzyloxy-2-ethyl-4-(2-
hydroxyacetyl)phenoxy]propoxy -2-propylphenoxy)benzoic acid
methyl ester.
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, 20~ ethyl acetate/80o hexane) of the residue provided
1
1.68 g (31°s) 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,
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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.
° I~
HO ~~
I / O~O ~ ( O ~ I
COOMe
/= N
o, I,
~ ono ~ 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
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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/90~
hexane) of the residue provided 89 mg (60) of the title
product as a colorless oil. 1H NMR (CDC13) 8 7.92 (s, 1H),
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, I/ / /
/ ono ~ I o ~
COOMe
~N OH
O ~
I / O~O ~ I O ~ I
COOMe
E. Preparation of 2-(3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl-
phenoxy)propoxy]-2-propylphenoxy]benzoic acid methyl ester.
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To a solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-oxazol-4-yl-
phenoxy)propoxyJ-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, 15~ ethyl acetate/85~
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
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 OH
/
/ O~O \ O
COOMe
/= N H
O ~
/ /
/ O~O ~ ~ O ~
COOH
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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 =
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 C3~H31N07: C, 69.62; H, 6.04; N, 2.71.
Found: C, 68.71; H, 5.82; N, 2.65.
30
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Example 2
Preparation of 2-(3-~3-[2-Ethyl-5-hydroxy-4-(3H-imidazol-4-
yl)phenoxy]propoxy?-2-propyl-phenoxy)benzoic acid
hydrochloride.
° I~
W
I / O~O ~ I O ~ I
COOMe
O
Ii i i
~ ,ono ~ I o
COOMe
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
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
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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/90o hexane) of
the residue provided 1.94 g (600) of the title compound as a
white solid. 1H NMR (CDC13) 8 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 C37H4~C107 (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.
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O
c1 I
I ~ O~O w I o w I
COOMe
S H
~N~
N ~
~ ono w I o w
COOMe
B. Preparation of 2-(3-i3-[5-benzyloxy-4-(2-benzylsulfanyl-
3H-imidazol-4-yl)-2-ethyl-phenoxy]propoxy~-2-
propylphenoxy)benzoic acid methyl aster.
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, 30o ethyl acetate/70~ hexane) of
the residue provided 376 mg (40~) of the title compound as a
1
yellow amorphous solid. H NMR (CDC13) 8 7.89 (d, J = 8 Hz,
1H), 7.36 (m, 9H), 7.20 (m, 5H), 7.21 (d, J = 9 Hz, 1H),
7.06 (d, J = 8 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.67 (d, J =
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8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J = 8 Hz, 1H), 5.07 (s,
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.
S H
~N~
N, I~
~ ono ~ I o ~
COOMe
S ,H
~N H
N ~
I / O~O w I O
COOMe
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C. Preparation of 2-(3-~3-[4-(2-benzylsulfanyl-3H-imidazol-
4-yl)-2-ethyl-5-hydroxyphenoxy]propoxy}-2-
propylphenoxy)benzoic acid methyl ester.
A solution of 2-(3-{3-[5-benzyloxy-4-(2-benzylsulfanyl-3H-
imidazol-4-yl)-2-ethyl-phenoxy]propoxy}-2-
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/80o
hexane) of the residue provided 154 mg (480) 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 C38H4~N206S: C, 69.92; H, 6.18; N, 4.29.
Found: C, 69.44; H, 6.25; N, 3.99.
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S H
~N~ H
N ~
/ /
/ O~O ~ ~ O ~
COOMe
~HCI
,H
~N H
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,
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TM
filtered through Celite , and the filtrate concentrated in
vacuo. The residue was diluted with water and adjusted to
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 C3~H33N206 (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 O
ono ~ I o
COOMe
/= N
s, \ I ,
~ 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
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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, 10~ ethyl acetate/90o hexane) of the residue provided
1
254 mg (50~) of the title compound as a colorless oil. H
NMR (CDC13) 8 8.91 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J = 8, 1
Hz, 1H), 7.84 (d, J = 1 Hz, 1H), 7.40 (m, 6H), 7.08 (m, 2H),
6.80 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz, 1H), 6.62 (s,
1H), 6.43 (d, J = 8 Hz, 1H), 5.16 (s, 2H), 4.21 (t, J = 6
Hz, 4H), 3.83 (s, 3H), 2.68 (m, 4H), 2.32 (quintet, J = 6
Hz, 2H), 1.56 (hextet, J = 8 Hz, 2H), 1.21 (t, J = 7 Hz,
3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass
calculated for C38H4~N06S (p+1): m/z = 638.2576. Found:
-1
638.2579. IR (CHC13, cm ) 2964, 1719, 1563, 1461.
/= N
S ~ I / / /
O~O ~ I O ~
COOMe
~N H
S ~
/ /
/ O~O \ I O \
COOMe
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B. Preparation of 2-(3-L3-(2-ethyl-5-hydroxy-4-thiazol-4-
yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl
ester.
A solution of 2-{3-f3-(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
water, once with saturated sodium bicarbonate solution,
dried (sodium sulfate), filtered, and concentrated in vacuo.
Chromatography (silica gel, 15~ ethyl acetate/85~ hexane) of
the residue provided 132 mg (65~) of the title compound as a
colorless oil. 1H NMR (CDC13) S 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), 2.56 (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 C31H34NO6S (p+1): m/z = 548.2107. Found:
548.2085.
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/=N H
S ~
0~0 ~ ~ O
COOMe
/= N H
S ~
O~O ~ I O
COOH
C. Preparation of 2-(3-L3-(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
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 (76~) 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 1H), 7.29 (m, 2H), 6.82(d, J = Hz, 1H),
(s, 8
6.71 (d, J 8 Hz, 1H) 6. (d, J 8 Hz, 1H) 6.54 (s,
= , 62 = ,
1H), 4.25 J = 6 Hz, 2H),4.22 (t, J = 6 Hz, 2H), 2.59
(t,
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(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 C30H32NO6S (p+1): m/z
-1
- 534.1950. Found: 534.1957. IR (CHC13, cm ) 2965, 1738,
1454.
Anal. Calcd for C30H31N06S: C, 67.52; H, 5.86; N, 2.62.
Found: C, 67.19; H, 5.72; N, 2.53.
Exan~le ~
Preparation of 2-(3-(3-[2-Ethyl-5-hydroxy-4-(2H-pyrazol-3-
yl)phenoxy]propoxy?-2-propyl-phenoxy)benzoic acid.
O
O \ I O \
COOMe
O
O~O O
COOMe
A. Preparation of 2-(3-(3-[5-benzyloxy-4-(3-
dimethylaminoacryloyl)-2-ethyl-phenoxy]propoxy)-2-
propylphenoxy)benzoic acid methyl ester.
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
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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, 30~
ethyl acetate/70~ hexane to ethyl acetate) of the residue
provided 2.1 g (63~) 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.
O
/ /
v w
O~O O
COOMe
N_N~H
/ /
O~O \ O
COOH
H. Preparation of 2-(3-t3-(5-benzyloxy-2-ethyl-4-(2H-
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
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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/69g 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 -
sample. 1H NMR (CDC13) 8 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.
Found: 607.2831. IR (CHC13, cm 1) 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.
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N_N.H I w
I w w I w I
/ 0~0 0
COOH
N_N.H H
i I
I ~ o'n'o ~ o ~
COOH
C. Preparation of 2-(3-~3-L2-ethyl-5-hydroxy-4-(2H-pyrazol-
3-yl)phenoxy]propoxy?-2-propylphenoxy)benzoic acid.
A solution of 2-(3-{3-f5-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
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, 15~ ethyl acetate/85~
hexane to 60~ ethyl acetate/40~ hexane) of the residue
provided 60 mg (24~) of the title compound as a white solid.
1H NMR (CDC13) S 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 = Hz, 1H),
8
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,
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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 C3pH33N2o6 (P+1): m/z = 517.2339. Found: 517.2334.
IR (CHC13, cm 1) 2965, 1738, 1454.
Anal. Calcd for C3pH32N2~6~ 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.
0
i i
I
O~O w O w
COOMe
_O
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
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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/90~ 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
for C38H40N07 (p+1): m/z = 622.2805. Found: 622.2817. IR
(CHC13, cm 1) 2964, 1720, 1461.
Anal. Calcd for C38H39N07: C, 73.41; H, 6.32; N, 2.25.
Found: C, 73.20; H, 6.34; N, 2.27.
i~ I ~ / / ~ / ~
/ O~O ~ O
COOMe
OH
/ O~O O
COOMe
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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
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.
Found: 532.2335. IR (CHC13, cm 1) 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.
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N-O H
/~ il
o'~o ~ o
COOMe
N-O H
O~O ~ ~ O w
COOH
C. Preparation of 2-~3-I3-(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
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
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(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 C3~H32N07
(p+1): m/z = 518.2179. Found: 518.2175.
Anal. Calcd for C3~H31N07: 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.
r I , ~ I_ ~
I / O~CI + HO O COOMe
Br I ~
~ ono ~ I o ~
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
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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, 6~ ethyl acetate/94~ hexane) of
the residue provided 1.34 g (68~) of the title compound as a
colorless oil. 1H 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) .
- O
Br I ~
I ~ ono ~ I o
COOMe
o I
I~ ~I ~I
O~O \ O
COOMe
B. Preparation of 2-i3-(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,
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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
(39~) of the title compound as a brown oil. H NMR (CDC13)
8 7.88 (dd, J = 8, 2 Hz, 1H), 7.79 (s, 1H), 7.20-7.50 (m,
6H), 7.10 (d, J 8 Hz, 1H),7.05 (d, J 8 Hz, 1H), 6.80
= =
(d, J Hz, 1H), 6.66 (d, J Hz, 1H),6.43 (m, 2H),
= =
8 8
5.16 (s, 2H),4.17 (t, = Hz,. 2H), 4.11(t, J = 6 Hz,
J 6
2H), 3.83 (s, 3H), 3.23 (s, 1H), 2.64 (t, J = 8 Hz, 2H),
2.53 (q, J 7 2H), 2.27(qui ntet,J 6 Hz, 2H), 1.53
= Hz, =
(m, 2H), 1.13(t, J = Hz, 3H), 0.89 (t, J = 7 Hz, 3H); TOF
7
MS ES+ mass calcu lated C37H 3906(p+1): m/z =
exact for
579.2747. Found: 579.2739.
I/
/ /
I / 0~0 w I o w I
COOMe
NN_N.H
I / O~O ~ I O ~ I
COOMe
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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 ester.
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, 10~ ethyl acetate/90~ hexane to 50~ ethyl
acetate/50~ hexane) of the residue provided 347 mg (88~
based upon recovered starting material) of the title
1
compound as a brown solid. H NMR (CDC13) 8 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 =
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 C37H4~N306 (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.
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NN-N'H p
O~O ~ I O w
COOMe
,H
N /
O
COOMe
D. Preparation of 2-(3-(3-I2-ethyl-5-hydroxy-4-(3ii-
[1,2,3]triazol-4-yl)phenoxy]-propoxy)-2-propyl-
phenoxy)benzoic acid methyl aster.
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
solution, dried (sodium sulfate), filtered, and concentrated
in vacuo. Chromatography (silica gel, 30~ ethyl acetate/70~
hexane to 50~ ethyl acetate/50~ hexane) of the residue
provided 180 mg (63~) 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,
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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~H34N3~6 (p+1): m/z = 532.2447.
Found: 532.2466. IR (CHC13, cm 1) 2964, 1718, 1453.
Anal. Calcd for C3~H33N3~6~ C. 67.78; H, 6.26; N, 7.90.
Found: C, 66.80; H, 6.02; N, 7.53.
H
,N_N. H
N ~
/ /
O~O ~ ~ O
COOMe
,N_N~H H
N ~
/ /
/ O~O
COOH
E. Preparation of 2-(3-~3-[2-ethyl-5-hydroxy-4-(3H-
[1,2,3]triazol-4-yl)phenoxy]-propoxy)-2-
propylphenoxy)benzoic acid.
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
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combined organic extracts were dried (sodium sulfate),
filtered, and concentrated in vacuo to provide 134 mg (86~)
1
of the title compound as a tan solid. H NMR (DMSO-d)
8 14 . 12 (bs, 1H) 10. 02 (bs,
98 (bs, . , 1H) , 8 .
1H) , 80 17 (bs,
1H), 7.77 (dd, 7, Hz, 1H), 7.60 (bs, 1H),7.47 (t, J
J = 2 =
8 Hz, 1H), 7.18 , 8 , , 7.14 (t, 8 Hz, 1H),
(t J Hz 1H) J =
=
6.82 (d, J = 8 1H), 6.68 (d, J = 8 Hz, 1H),6.57 (s,
Hz,
1H), 6.35 (d, J 8 1H), 4.22 (t, J = 6 Hz, 2H), 4.15
= Hz,
(t, J = 6 Hz, 2H), 2.54 (m, 4H), 2.25 (quintet,J = 6 Hz,
2H), 1.45 (hextet,J 8 2H), 1.11 (t, J 7 Hz, 3H),
= Hz, =
0.81 (t, J = 7 3H); TOF MS exact mass calculated
Hz, ES
for C29H32N306 (p+1): m/z = 518.2291. Found: 518.2302.
IR (CHC13, cm 1) 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-I3-(2-Ethyl-5-hydroxy-4-pyrrol-1-yl-
phenoxy)propoxy]-2-propyl-phenoxy~benzoic acid methyl ester.
OH 1 O
CN
OH I ~ OH
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-
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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 (2~) 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]-1X-pyrrole.
O ~ ~ p
\ N 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-
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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, 5$ ethyl
acetate/95~ 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.
~/ ~~ /~
Ho / o
/ O~CI + COOMe
CN I / /
/ O~O ~ ( O ~
COOMe
C. Preparation of 2-(3-[3-(5-benzyloxy-2-ethyl-4-pyrrol-1-
yl-phenoxy)propoxy]-2-propylphenoxy?benzoic acid methyl
ester.
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
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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.
/ /
O~O ~ ~ O
COOMe
OH
/ O~O ~ ~ O ~
COOMe
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D. Preparation of 2-~3-[3-(2-ethyl-5-hydroxy-4-pyrrol-1-yl-
phenoxy)propoxy]-2-propyl-phenoxy?benzoic acid methyl ester.
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, 10o ethyl acetate/90~ hexane) of
the residue provided 39 mg (23~) of the title compound as a
colorless oil. 1H NMR (CDC13) 8 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), 5.04 (bs, 1H), 4.19 (m, 2H), 3.83 (s,
3H), 2.64 (t, J = 8 Hz, 2H), 2.58 (q, J = 7 Hz, 2H), 2.32
(quintet, J = 6 Hz, 2H) , 1.55 (m, 2H) , 1. 14 (t, J = 7 Hz,
3H), 0.90 (t, J = 7 Hz, 3H); TOF MS ES exact mass
calculated for C32H36N06 (p+1): m/z = 530.2543. Found:
530.2516.
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Example 8
Preparation of 2-(3-{3-[4-(3-Hromo-11,2,4]thiadiazol-5-yl)-
2-ethyl-5-hydroxyphenoxy]-propoxy?-2-propylphenoxy)benzoic
acid.
Br I i i i
I
I ~ ono ~ o
COOMe
O
,e I i , i
o I ~ ono ~ I o ~
COOMe
A. Preparation of 2-(3-t3-L5-benzyloxy-2-ethyl-4-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-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 (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 30~ ethyl acetate/70o hexane) to give 7.70 g (84~)
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of the title compound. 1H NMR (CDC13) 8 7.86 (dd, J = 8, 2
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,
cm 1) 2964, 1720, 1604, 1453.
Anal. Calcd for C41H49B08: C, 72.35; H, 7.26. Found: C,
72.30; H, 7.12.
O
,B ~ / , /
~I ~I
O O O
COOMe
Br
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.
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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 (310 mg, 0.46 mmol),
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 35~ ethyl acetate/65~ hexane and filtered down a short
column of silica gel. The filtrate was concentrated in
vacuo. Chromatography (silica gel, hexane to 30~ 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.
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Br
S ~ i ~ \ ~ \ ~
~o o -o
COOMe
Br
N H
.s ~ \ / ~ / ~
/ oho \ 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.
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 (23~)
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of the title compound as a yellow solid. 1H NMR (DMSO-d6) 8
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
m/e 551 (p+NH4+-Br); IR (KBr, cm 1) 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-i3-[3-(2-Ethyl-5-hydroxy-4-thiophen-2-yl-
phenoxy)propoxy]-2-propyl-phenoxy~benzoic acid sodium salt.
A. Preparation of 2-i3-[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, 30~ ethyl acetate/70~ hexane) of the residue provided
an oil that was dissolved in ethanethiol (4 mL) and treated
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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 (50~) of the title
compound as a yellow film. 1H NMR (CDC13) 8 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).
B. Preparation of 2-~3-[3-(2-ethyl-5-hydroxy-4-thiophen-2-
yl-phenoxy)propoxy]-2-propylphenoxy)benzoic acid sodium
salt.
OH
I / ono ~ I o ~ I
COOMe
off
/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
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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 (98~) of the title compound as a green film. H NMR
(DMSO-d6) 8 7.71 = 8 Hz,
(d, J 1H), 7.42
(m, 2H),
7.31 (m,
2H), 7.10(m, 2H), 6.99(m, 1H), 6.76 (t, J = 7 2H),
Hz,
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 2H),
7 (m,
1.40 (m, 2H), 1.06 (t, J = 8 Hz, 3H), 0.77 (t, J 7 Hz,
=
+ 1 - Na+). (CHC1 , cm 2900,
3H); MS (p IR 1)
ES 3
m/e
533
1738, 1604, 1454.
2 0 Exa~le 10
Preparation of 2-(3-{3-[2-Ethyl-5-hydroxy-4-(1-methyl-1S-
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
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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 (95~) of the title
1
compound as a colorless oil. H NMR (CDC13) 8 7.47 (s, 1H),
7.38 (s, 1H), 3.90 (s, 3H).
H. Preparation of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(1-methyl-
iH-pyrazol-4-yl)phenoxy]-propoxyy-2-propylphenoxy)benzoic
acid methyl aster.
A mixture of 2-(3-~3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-y1)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
(~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
65~ ethyl acetate/35~ hexane) of the residue provided 710 mg
(76~) of the title compound. 1H 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),
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2.63 (t, J 8 Hz, 2H), 2.59 (q, J = 7 Hz, 2H), 2.30
=
(quintet, 6 Hz, 2H), 1.55 (hextet, J = 8 Hz, 2H), 1.23
J =
(t, J = 7 3H), 0.89 (t, = 7 Hz, 3H).
Hz, J
N,
-N ~ ~ ~ i i
~I ~I
~o o _o
COOMe
N, H
-N ~
ono ~ o
COOH
C. preparation of 2-(3-~3-L2-ethyl-5-hydroxy-4-(1-methyl-
1H-pyrazol-4-yl)-phenoxylpropoxy?-2-propylphenoxy)benzoic
acid.
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
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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/90~ methylene chloride) provided 338 mg (57~) 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
m/e 531 (p+1); IR (KBr, cm 1) 2961, 1697, 1602, 1460, 1222.
Anal. Calcd for C31H34N206: C, 70.17; H, 6.46; N, 5.28.
Found: C, 69.27; H, 6.08; N, 4.63.
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Example 11
Preparation of 2-{3-[3-(2-Ethyl-5-hydroxy-4-thiazol-2-yl-
phenoxy)propoxy]-2-propyl-phenoxy?benzoic acid.
O O
O-B ~ I / / / ~ N
~~ Br ---
~O O ~O
COOMe
O I w
/ / /
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.
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Chromatography (silica gel, hexane to 35~ ethyl acetate/65~
hexane) of the residue provided 282 mg (31~) of the title
compound. 1H NMR (CDC13) S 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
~o o ~o
COOMe
~N H
I ~ ono ~ I o ~ I
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 r~om
temperature for 3 h. The reaction mixture was diluted with
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water, concentrated in vacuo, and extracted with diethyl
ether. The organic layer was dried (magnesium sulfate),
filtered, and concentrated in vacuo. Chromatography (silica
gel, ethyl acetate/hexane) provided 107 mg (44~) of the
title compound. 1H NMR (CDC13) 8 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) .
__. ~N H
S
O~O O
COOMe
~N H
S ~ W
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
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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
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) S 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);
MS ES+ m/e 534 (p+1); IR (KBr, cm 1) 2957, 1695, 1599, 1457.
Anal. Calcd for C3~H31N06S: C, 67.52; H, 5.86; N, 2.62.
Found: C, 67.44; H, 5.95; N, 2.55.
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Example 12
Preparation of 2-(3-(3-[~4-(3,5-Dimethylisoxazol-4-yl)-2-
ethyl-5-hydroxyphenoxy]propoxy)-2-propylphenoxy)benzoic acid
sodium salt.
O O
I ~N
O,s ~ ~ / / ~ / ~ -~ \
/ O'~O ~ O ~ O
COOMe
NO ~ O
/
~O O ~O
COOMe
OH
N~ 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,
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concentrated in vacuo, diluted with methylene chloride, and
filtered down a short plug of silica gel with 20o 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
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 (23~) of the title compound as an
off-white solid. 1H NMR (DMSO-d6) 8 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.
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Example 13
Preparation of 2-~3-[3-(2-Ethyl-4-furan-2-yl-5-
hydroxyphenoxy)propoxy]-2-propylphenoxy?-benzoic acid sodium
salt.
Br I ~
~ ono w I o w
COOMe
H
Br I ~ ~ I ~ I
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 (520) 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
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(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
(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
TBS
Br ~
O~O w I O
COOMe
B. Preparation of 2-(3-{3-[4-bromo-5-(tert-
butyldimethylsilanyloxy)-2-ethylphenoxy]-propoxy}-2-
propylphenoxy)benzoic acid methyl ester.
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
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provide 1.1 g (910) of the title compound as a colorless
oil. 1H NMR (CDC13) 8 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,
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 I ~
O
COOMe
OH
O,
O~O ~ 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
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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/90~ hexane) of the residue provided 0.8 g
1
(94~) 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 =
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,
O~O ~ O
COOMe
H
O, ~ ~ ~ ~ ~
O~O \ O \
COONa
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D. Preparation of 2-(3-[3-(2-ethyl-4-furan-2-yl-5-
hydroxyphenoxy)propoxy]-2-propylphenoxy)benzoic 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
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 (66~) 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 C31H33O7 (p+1): m/z = 517.2226.
-1
Found: 517.2230. IR (KBr, cm ) 3400, 2961, 1599, 1460.
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Example 14
Preparation of 2-(3-(3-[2-Ethyl-5-hydroxy-4-furan-3-
yl]phenoxy]propoxy~-2-propylphenoxy)benzoic acid.
OTBS
Br ~ / /
/ Ono ~ I o ~
COOMe
H
O ~
I~ /I /I
/ O~O \ O
COOMe
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, 15~
ethyl acetate/85~ hexane) of the residue provided 0.29 g
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(17~) of the title compound as a yellow oil. TOF MS ES
exact mass calculated for C32H3507 (p+1): m/z = 531.2383.
Found: 531.2396.
H
O ~
/ /
O~O ~ ~ O
COOMe
H
O ~
/
/ O~O \ O \
COOH
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, 2~ methanol/98% chloroform) of the residue gave 45 mg
of material that was again submitted to chromatography
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(silica gel, 1o methanol/99~ chloroform) to provide 25 mg
(15~) of the title compound as an oil.
TOF MS ES exact mass calculated for C31H3307 (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.
° I
Br ~~ / /
I / O~O ~ I O ~ I
COOMe
\~ o I /
I~ /I /I
/ o'~o ~ o
COOMe
A. Preparation of 2-~3-[3-(5-benzyloxy-2-ethyl-4-furan-3-
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 (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 te-trahydrofuran (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
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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
(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 ~
COOMe
B. Preparation of 2-(3-(3-[2-ethyl-5-hydroxy-4-
(tetrahydrofuran-3-yl)phenoxy]-propoxy~-2-
propylphenoxy)benzoic acid methyl ester.
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-furan-3-yl-
phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester
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(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),
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 OH
/ ono ~ o
COOMe
O H
/ ono ~ I o ~
COONa
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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
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 1VMR (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,
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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.
O
Br ~ ~
~ O~O ~ I O
COOMe
O O ~ O'~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
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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/90~ hexane) of the residue provided 2.6 g
1
(76~) of the title compound as a solid. H 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 =
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
C44H53N2~8 (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.
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i i~ i~
0 0 ~ o'~o ~ o
COOMe
H
o O ~ 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 ,
and the filtrate concentrated in vacuo to provide 0.76 g
1
(88~) of the title compound as a colorless oil. H NMR
(CDC13) 7.87 (dd, J = 8, Hz, 1H), 7.37(dt, J 8, 2
8 2 = Hz,
1H), 7.10 (d, J Hz, 1H), 7.04 (d, J 9 1H), 6.91
= = Hz,
9
(s, 1H), 6.81 (d, = 9 Hz, 1H), 6.67 (d, J Hz, 1H),
J =
9
6.47 (s, 1H) 6.44 (d, J Hz, 1H) 5.09(m, 1H) 4.18
, = 9 , , (d,
J 6 2H), 4.14 (t, J 6 2H), 3.8 4 3H), 3.45
= Hz, = Hz, (s,
(m, 2H), 2.64 (t, = 8 Hz, 2H), 2.54 (m, 3H), 2.25 (m, 5H),
J
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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).
H
il i~
O O ~ O~O \ O \
COOMe
H
O O ~ O~O \ O
COOLi
C. Preparation of 2-(4-~3-[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
dissolved in water. The resulting mixture 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
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+ -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
i
H
O~O ~ O \
COOH
D. Preparation of 2-(3-[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
residue provided a tan solid. This material was dissolved
in ether and treated with gaseous HC1. This mixture was
concentrated in vacuo to provide 48 mg (52~) of the title
compound. 1H NMR (DMSO-d6) 8 12.80 (bs, 1H), 10.12 (s, 1H),
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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.
S
Br ~ I i ~ ~ o 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-
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
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saturated sodium chloride solution. The organic layer was
dried (magnesium sulfate), filtered, and concentrated in
vacuo. Chromatography (silica gel, 5o ethyl acetate/95~
hexane) of the residue provided 1.54 g (80~) of the title
1
product as a white solid: mp 65-67 °C. H 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 Ho ~ o
O~CI CN
Known compound:
Sawyer et al.,
J. Med. Chem. 1995, 38, 4411.
\ I o I
I I I
O
CN
B. Preparation of 2-[2-propyl-3-[3-[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-
propylphenol (0.82 g, 3.2 mmol), potassium iodide (0.21 g,
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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, 5o ethyl
acetate/95o hexane) of the residue provided 1.31 g (670) of
product as a colorless oil. H NMR (CDC13) 8 7.66
the title 1
(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.
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C. Preparation of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-
(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzonitrile.
o I
o'~o ~ o
CN
OH
\ ( \ ~ 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, 25o ethyl acetate, 75% hexane)
provided 400 mg (52~) 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 =
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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).
D. Preparation of 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-
(thiophen-3-yl)phenoxy]propoxy]phenoxy]benzoic acid hydrate.
OH
i I i
O~O \ O
CN
OH
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
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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
(br), 2961, 1697, 1457, 1110. Anal. Calcd for C31H3206S '
H20: C, 67.62; H, 6.22. Found:. C, 67.34; H, 5.87.
The previously described LTB4 antagonists and anti-
cangel agents used in the composition and method of the
invention are often advantageously used in the form of salt
derivatives which are an additional aspect of the invention.
ln~hen compounds of the invention possess an Acidic Groups)
or other reactive group, 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 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 LTB4 antagonist compounds of
this invention (see, for example, S. M. Berge, et al.,
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"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 LTB4 antogonist and
anti-cancer compounds used in the invention which have
chemically or metabolically 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
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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, tert-butyl, morpholinoethyl,
and N,N-diethylglycolamido.
Esters of carboxylic acids are preferred prodrugs of
the compounds of the composition of the invention.
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-
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 LTBg compounds and anti-cancer compounds of
the compositions of the wherein the acid, salt and prodrug
derivatives thereof are respectively selected from:
carboxylic acid, sodium salt, and ester prodrug.
The compositions of the present invention are a
combination of therapeutically effective amounts of the
leukotriene (LTB4) antagonists, noted above, and a
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therapeutically effective amount of the anti-cancer agents
noted above. The composition may be formulated with common
excipients, diluents or carriers, and compressed into
tablets, or formulated elixirs or solutions for convenient
oral administration or administered by intramuscular
intravenous routes. The compounds can be administered
transdermally and maybe formulated as sustained relief
dosage forms and the like.
In another embodiment, the invention relates to a
method of treating a patient suffering from a non-multi drug
resistant cancerous condition which comprises the separate
administration of a therapeutically effective amount of the
leukotriene (LTB4) antagonists, and the anti-cancer agent.
V~hen administered separately, the leukotriene (LTBg)
antagonists, and the anti-cancer agent may be administered
on a different schedule. One may be administered before the
other as long as the time between the two administrations
falls within a therapeutically effective interval.
Therapeutically effective interval is a period of time
beginning when one of either (a) the leukotriene (LTB4)
antagonist or (b) the anti-cancer agent is administered to a
human and ending at the limit of the beneficial effect in
the treatment of cancer of the combination of (a) and (b).
The methods of administration of the leukotriene LTB4
antagonist and the anti-cancer agent may vary. Thus, one
agent may be administered orally, while the other is
administered intravenously. It is possible that one of the
products may be administered as a continuous infusion while
the other is provided in discreet dosage forms. It is
particularly important that the anti-cancer drug be given in
the manner known to optimize its performance.
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Pharmaceutical Compositions of the Invention
Preferably compounds of the invention 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 anti-cancer agent (e. g., a 2',2'-
difluoronucleoside and an LTBg antagonist, such as the
compound of Formula A, 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
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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. When 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
can be in the form of tablets, pills, powders, lozenges,
elixirs, suspensions, emulsions, solutions, syrups,
injectable liquids, 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
sterile water, sterile saline, or sterile water or saline
containing sugars and/or buffers at a concentration of about
0.05 to about 5.0 mg/ml in a 4~ dextrose/0.5~ 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
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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
inhalation administration, and from about 25 to 500 mg in
the case of oral or rectal administration. 0.5 to 20 mg/kg,
of Active Ingredient may be administered although it will,
of course, readily be understood that Dosages from about 0.5
to about 300 mg/kg per day, preferably 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.
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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 22 are
illustrative only and are not intended to limit the scope of
the invention in any way. "Active Ingredient", refers to a
2',2'-difluoronucleoside or a compound according to Formula
A, Formula (I) or (II) or a pharmaceutically acceptable
salt, solvate, or prodrug thereof.
In one embodiment the compositions of the present
invention are a combination of therapeutically effective
amounts of the leukotriene (LTBg) antagonists, noted above,
and a therapeutically effective amount of a 2',2'-
difluoronucleoside anti-cancer agent. The composition may
be formulated with common excipients, diluents or carriers,
and compressed into tablets, or formulated elixirs or
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solutions for convenient oral administration or administered
by intramuscular intravenous routes. The compounds can be
administered transdermally and maybe formulated as sustained
relief dosage forms and the like.
In another embodiment, the 2',2'-difluoronucleoside
anti-cancer agents are formulated independently of the
leukotrienes (LTB4) antagonists and are administered
separately. The anti-cancer agents may be formulated with
common excipients, diluents or carriers and administered by
intravenous infusion. On the other hand, the anti-cancer
agents may be formulated into liquids suitable for oral
administration. Anti-cancer agents may also be compressed
into tablets and administered orally. If the anti-cancer
agents and the leukotrienes (LTBg) antagonists are
administered separately, the anti-cancer agents may be
administered before, after or during the administration of
the leukotriene (LTB4) antagonists. If the anti-cancer
agents are administered separately from the leukotrienes
(LTBg) antagonists, they must be administered within a
therapeutically effective interval.
The method of treating a human patient according to the
present invention includes both the administration of the
combination of leukotriene (LTB4) antagonists and an anti-
cancer agent as well as the separate administration of the
leukotriene (LTB4) antagonists and the anti-cancer agent.
When administered separately, the leukotriene (LTBg)
antagonists are formulated into formulations which may be
administered by the oral and rectal routes, topically,
parenterally, e.g., by injection and by continuous or
discontinuous intra-arterial infusion, in the form of, for
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example, tablets, lozenges, sublingual tablets, sachets,
cachets, elixirs, gels, suspensions, aerosols, ointments,
for example, containing from 1 to 10~ by weight of the
active compound in a suitable base, soft and hard gelatin
capsules, suppositories, injectable solutions and
suspensions in physiologically acceptable media, and sterile
packaged powders adsorbed onto a support material for making
injectable solutions. Advantageously for this purpose,
compositions 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
inhalation administration, and from about 25 to 500 mg in
the case of oral or rectal administration) of a compound of
Formula I or Formula II. 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 including the condition to be treated, the
choice of compound to be administered and the choice of
route of administration and therefore the above preferred
dosage range is not intended to limit the scope of the
present invention in any way.
The formulations useful for separate administration of
the leukotriene (LTBg) antagonists will normally consist of
at least one compound selected from the compounds of Formula
A and Formula I mixed with a carrier, or diluted by a
carrier, or enclosed or encapsulated by an ingestible
carrier in the form of a capsule, sachet, cachet, paper or
other container or by a disposable container such as an
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ampoule. A carrier or diluent may be a solid, semi-solid or
liquid material which serves as a vehicle, excipient or
medium for the active therapeutic substance. Some examples
of the diluents or carrier which may be employed in the
pharmaceutical compositions of the present invention are
lactose, dextrose, sucrose, sorbitol, mannitol, propylene
glycol, liquid paraffin, white soft paraffin, kaolin, fumed
silicon dioxide, microcrystalline cellulose, calcium
silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol,
starch, modified starches, gum acacia, calcium phosphate,
cocoa butter, ethoxylated esters, oil of theobroma, arachis
oil, alginates, tragacanth, gelatin, syrup, methyl
cellulose, polyoxyethylene sorbitan monolaurate, ethyl
lactate, methyl and propyl hydroxybenzoate, sorbitan
trioleate, sorbitan sesquioleate and oleyl alcohol and
propellants such as trichloromonofluoromethane,
dichlorodifluoromethane and dichlorotetrafluoroethane. In
the case of tablets, a lubricant may be incorporated to
prevent sticking and binding of the powdered ingredients in
the dies and on the punch of the tableting machine. For
such purpose there may be employed for instance aluminum,
magnesium or calcium stearates, talc or mineral oil.
Preferred pharmaceutical forms of the present invention
are capsules, tablets, suppositories, injectable solutions,
creams and ointments. Especially preferred are formulations
for inhalation application, such as an aerosol, and for oral
ingestion.
The following formulation examples may employ as active
compounds any of the leukotriene (LTB4) antagonists noted
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above. The examples are illustrative only and are not
intended to limit the scope of the invention in any way.
FORMULATION EXAMPLE 1
Hard gelatin capsules are prepared using the following
ingredients:
Quantity
(mg/capsule)
3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-(4-carboxy-
phenoxy)phenyl)propanoic acid 250
Starch 200
Magnesium stearate 10
The above ingredients are mixed and filled into hard
gelatin capsules in 460 mg quantities.
FORMULATION EXAMPLE 2
A tablet is prepared using the ingredients below:
Quantity
(mg/capsule)
1-(4-(Carboxymethoxy)phenyl)-1-(1H-
tetrazol-5-yl)-6-(2-ethyl-4-(4-
fluorophenyl)-5-hydroxyphenoxy)hexane 250
Cellulose, microcrystalline 400
Silicon dioxide, fumed 10
Magnesium stearate 5
The components are blended and compressed to form
tablets each weighing 665 mg.
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FORMULATION EXAMPLE 3
An aerosol solution is prepared containing the
following components:
Weight o
3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4-
(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]-
9H-xanthene]]propanoic acid 0.25
Ethanol 30.00
Propellant 11 10.25
(trichlorofluoromethane)
Propellant 12 29.75
(Dichlorodifluoromethane)
Propellant 114 29.75
(Dichlorotetrafluoroethane)
The active compound is dissolved in the ethanol and the
solution is added to the propellant 11, cooled to -30°C. and
transferred to a filling device. The required amount is then
fed to a container and further filled with the pre-mixed
propellants 12 and 114 by means of the cold-filled method or
pressure-filled method. The valve units are then fitted to
the container.
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FORMULATION EXAMPLE 4
Tablets each containing 60 mg of active ingredient are
made up as follows:
2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]-
benzoic acid sodium salt 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone 4 mg
(as 10~ solution in water)
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 solution of polyvinylpyrrolidone is mixed
with the resultant powders which are then passed through a
No. 14 mesh U.S. sieve (1.4 mm). The granules so produced
are dried at 50-60° and passed through a No. 18 mesh U.S.
sieve (1.00 mm). 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 compressed on a tablet machine to yield
tablets each weighing 150 mg.
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FORMULATION EXAMPLE 5
Capsules each containing 80 mg of medicament are made
as follows:
5-[3-[2-(1-Carboxy)ethyl]-4-[3-[2-ethyl-4-(4-
fluorophenyl)-5-hydroxyphenoxy]propoxy]-
phenyl]-4-pentynoic acid 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 mesh U.S.
sieve (355 Vim), and filled into hard gelatin capsules in 200
mg quantities.
FORMULATION EXAMPLE 6
Suppositories each containing 225 mg of active
ingredient are made as follows:
3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2-
ethylphenoxy)propoxy)-2-carboxymethyl-
1,2,3,4-tetrahydronaphthalen-1(2H)-
one)propanoic acid 225 mg
Unsaturated or saturated fatty
acid glycerides to 2,000 mg
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The active ingredient is passed through a No. 60 mesh
U.S. sieve (250 Vim) and suspended in the fatty acid
glycerides previously melted using the minimum heat
necessary. The mixture is then poured into a suppository
mold of nominal 2 g capacity and allowed to cool.
FORMULATION EXAMPLE 7
Suspensions each containing 50 mg of medicament per 5
mL dose are made as follows:
2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)
5-hydroxyphenoxy]propoxy]phenoxy]benzoic
acid 50 mg
Sodium carboxymethyl cellulose 50 mg
Sugar 1 g
Methyl paraben 0.05 mg
Propyl paraben 0.03 mg
Flavor q.v.
Color q.v.
Purified water to 5 mL
The medicament is passed through a No. 45 mesh U.S.
sieve (355 ~,m) and mixed with the sodium
carboxymethylcellulose, sugar, and a portion of the water to
form a suspension. The parabens, flavor and color are
dissolved and diluted with some of the water and added, with
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stirring. Sufficient water is then added to produce the
required volume.
FORMULATION EXAMPLE 8
Hard gelatin capsules are prepared using the following
ingredients:
Quantity (mg/capsule)
1-(4-amino-5-methyl-2-oxo-1H-
pyrimidin-1-yl)-2-desoxy- 250
2',2'-difluororibose
Starch dried 200
Magnesium stearate 10
The above ingredients are mixed and filled into hard gelatin
capsules in 460 mg quantities.
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FORMULATION EXAMPLE 9
A tablet formula is prepared using the ingredients below:
Quantity (mg/tablet)
1-(2-oxo-4-amino-1H-pyrimidin-
1-yl)-2-desoxy-2',2'-difluoro- 250
ribose
Cellulose, microcrystalline
400
Silicon dioxide, fumed
15 Stearic acid 5
The components are blended and compressed to form tablets
each weighing 665 mg.
FORMULATION EXAMPLE 10
An aerosol solution is prepared containing the following
components:
Weight . o
1-(2,4-dioxo-1H,3H-pyrimidin-
1-yl)-2-desoxy-2',2'-difluoro-
ribose 0.25
Ethanol 29.75
Propellant 22 70.00
(Chlorodifluoromethane)
The active compound is mixed with ethanol and the mixture
added to a portion of the propellant 22, cooled to -
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30° C. and transferred to a filling device. The
required amount is then placed in a stainless steel
container and diluted with the remainder of the propellant.
The valve units are then fitted to the container.
FORMULATION EXAMPLE 11
Tablets each containing 60 mg of active ingredient are made
up as follows:
1-(4-amino-2-oxo-1H-pyrimidin-
1-yl)-2-desoxy-2',2'-difluoro-
ribose 60 mg
Starch 45 mg
Microcrystalline cellulose
35 mg
Polyvinylpyrrolidone 4 mg
(as 10o solution in water)
Sodium carboxymethyl starch
4.5 mg
Magnesium stearate 0.5 mg
Talc 1 mg
The difluoronucleoside starch and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The
solution of polyvinylpyrrolidone is mixed with the resultant
powders which are then passed through a No. 14 mesh U.S.
sieve. The granules so produced are dried at 50°-
60° C. and passed through a No. 18 mesh U.S. sieve.
The sodium carboxymethyl starch, magnesium stearate and
talc, previously passed through a No. 60 mesh U.S. sieve,
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are then added to the granules which, after mixing, are
compressed on a tablet machine to yield tablets each
weighing 150 mg.
FORMULATION EXAMPLE 12
Capsules each containing 80 mg of medicament are made as
follows:
1-(4-amino-2-oxo-1H-pyrimidin-
1-yl)-2-desoxy-2',2'-difluor-
oxylose 80 mg
Starch 59 mg
Microcrystalline cellulose
59 mg
Magnesium stearate 2 mg
The active ingredient, cellulose, starch and magnesium
stearate are blended, passed through a No. 45 mesh U.S.
sieve, and filled into hard gelatin capsules in 200 mg
quantities.
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FORMULATION EXAMPLE 13
Suppositories each containing 225 mg of nucleoside are made
as follows:
1-(2,4-dioxo-1H,3H-pyrimidin-
1-yl)-2-desoxy-2',2'-difluoro-
ribose 225 mg
Saturated fatty acid 2 g
glycerides to
The nucleoside is passed through a No. 60 mesh U.S. sieve
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 2
g capacity and allowed to cool.
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FORMULATON EXAMPLE 14
Suspensions each containing 50 mg of medicament per 5 ml
dose are made as follows:
1-(4-amino-5-methyl-2-oxo-1H-
pyrimidin-1-yl)-2-desoxy-2',2'-
difluororibose 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 5, ml
FORMULATION EXAMPLE 15
An intravenous formulation is prepared as follows:
1-(4-amino-2-oxo-1H-pyrimidin
1-yl)-2-desoxy-2',2'-difluoro
ribose 100 mg
isotonic saline 1000 ml
The solution of the above ingredients is administered
intravenously at a rate of 1 ml/minute to a mammal in need
of treatment from susceptible neoplasms.
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FORMULATION EXAMPLE 16
Hard gelatin capsules are prepared using the following
ingredients:
Quantity
(mg/capsule)
3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-
hydroxyphenoxy)propoxy)-6-(4-carboxy-
phenoxy)phenyl)propanoic acid
250
2',2'-Diflouro-2'-deoxycytidine monohydrochloride
250
Starch 200
Magnesium stearate 10
The above ingredients are mixed and filled into hard
gelatin capsules in 710mg quantities.
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FORMULATION EXAMPLE 17
A tablet is prepared using the ingredients below:
Quantity
(mg/capsule)
1-(4-(Carboxymethoxy)phenyl)-1-(1H-
tetrazol-5-yl)-6-(2-ethyl-4-(4-
fluorophenyl)-5-hydroxyphenoxy)hexane
250
2',2'-Difluoro-2'-deoxycytidine monochloride 250
Cellulose, microcrystalline 400
Silicon dioxide, fumed 10
Magnesium stearate 5
The components are blended and compressed to form
tablets each weighing 915 mg.
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FORMULATION EXAMPLE 18
An aerosol solution is prepared containing the
following components:
Weight
15
3-[4-[7-Carboxy-9-oxo-3-[3-[2-ethyl-4-
(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]-
9H-xanthene]]propanoic acid 0.25
2',2'-difluoro-2'-deoxycytidine monohydrochloride
0.25
Ethanol 30.00
Propellant 11 10.00
(trichlorofluoromethane)
Propellant 12 29.75
(Dichlorodifluoromethane)
Propellant 114 29.75
(Dichlorotetrafluoroethane)
The active compound is dissolved in the ethanol and the
solution is added to the propellant 11, cooled to -30°C. and
transferred to a filling device. The required amount is then
fed to a container and further filled with the pre-mixed
propellants 12 and 114 by means of the cold-filled method or
pressure-filled method. The valve units are then fitted to
the container.
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FORMULATION EXAMPLE 19
Tablets each containing 60 mg of active ingredient are
made up as follows:
2-[2-Propyl-3-[3-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]-
benzoic acid sodium salt 60 mg
2',2'-difluoro-2'deoxycytidine
monohydrochloride 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone 4 mg
(as 10~ solution in water)
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1 mg
Total 210 mg
The active ingredient, starch and cellulose are passed
through a No. 45 mesh U.S. sieve (355 Vim) and mixed
thoroughly. The solution of polyvinylpyrrolidone is mixed
with the resultant powders which are then passed through a
No. 14 mesh U.S. sieve (1.4 mm). The granules so produced
are dried at 50-60° and passed through a No. 18 mesh U.S.
sieve (1.00 mm). The sodium carboxymethyl starch, magnesium
stearate and talc, previously passed through a No. 60 mesh
U.S. sieve (250 ~.m), are then added to the granules which,
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after mixing, are compressed on a tablet machine to yield
tablets each weighing 210 mg.
FORMULATION EXAMPLE 20
Capsules each containing 80 mg of medicament are made
as follows:
5-[3-[2-(1-Carboxy)ethyl]-4-[3-[2-ethyl-4-(4-
fluorophenyl)-5-hydroxyphenoxy]propoxy]-
phenyl]-4-pentynoic acid 80 mg
2',2'-difluoro-2'deoxycytidine
monohydrochloride 80 mg
20
Starch 59 mg
Microcrystalline cellulose 59 mg
Magnesium stearate 2 mg
Total 280 mg
The active ingredient, cellulose, starch and magnesium
stearate are blended, passed through a No. 45 mesh U.S.
sieve (355 ~,m), and filled into hard gelatin capsules in 280
mg quantities.
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FORMULATION EXAMPLE 21
Suppositories each containing 225 mg of active
ingredient are made as follows:
3-(5-(6-(4-(4-Fluorophenyl)-5-hydroxy-2-
ethylphenoxy)propoxy)-2-carboxymethyl-
1,2,3,4-tetrahydronaphthalen-1(2H)-
one)propanoic acid 225 mg
2',2'-difluoro-2'-deoxycytidine monochloride 225 mg
Unsaturated or saturated fatty
acid glycerides to 2,000 mg
The active ingredient is passed through a No. 60 mesh
U.S. sieve (250 Vim) and suspended in the fatty acid
glycerides previously melted using the minimum heat
necessary. The mixture is then poured into a suppository
mold of nominal 2 g capacity and allowed to cool.
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FORMULATION EXAMPLE 22
Suspensions each containing 50 mg of medicament per 5
mL dose are made as follows:
2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-
5-hydroxyphenoxy]propoxy]phenoxy]benzoic
acid 50 mg
2',2'-difluoro-2'-deoxycytidine
monohydrochloride 50 mg
Sodium carboxymethyl cellulose 50 mg
Sugar 1 g
Methyl paraben 0.05 mg
Propyl paraben
0.03 mg
Flavor q .v.
Color q .v.
Purified water to 5 mL
The medicament is passed through a No. 45 mesh U.S. sieve
(355 E.tzn) and mixed with the sodium carboxymethylcellulose,
sugar, and a portion of the water to form a suspension. The
parabens, flavor and color are dissolved and diluted with
some of the water and added, with stirring. Sufficient
water is then added to produce the required volume.
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Pharmaceutical Compositions of the Invention
The pharmaceutical composition of the invention
comprises as essential ingredients:
(a) an LTB4 antagonist, and
(b) an anti-cancer agent.
When the pharmaceutical composition of the invention is
prepared in injectable form it is a composition comprising
as ingredients:
(a) an LTB4 antagonist,
(b) an anti-cancer agent, and
(c) an injectable liquid carrier.
Pharmaceutically acceptable carriers are those well known in
the medical arts, such as sterile water, sterile water
containing saline, and sterile water containing sugars
and/or saline.
atio and Amount of Ingredients in the Composition of the
Invention
The essential ingredients (a) an LTB4 antagonist and
(b) anti-cancer compound are present in the formulation in
such proportion that a dose of the formulation provides a
pharmaceutically effective amount of each ingredient to the
patient being treated. Typically, the weight ratio of LTBg
antagonist to anti-cancer agent 1:100 to 100 to 1,
preferable from 10:1 to 1:10 and most preferable from 1:4 to
4:1.
The leukotriene (LTB4) antagonists are generally
administered prior, during and after the 2',2'-
difluoronucleoside anti-cancer agent is administered. If
the leukotriene (LTB4) antagonists are administered after
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the 2',2'-difluoronucleoside anti-cancer agent they should
be administered within a therapeutically effective interval.
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ASSAY EXAMPLE 1
The Nude Mouse Xenograft test used to evaluate anti-
oncolytic agents of this invention is well known and
generally described in the textbook; Beverly A Teicher,
Editor, Anticancer Drug Development Guide, Humana Press,
Totowa, New Jersey, 1997, p.75-124 (ISBN 0-89603-461-5); the
disclosure of which is incorporated herein by reference.
The xenograft test is more particularly described as
follows:
Male or female nude mice, selected as appropriate to
the gender of the tumor (Charles River), were treated with
total body gamma Radiation (450 rads). After 24 hours,
human LNCaP and DU-145 prostate carcinomas, Panc-1 and BxPC-
3 pancreatic carcinomas, and H460 and Calu-6 non-small cell
lung carcinomas (all carcinomas available from American Type
Culture Collection, Manassas, VA) prepared from a brie of
donor tumors (5 x 106 cells) were implanted subcutaneously
in a hind-leg of the mice. The mice were treated with 2-[2-
propyl-3-[3-[2-ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy] benzoic acid (Formula
IV), at dosages of 30, 100, 200, or 300 mg per kilogram
daily, administered orally, beginning 4 days after the tumor
cell implantation. Gemcitabine (60 mg/kg) was administered
intraperitoneally.
Tumor response was monitored by tumor volume
measurement performed twice per week over the course of 60-
90 days. Body weights were determined as a general
measurement of toxicity. The mice were divided into an
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untreated control group and multiple treatment groups with
five mice in each group.
The data was analyzed by determining the mean tumor
volume for the control group and each treatment group over
the course of the experiment and calculated the tumor growth
delay as the difference in days for the treatment versus the
control tumors to reach the volume of 1000 mm3.
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Table 1
Mouse Xenograft Test Results
Growth Delay of Prostate Tumor~l~
Treatment dose dose TGD TGD, sem
Formula IV GEM
Formula IV 30 - 1.2 0.30
Formula IV 100 - 2.0 0.30
Formula IV 200 - 2.2 0.30
GEM - 60 12.2 0.50
Formula IV 30 60 43.2 3.00
+ GEM
Formula IV 100 60 51.2 3.50
+ GEM
(1) - LNCaP prostate carcinoma
Formula IV = the LTB4 antagonist, 2-[2-propyl-3-[3-[2-
ethyl-5-hydroxy-4-(4-
fluorophenyl)phenoxy]propoxy]phenoxy]benzoic acid
GEM = gemcitabine hydrochloride, a 2',2'-
difloronucleoside anti-cancer agent, product of Eli
Lilly and Company
LNCaP = LNCaP Prostate Carcinoma
dose = milligrams per kilogram mouse body weight
TGD = average tumor growth delay in days
sem = standard error of the mean
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Table 2
Mouse Xenograft Test Results
Growth Delay of Prostate Tumor~2~
Treatment dose dose TGD TGD, sem
Formula IV GEM
Formula IV 30 - 5.8 0.50
Formula IV 100 - 7.7 0.60
Formula IV 300 - 12.7 1.00
GEM - 60 9.6 0.80
Formula IV 30 60 15.6 1.40
+ GEM
Formula IV 100 60 25.2 2.20
+ GEM
(2) - DU-145 prostate carcinoma
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Table 3
Mouse Xenograft Test Results
Growth Delay of Pancreatic Tumor~3~
Treatment dose dose TGD TGD, sem
Formula IV GEM
Formula IV 30 - 7.4 0.50
Formula IV 100 - 21.6 2.00
Formula IV 300 - 30.2 3.20
GEM - 60 17.1 1.50
Formula IV 30 60 22.9 1.90
+ GEM
Formula IV 100 60 27.0 2.30
+ GEM
(3) - tumor is BxPC3 pancreatic cancer
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Table 4
Mouse Xenograft Test Results
Growth Delay of Pancreatic Tumor~4~
Treatment dose dose TGD TGD, sem
Formula IV GEM
Formula 30 - 10.2 1.40
IV
Formula 100 - 16.7 2.00
IV
Formula 200 - 19.4 2.40
IV
GEM - 60 7.70 0.80
Formula 30 60 18.2 1.50
IV
+ GEM
Formula 100 60 23.3 2.30
IV
+ GEM
Formula 200 60 29.1 3.00
IV
+ GEM
(4) - tumor is Panc-1 pancreatic cancer
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Table 5
Mouse Xenograft Test Results
Growth Delay of non-Small cell Lung Tumor~s~
Treatment dose dose TGD TGD, sem
Formula GEM
IV
Formula IV 30 - 10.9 1.00
Formula IV 100 - 13.2 1.20
Formula IV 200 - 13.9 1.30
GEM - 60 9.3 0.90
Formula IV 30 60 20.2 2.00
+ GEM
Formula IV 100 60 21.3 2.20
+ GEM
Formula IV 200 60 32.0 3.10
+ GEM
(5) - non-Small cell Lung tumor is Human
H460 NSCLC
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Table 6
Mouse Xenograft Test Results
Growth Delay of non-Small cell Lung Tumor~6~
Treatment dose dose TGD TGD, sem
Formula GEM
IV
Formula IV 30 - 7.4 0.60
Formula IV 100 - 10.0 0.80
Formula IV 200 - 17.9 1.60
GEM - 60 14.0 1.20
Formula IV 30 60 17.4 1.60
+ GEM
Formula IV 100 60 22.5 2.00
+ GEM
(6) - non-Small cell Lung tumor is Calu-6
carcinoma
Detailed Description of the Drawings:
Figures 1 thru 6 in the Drawings display the data in
the Tables 1 thru 6, supra. The Figures illustrate the
increased effectiveness of a combination treatment of (i)
Formula IV and (ii) gemcitabine hydrochloride in delaying
tumor growth over use of the individual agents (i) or (ii).
Fig. 1 - displays various treatments for LNCaP prostate
carcinoma.
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Bars (1), (2), and (3) display tumor growth delay
resulting from use of LTB4 inhibitor, Formula IV, alone at
doses of 30, 100, and 200 mg/kg, respectively.
Bar (4) displays tumor growth delay for the anti-cancer
agent, gemcitabine hydrochloride, alone at a dose of 60
mg/kg.
Bars (5) and (6) display tumor growth delay resulting
from combined use of Formula IV (at doses of 30 and 100
mg/kg) and gemcitabine hydrochloride (at a dose of 60
mg/kg); respectively.
Fig. 2 - displays various treatments for DU-145 prostate
carcinoma.
Bars (1), (2), and (3) display tumor growth delay
resulting from use of LTB4 inhibitor, Formula IV, alone at
doses of 30, 100, and 300 mg/kg, respectively.
Bar (4) display tumor growth delay for the anti-cancer
agent, gemcitabine hydrochloride, alone at a dose of 60
mg/kg.
Bars (5) and (6) display tumor growth delay resulting
from combined use of Formula IV (at doses of 30 and 100
mg/kg) and gemcitabine hydrochloride (at a dose of 60
mg/kg); respectively.
Fig. 3 - displays various treatments for BxPC3 pancreatic
carcinoma.
Bars (1), (2), and (3) display tumor growth delay
resulting from use of LTB4 inhibitor, Formula IV, alone at
doses of 30, 100, and 300 mg/kg, respectively.
Bar (4) display tumor growth delay for the anti-cancer
agent, gemcitabine hydrochloride, alone at a dose of 60
mg/kg.
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Bars (5) and (6) display tumor growth delay resulting
from combined use of Formula IV (at doses of 30 and 100
mg/kg) and gemcitabine hydrochloride (at a dose of 60
mg/kg); respectively.
Fig. 4 - displays various treatments for Panc-1 pancreatic
carcinoma.
Bars (1), (2), and (3) display tumor growth delay
resulting from use of LTBg inhibitor, Formula IV, alone at
doses of 30, 100, and 200 mg/kg, respectively.
Bar (4) display tumor growth delay for the anti-cancer
agent, gemcitabine hydrochloride, alone at a dose of 60
mg/kg.
Bars (5), (6) and (7) display tumor growth delay
resulting from combined use of Formula IV (at doses of 30,
100 and 200 mg/kg) and gemcitabine hydrochloride (at a dose
of 60 mg/kg); respectively.
Fig. 5 - displays various treatments for Human H460 non-
Small cell Lung carcinoma.
Bars (1), (2), and (3) display tumor growth delay
resulting from use of LTB4 inhibitor, Formula IV, alone at
doses of 30, 100, and 200 mg/kg, respectively.
Bar (4) display tumor growth delay for the anti-cancer
agent, gemcitabine hydrochloride, alone at a dose of 60
mg/kg.
Bars (5),(6) and (7) display tumor growth delay
resulting from combined use of Formula IV (at doses of 30,
100 and 200 mg/kg), and gemcitabine hydrochloride (at a dose
of 60 mg/kg); respectively.
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Fig. 6 - displays various treatments for Calu-6 non-small
cell Lung carcinoma.
Bars (1), (2), and (3) display tumor growth delay
resulting from use of LTB4 inhibitor, Formula IV, alone at
doses of 30, 100 and 200 mg/kg, respectively.
Bar (4) display tumor growth delay for the anti-cancer
agent, gemcitabine hydrochloride, alone at a dose of 60
mg/kg.
Bars (5) and (6) display tumor growth delay resulting
from combined use of Formula IV (at doses of 30 and 100
mg/kg) and gemcitabine hydrochloride (at a dose of 60
mg/kg); respectively.
