Note: Descriptions are shown in the official language in which they were submitted.
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w0 97I28I37 ' .' ~ PCTIUS97101749
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BENZOHETEROCYCLIC DERIVATIVES AS ANTIDIABETIC AND ANTIOBESITY
AGENTS
BACKGROUND l~F THE ~N~VF~,NTIQN
Diabetes refers to a disease process derived from multiple
causative factors and characterized by elevated Levels of plasma glucose
or hyperglycemia. ~3ncontrolled hyperglycemia is associated with
increased and premature mortality due to an increased risk for
microvascular and macrovascular diseases, including nephropathy,
neumpathy, retinopathy, hypertension, stroke, and heart disease..
Therefore, control of glucose homeostasis is a critically important
approach for the treatment of diabetes.
Type I diabetes (IDDM) is the result of an absolute
deficiency of insulin, the hormone which regulates glucose utilization.
~'ype II, noninsulin dependent diabetes mellitus (NInDM) is due to a
profound resistance to insulin stimulating or regulatory effect on
glucose and lipid metabolism in the main insulin-sensitive tissues,
muscle, liver and adipose rissue. This resistance to insulin
responsiveness results in insufficient insulin activation of glucose uptake,
oxidation and storage in muscle and inadequate insulin repression of
Iipolysis in adipose tissue and of glucose production and secretion in
liver.
The several treatments for N1DDM; which has not changed
substantially in many years, are all with limitations. While physical
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exercise and reductions in dietary intake of calories will dramatically
improve the diabetic condition, compliance with this treatment is very
poor because of well-entrenched sedentary lifestyles and excess food
consumption, especially high fat-containing food. Increasing the plasma
level of insulin by administration of sulfonylureas (e.g. tolbutamide,
glipizide) which stimulate the pancreatic (3-cells to secrete more insulin
or by injection of insulin after the response to sulfonylureas fails, will
result in high enough insulin concentrations to stimulate the very
insulin-resistant tissues. However, dangerously low levels of plasma
glucose can result from these last two treatments and increasing insulin
resistance due to the even higher plasma insulin levels could
theoretically occur. The biguanides increase insulin sensitivity resulting
in some correction of hyperglycemia. However, the two biguanides,
phenformin and metformin, can induce lactic acidosis and
nausea/diarrhea, respectively.
Thiazolidinediones (glitazones) are a recently disclosed
class of compounds that are suggested to ameliorate many symptoms of
NTDDM. These agents increase insulin sensitivity in muscle, liver and
adipose tissue in several animal models of hTIDDM resulting in complete
correction of the elevated plasma levels of glucose, triglycerides and
nonesterified free fatty acids without any occurrence of hypoglycemia.
However, serious undesirable effects have occurred in animal and/or
human studies including cardiac hypertrophy, hemadilution and liver
toxicity resulting in few glitazones progressing to advanced human
trials.
Hyperlipidemia is a condition which is characterized by an
abnormal increase in serum lipids, such as cholesterol, triglycerides and
phospholipids. These lipids do not circulate freely in solution in plasma,
but are bound to proteins and transported as macromolecular complexes
called lipoproteins. See the Merck Manual, I6th Ed. 1992 (see for
example pp. 1039-1040) and "Structure and Metabolism of Plasma
Lipoproteins" in Metabolic Basis of Inherited Disease, 6th Ed. 1989, pp.
1129-1138. One form of hyperlipidemia is hypercholesterolemia, -,
characterized by the existence of elevated LDL cholesterol levels. The
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t' initial treatment for hypercholesterolemia is often to modify the diet to
one low in fat and cholesterol, coupled with appropriate physical
exercise, followed by drug therapy when LDL-lowering goals are not
met by diet and exercise alone. LDL is commonly known as the "bad"
cholesterol, while HDL is the "good" cholesterol. Although it is
desirable to lower elevated levels of LDL cholesterol, it is also desirable
to increase levels of HDL cholesterol. Generally, it has been found that
increased levels of HDL are associated with lower risk for coronary
heart disease (CHD). See, for example, Cordon, et al., Am. J. Med., 62,
707-714 (1977); Stampfer, et al., N. England J. Med., 325, 373-381
(1991); and Kannel, et al., Ann. Internal Med., 90, 85-9I (1979). An
example of an HDL raising agent is nicotinic acid, but the quantities
needed to achieve HDL raising are associated with undesirable effects,
such as flushing.
It is suggested that thiazoiidinedione compounds exert their
effects by binding to the peroxisome proiiferator activated receptor
(PPAR) family of receptors, controlling certain transcription elements
having to do with the biological entities listed above. See Hulin et al.,
Current Pharm. Design (1996) 2, 85-102. Three sub-types of PPARs
have been discovered and described; they are PPARa, PPARy and
PPARB. PPARoc is activated by a number of medium and long-chain
fatty acids, and it is involved in stimulating ~3-oxidation of fatty acids.
PPARoc is also involved with the activity of fibrates in rodents and
humans. Fibric acid derivatives such as clofibrate, fenofibrate,
bezafibrate, ciprofibrate, beclofibrate and etofibrate, as well as
gemfibrozil, produce a substantial reducrion in plasma triglycerides
along with moderate reduction in LDL cholesterol, and they are used
particularly for the treatment of hypertriglyceridemia.
The PPARy receptor subtypes are involved in activating the
program of adipocyte differentiation and are not involved in stimulating
peroxisome proliferation in the liver. The DNA sequences for the
PPARyreceptors are described in Elbrecht, et al., BBRC 224;431-437
(1996). Although peroxisome proliferators, including the fibrates and
fatty acids, activate the transcriptional activity of PPAR's, only
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prostaglandin J2 derivatives have been identified as natural ligands of
the PPAR~y subtype, which also binds thiazolidinedione antidiabetic
agents with high affinity. The glitazones have been shown to bind
exclusively to the PPARy subtype.
The human nuclear receptor gene PPARB (hPPARs) has
been cloned from a human osteosarcoma cell cDNA library and is fully
described in A. Schmidt et aL, Molecular Endocrinology, 6 :I634-1642
(i 992) . It should be noted that .
PPAR~ is also referred to in the literature as PPAR(3 and as NUC1, and
each of these names refers to the same receptor; in Schmidt et al, the
receptor is referred to as NUC1.
SUMMARY OF THE INVENTION
This invention is concerned with the compounds of formula
I below and its analogs, pharmaceutically acceptable salts thereof, and
bioprecursors thereof, which differ from the thiazolidinediones in that
they lack the thiazolidinedione moiety and they do not lead to the array
of toxicity's associated with the thiazolidinediones. . The instant
compounds are effective in treating diabetes, atherosclerosis,
hyperglycemia, hyperlipidemia and/or obesity because they lower one
or more of the following biological entities in mammals; glucose,
insulin, triglycerides, fatty acids, cholesterol and the like. Thus, it is an
object of this invention to describe such compounds. It is a further
object to describe the specific preferred stereoisomers of the substituted
compounds. A still furtlier object is to describe processes for the
preparation of such compounds. Another object is to describe methods
and compositions which use the compounds as the active ingredient
thereof. Further objects will become apparent from reading the
following description.
DESCRIPTION OF THE IN~VENTIQI~T
The present invention is directed to a compound
represented by formula I:
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.i _ _ 5 _
w
(X! ~0-3
(Z'W t '~~ ~ R a
w
(Z-~)
R
or a pharmaceutically acceptable salt thereof, wherein:
R is selected from the group consisting of H, C1_6 alkyl, CS_10 aryl,
and CS_10 heteroaryl, said alkyl, aryl and heteroaryl optionally
substituted with 1 to 3 groups of Ra;
R 1 is selected from a group consisting of: H, C 1 _ 15 alkyl, CZ_ T 5
alkenyl, C2_15 alkynyl and C3_10 cycloalkyl, said alkyl, alkenyl,
alkynyl, and cycloalkyl optionally substituted with 1 to 3 groups of Ra;
R3 is selected from a group consisting of: H, NHR1, NHacyl, Cl_15
alkyl, C3_10 cycloalkyl, C2_15 alkenyl, Cl_i~ alkoxy, C02alkyl, OH,
C2-15 alkynyl, CS_10 aryl, CS_l0 heteroaryl said alkyl, cycloalkyi,
alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3
groups of Ra
Z-W- ~is Z-CR6R7- Z-CH=CH- or Z~/ Rs-
C ) > > >
Rg is selected from the group consisting of CR6R', O, NR6, and
S{O)p;
R6 and R7 are independently selected from the group consisting of H,
Cl_6 alkyl;
B is a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and
2 heteroatoms independently selected from the group consisting of O, N
and S, said heteroatoms are optionally substituted at any position on the
._
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five or six membered heterocycIe, the heterocycle being optionally
unsubstituted or substituted with 1 to 3 groups of Ra;
X 1 and XZ are independently selected from a group consisting of: H,
OH, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyi, halo, OR3, ORCF3,
C~_l0 aryl, CS-10 aralkyl, CS-10 heteroaryl and C1-10 acyl, said alkyl,
alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3
groups of Ra;
Ra represents a member selected from the group consisting of: halo,
acyl, aryl, heteroaryl, CF3, OCF3, CN, N02, R3, OR3; SRS, S(O)R3,
=N(OR), S02R3, NR3R3, NR3COR3, NR3C02R3, NR3CON{R3)2,
NR3S02R3, COR3, C02R3, CON(R3)2, SOZN(R3)2, OCON(R3)2 said
aryl and heteroaryl optionally substituted with 1 to 3 groups of halo or
C 1-6 alkyl;
Y is~ selected from the group consisting of: S{O)p, -CH2-,
-C(O)-, -C(O)NH-, -NR-, -O-, -SO2NH, -NHS02;
Y 1 is selected from the group consisting of: O and C;
Z is selected from the group consisting of: C02R3,
CONHS02R, CONHZ and 5-(1H-tetrazole);
t and v are independently 0 or 1 such that t + v = 1;
Q is a saturated or unsaturated straight chain hydrocarbon containing 2-
4
carbon atoms and
p is 0-2.
Included in the invention is a pharmaceutical composition
which is comprised of a compound of formula I in combination with a r
pharmaceutically acceptable carrier.
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.~
Also included in the invention is a pharmaceutical
composition which is comprised of a compound of formula I in
combination with one or more known sulfonylureas, biguanides, a-
glucosidase inhibitors, other insulin secretogogues as well as insulin.
Also included in the invention is a method for raising high
densisty lipoprotein (HDL) plasma levels in a mammal in need of such
treatment comprising administering an effective amount of a compound
of formula I.
Also included in the invention is a method for preventing,
halting or slowing the progression of atherosclerotic cardiovascular
diseases and related conditions and disease events in a mammal in need
of such treatment comprising administering an effective amount of a
compound of formula I.
Also included in the invention is a method for preventing,
halting or slowing the progression of atherosclerotic cardiovascular
diseases and related conditions and disease events in a mammal in need
of such treatment comprising administering an effective amount of a
compound of formula I in combination with one or more active agents
such as antihyperlipidemic agents, HMG-CoA synthase inhibitors,
squalene epoxidase inhibitors and the like..
Also included in the invention is a method of treating or
controlling diabetes, which comprises administering to a diabetic patient
an effective amount of a compound of formula I.
Also included in the invention is a method of treating or
controlling diabetes, which comprises administering a compound of
formula I in combination with one or more known sulfonylureas,
biguanides, a-glucosidase inhibitors, other insulin secretogogues as
well as insulin.
The invention is described herein in detail using the
terms defined below unless otherwise specified.
The term "alkyl" refers to a monovalent aikane
(hydrocarbon) derived radical containing from 1 to 15 carbon atoms
unless otherwise defined. It may be straight, branched or cyclic.
Preferred straight or branched alkyl groups include methyl, ethyl,
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propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups
include cyclopentyl and cyclohexyl. w
Alkyl also includes a straight or branched alkyl group
which contains or is intemlpted by a cycloalkylene portion.
Examples include the following:
and -(CH2)w ~ (CH )
- (C H2)x ~J (C H2)y ~ 2 z
wherein: x and y = from 0-10; and w and z = from 0-9.
The allcylene and monovalent alkyl portions) of the
alkyl group can be attached at any available point of attachment to
the cycloalkylene portion.
When substituted alkyl is present, this refers to a
straight, branched or cyclic alkyl group as defined above, substituted
with 1-3 groups as defined with respect to each variable.
The term "alkenyl" refers to a hydrocarbon radical
straight, branched or cyclic containing from 2 to 15 carbon atoms
and at least one carbon to carbon double bond. Preferably one
carbon to carbon double bond is present, and up to four non-
aromatic (non-resonating) carbon-carbon double bonds may be
present. Preferred alkenyl groups include ethenyl, propenyl, butenyl
and cyciohexenyl. As described above with respect to alkyl, the
straight, branched or cyclic portion of the alkenyl group may contain
double bonds and may be substituted when a substituted alkenyl
group is provided.
The term "alkynyl" refers to a hydrocarbon radical
straight, branched or cyclic, containing from 2 to 15 carbon atoms and
at least one carbon to carbon triple bond. Up to three carbon-carbon
triple bonds may be present. Preferred alkynyl groups include ethynyl,
propynyl and butynyl. As described above with respect to alkyl, the
strai ht, branched or c clic onion of the aIk
g Y P ynyl group may contain ,
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r
triple bonds and may be substituted when a substituted alkynyl group is
f'
y provided.
The term "alkoxy" refers to those groups of the designated
carbon length in either a straight or branched configuration attached
through an oxygen linkage and if two or more carbon atoms in length,
they may include a double or a triple bond. Exemplary of such alkoxy
groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy,
propargyloxy, and the like.
The term halo as used herein, represents fluoro, chloro,
bromo or iodo.
Aryl refers to aromatic rings e.g., phenyl, substituted
phenyl and like groups as well as rings which are fused, e.g., naphthyl
and the like. Aryl thus contains at least one ring having at least 5 atoms,
with up to two such rings being present, containing up to 10 atoms
therein, with alternating (resonating) double bonds between adjacent
carbon atoms. The preferred aryl groups are phenyl and naphthyl.
Aryl groups may likewise be substituted with 0-3 groups selected from
Ra. The preferred aryl groups are phenyl and naphthyl. Aryl groups
may likewise be substituted as defined below. Preferred substituted
aryls include phenyl and naphthyl substituted with zero or three groups
of Ra.
Heteroaryl is a group containing from 5 to 10 atoms, 1-4 of
which are heteroatoms, 0-4 of which heteroatoms are N and 0-1 of
which are O or S, said heteroaryl group being unsubstituted or
substituted with 0-3 Ra groups; examples of heteroaryls are pyridyl,
quinolyl, purinyl, imidazolyl, imidazopyridyl and pyrimidinyl.
One embodiment of the novel compounds of the instant
invention is realized when:
Y is O and all other variables are described as above.
Another embodiment of the novel compounds of the instant
invention is realized when:
Y is S(O)p, p is 0-2 and all other variables are described as
- above.
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Still another embodiment of the novel compounds of the
instant invention is realized when:
Y is -CHZ- and alI other variables are described as above.
Yet another embodiment of the novel compounds of the
instant invention is realized when:
Y is CO and all other variables are described as above.
A further embodiment of the novel compounds of the
instant invention is realized when:
Y is NR and all other variables are described as above.
Another embodiment of the novel compounds of the instant
invention is realized when:
Y is NHS02 or SO~ and all other variables are described as
above.
Another embodiment of the novel compounds of the instant
invention is realized when:
Y is -C(O)NH- and aII other variables are described as above.
Another embodiment of the novel compounds of the instant
invention is realized when:
B is a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and
2 heteroatoms G and J, which are substituted at any position on the five
or six membered heterocycle, the heterocycle being optionally
unsubstituted or substituted with 1 to 3 groups of Ra and aII other
variables are described as above.
Another embodiment of the novel compounds of the instant
invention is realized when:
6 7 ' ~~ 7 8-- .
{Z-W-) is Z-CR R -, Z-CH-CH-, or Z - R
and all other variables are described as above and a1I other variables
are
described as above.
Still another embodiment of the novel compounds of the
instant invention is realized when: 1
s R~
(Z-W-) is Z-CR6R7- or Z~/ Rte'
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and all other variables are described as above and all other variables
are
described as above.
Another embodiment of the novel compounds of the
instant invention is realized when:Ra is selected from the group
consisting
of C1-6 alkyl, CF3, aryl, halo, aryl, OCF3, -N02, OR3; COR3, C02R3,
CON(R3)2, and SOzN(R3)2; and X1 is selected from the group
consisting of
H, OH, C1 _6 alkyl, C2-i5 alkenyl, halo and OR3 and all other variables
are
described as above.
Another preferred embodiment of the novel compounds of
the instant invenrion is realized when:
R is C1_g alkyl or CS-10 aryl, said alkylor aryl optionally substituted
with 1 to 3 groups of Ra;
R1 is C1-15 alkyl;
X1 & X2 are independently H, C1-6 alkyl or halo;
Y is O, NH or S;
Y1 is O;
s
Z-W- is Z-CR6R7- or Z~/ Rs-
( )
Ra is a member selected from the group consisting of: halo, aryl, aryl,
heteroaryl, CF3, OCF3, -O-, CN, N02, R~, OR3; SR3, S(O)R3, S02R3,
NR3COR3, COR3, CON(R3)2, S02N(R3)2, said aryl and heteroaryl
;, optionally substituted with 1 to 3 groups of halo or C1-6 alkyl; and
- Z is C02R3, CONHS02R, CONH2 or 5-{1H-tetrazole).
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Examples of the compounds of the instant invention are:
Methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylthio)phenylacetate;
3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propylthio)-
phenylacetic acid;
Methyl 3-chloro-4-(3-(3-methoxy-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetate;
3-chloro-4-(3-{3-methoxy-7-propyl-6-benz-[4,5]-isoxazoloxy)
propylthio)-phenylacetic acid;
Methyl 3-chloro-4-{3-(3-ethyl-7-propyl-6-bent-[4,5]-isothiazoloxy)-
propylthio)phenyl acetate;
3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5J-isothiazole)oxy)propylthio
phenyiacetic acid;
Methyl 3-chloro-4-(3-(3-methyl-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetate;
3-chloro-4-{3-{3-methyl-7-propyl-6-Benz-[4,5]-isoxazoloxy)propylthio)-
phenylacetic acid;
Methyl 3-chloro-4-(3-(3,7-dipropyl-6-benz-[4,5]-isoxazoloxy)
propylthio)-phenylacetate;
3-chloro-4-(3-(3,7-dipropyl-6-bent-[4,5]-isoxazoloxy)propylthio)
phenyl-acetic acid;
1
1
Methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetate S-oxide;
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s 3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoioxy)propylthio)-
phenylacetic acid S-oxide;
Methyl 3-chloro-4-(3-{3-ethyl-7-propyl-5-benz-[4,5]-isoxazoloxy)
propyl-thio)phenylacetate S,S-dioxide;
3-Chloro-4-(3-(3-ethyl-7-propyl-6-Benz-[4,5]-isoxazole)oxy)-propylthio
phenylacetic acid S,S-dioxide;
tert-Butyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenyl acetate;
2-methyl-2-(3-chloro-4-(3-(3-phenyl-7-propylbenz[4,5]isoxazol-6-
oxy)propyl)thio)phenyl propionic acid;
Methyl 3-chloro-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-benz-[4,5]-
isoxazoloxy)-propylamino)phenylacetate;
3-Chloro-4-(3-{3-(2,2-dimethylpropyl)-7-propyl-6-benz-[4,5]-
isoxazoloxy)-propylamino)phenylacetic acid;
3-Chloro-4-(3-(2-phenyl-6-propyl-5-bent-[4,7]-oxazoloxy)
propylthio)phenylacetic acid;
Methyl 3-propyl-4-(3-(3-trifluoromethyl-7-propyl-6-bent-[4,5]-
isoxazoloxy)-propylthio)phenylacetate;
3-propyl-4-(3-(3-trifluoromethyl-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid;
3-chloro-4-(3-(2-propyl-3-trifluorornethyl-6-bent-[4,5]-
isoxazoloxy)propylthio)phenylacetic acid;
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3-chloro-4-(3-(3-phenyl-7-cyclopropylmethyl-6-benz-[4,5]-
isoxazoloxy)-butyloxy)phenylacetic acid;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylthio)-phenyl(2,2-
dimethyl)acetic acid;
3-(3-(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy)propylamino)-
phenyl(2,2-dimethyl)acetic acid;
4-(3-(3-Phenyl-7-propylbenz[c]pyrazoi-6-yloxy)propylamino)-
phenyl(2,2-dimethyl)acetic acid;
4-{3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propyloxy)-
phenylpropan-3-oic acid;
4-(4-(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy)butylamino)-
phenylpropan-3-oic acid;
3-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylthio)-
phenoxyaceric acid;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylthio)-
phenoxyacetic acid;
4-(4-( 1-Phenyl-4-propylbenz [d] triazol-5-yloxy)butyl oxy)-phenoxyacetic
acid;
N-[4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylamino)-
phenyl] glycine;
N-[3-(4-(4-Phenyl-$-propylquinazoiin-7-yloxy)butyloxy)-
phenyl] glycine;
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N-[4-(4-(4-Phenyl-8-propylquinazolin-7-yloxy)butyloxy)-
phenyl] glycine;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylamino)-
phenylacetic acid;
4-(3-(4-Phenyl-8-propylquinazolin-7-yloxy)propylthio)-phenylacetic
acid;
3-(3-(2-Phenyl-6-propylbenzoxazol-S-yloxy)propylamino)-3-
chlorophenylacetic acid;
4-(3-(2-Phenyl-6-propylbenzoxazol-5-yloxy)propylamino)-3-
chlorophenylacetic acid;
4-(3-(2-Phenyl-6-propylbenzoxazoI-5-yloxy)propylamino)-phenylacetic
acid;
3-(3-(2-Phenyl-5-propylbenzisoxazol-5-yloxy)propyiamino)-3-
chlorophenylacetic acid;
4-(3-( i -Phenyl-4--propylbenzjd]triazol-5-yloxy)propylamino)-3-
chlorophenyiacetic acid;
3-(3-(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy)propylamino)-3-
chlorophenylacetic acid;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylamino)-3-
chlorophenylacetic acid;
4-(4-(3-Phenyl-7-prop-2-enylbenzisoxazol-6-yloxy)butyloxy)-3-
chlorophenylacetic acid;
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4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylamino)-
phenoxyacetic acid;
3-(3-{3-Phenyl-7-butylbenzisoxazol-6-yloxy)propylthio)-phenylpropan-
3-oic acid;
4-(3-(3-Phenyl-7-butylbenzisoxazol-6-yloxy)propylthio)-phenylpropan-
3-oic acid;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propyloxy)-2-phenyl-2,2-
dimethylacetic acid;
4-(4-(3-Phenyl-7-{cyclopropylmethyl)benzisoxazol-6
yloxy)butylamino)-phenoxy-2,2-dimethylacetic acid;
3-(3-{3-NeopentyI-7-propylbenzisoxazol-6-yloxy)propylthio)-3-
methylphenylacetic acid
4-(3-(3-(2-Phenyl-2,2-dimethyl)-7-propylbenzisoxazol-6-
yloxy)propyloxy}-3-butylphenylacetic acid;
4-(3-(3-Chloro-7-propylbenzisoxazol-6-yloxy)propylamino)-2-
propylphenylacetic acid;
3-(3-{3-Chloro-7-propylbenzisoxazol-6-yloxy)propylamino)-2-
propylphenylacetic acid;
4-(4-(3-Butoxy-7-propylbenzisoxazol-6-yloxy)butylthio)-2-
fluorophenylacetic acid;
4-(3~(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylamino)-.
phenoxyacetic acid;
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3-(3-(3-(3-Butylphenyl}-7-butylbenzisoxazol-6-yloxy)propylthio)-
phenylpropan-3-oic acid;
4-(3-(3-(2-Tolyl)-7-butylbenzisoxazol-6-yloxy}propylthio)-
phenyipropan-3-oic acid;
4-(3-(3-(4-Fiuorophenyl)-7-propylbenzisoxazol-6-yloxy)propyloxy}-2-
phenyl-2,2-dimethylacetic acid;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy}propyloxy)-phenoxy-2-
spiro-cyclopropylacetic acid;
3-(3-(3-Phenyl-'7-propylbenzisoxazol-6-yloxy)propyloxy)-phenoxy-2-
spiro-cyclopropylacetic acid;
5-(4-(3-(3-Phenyl-7-propyibenz[c]pyrazol-6-yloxy)propylamino)phenyl-
2-(2,2-dimethyl)-ethyl)-tetrazole;
5-(4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propyloxy)phenyl-3-
propyl}-tetrazole;
5-(4-(4-( 1-Phenyl-4-propylbenz[d]triazoI-S-yloxy)butylamino)phenyl-3-
propyl)-tetrazole;
5-(3-(3-(3-Phenyl-7-propylbenzisoxazol-5-yloxy)propylthio)phenoxy-2-
ethyl)-tetrazole;
5-(4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylthio)phenoxy-2-
ethyl )-tetrazole;
3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)-but-2-en-
thio)phenylacetic acid;
4-(3-(3-ethyl-7-propyl-6-benz[4,5]isoxazole)oxy)propyloxy phenoxy
acetic acid;
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N-Methylsulfonyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-bent[4,5]
isoxazole)oxy)propylthio phenyl acetamide;
3,5-dimethoxy-4-(3-(3-(Ethyl}-7-(propyl)-6-bent-[4,5)-isoxazoloxy)-
propyloxy)phenyl acetic acid;
3,5-dichloro-4-(3-(3-(Ethyl)-7-(propyl)-5-bent-[4,5]-isoxazoloxy)-
propyloxy)phenyl acetic acid;
3,5-dimethyl-4-(3-(3-(Ethyl)-7-{propyl)-6-benz-[4,5]-isoxazoloxy}-
propyloxy)phenyl acetic acid;
4-(3-(3-{Ethyl)-7-(propyl)-6-benz-[4,5]-isoxazoloxy}-propyloxy)-phenyl
propionic acid;
3-chloro-4-(3-phenylmethyl-7-(n-propyl)-6-
benz[4,5]isoxazoloxy)propyl-thio)phenylacetic acid;
3-chloro-4-(3-(2,2-dimethylpropyl)-7-(n-propyl)-f>-
benz[4,5]isoxazoloxy)-propylthio)phenyiacetic acid;
2-methyl-4-(3-(3-(Ethyl)-7-(propyl)-6-bent-[4,5]-
isoxazoloxy)propyloxy)-phenyl propionic acid;
3-Propyl-4-(3-{3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propyloxy)phenylacetic acid;
4-(3-(3-(Ethyl)-7-propyl-6-benz-[4,5]-isoxazoloxy)butyl)phenylacetate;
3-chloro-4-(7-(n-propyl)-3-(3,3,3-trifluoropropyl)-6-bent[4,5]isoxazol-
oxy)propylthio)phenylacetic acid;
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3-chloro-4-(3-(4-chlorophenylinethyl)-7-(n-propyl)-6-
benz[4,5]isoxazol-oxy)propylthio)phenylacetic acid;
3-Chloro-4-(3-(3-(2,2-dirnethylpropyl)-7-propyl-6-bent-[4,5]-
isoxazoloxy)propyl- N-methylamino)phenylacetate;
3,5-Dipropyl-4-(3-(3-ethyl-7-propyl-6-Benz-[4,5]-isoxazoloxy}-
propyloxy)phenylacetic acid;
3-fluoro-4.-(3-(7-propyl-3-trifluoromethyl-6-bent-[4, 5]isoxazoloxy)-
propyloxy)phenylacetic acid;
3-chloro-4-(3-(3-trifluoromethyl-7-propyl-6-bent-[4, 5]-
isoxazoloxy)propylamino)phenylacetic acid;
3-Isobutyl-4-(3-(3-neo-pental-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propyloxy)phenylacetic acid;
3-Propyl-4-(3-(3-neo-pental-7-propyl-6-benz-[4,5]-isoxazoloxy)
propylthio)phenylacetic acid S,S-dioxide;
-Chloro-4-(3-(3-phenyl-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylsulfoxy)phenylacetic acid;
3-fluoro-4-(4-(3-phenyl-7-propyl-6-Benz-[4, 5]-isoxazoloxy)-
butyloxy)phenylacetic acid;
3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-bent-[4, 5]-isoxazoloxy)-
propyl-thio)phenylacetic acid S, S-dioxide;
3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benz-[4, 5]-isoxazoloxy)-
propyl-thio)phenylacetic acid S-oxide;
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3-chloro-4-(3-(2-phenylethyl)-7-propyl-6-bent[4,5]isoxazoloxy)propyl-
thio)phenylacetic acid;
3-Chloro-4-{3-(3-(4-fluorophenyl)-7-propyl-6-benz-[4,5]-isoxazoloxy}-
propylthio)phenylacetic acid;
3-Chloro-4-(3-(3-(4-fluorophenyl)-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylsulfmyl)phenylacetic acid;
3-Chloro-4-(3-(3-(4-fluorophenyl)-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propylsulfonyl)) phenylacetic acid;
2,3-Dichloro-4-(3-(3-neo-pental-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid;
2-Trifloroethoxy-4-(3-(3-neo-pental-7-propyl-6-benz-[4,5]-
isoxazoloxy)propyloxy)phenyIacedc acid;
3-Chloro-4-{3-(3-cyclopropyl)-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propylamino}phenylacetate;
2-(3-chloro-4-(3-{3-ethyl-7-propyl-6-bent-[4,5]-
isoxazoloxy)propylthio)) phenylpropionic acid;
3-(4-(3-(3-phenyl-7-propyl-6-Benz-[4,5]-isoxazoloxy)propyloxy))
phenyipropionic acid;
3-Chioro-4-(3-(3-(3-fluorophenyl)-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid;
3-Chloro-4-(3-(3-neo-pental-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propyloxy)phenoxylacetic acid;
4-(3-(3-phenyl-7-propyl-6-benz[4,5]isoxazole)oxy)propyloxy phenoxy
acetic acid;
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(3-(4-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)butyloxy))
phenylacetic acid;
z
3-(4-(4-(3-phenyl-7-propyl-6-bent-[4,5]-isoxazoloxy)butyloxy))
phenylpropionic acid;
3-chloro-4-(3-(2-methyl-2-phenylpropyl}-7-(n-propyl)-6-bent[4,5]isox-
azoloxy)propylthio)phenylacetic acid;
3-Methoxy-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-benz-[4,5]-
isoxazoloxy)propyIoxy)phenylacetate;
3-(4-(2-(3-phenyl-7-propyl-6-bent-[4,5]-isoxazoloxy)ethyloxy))
phenylpropionic acid;
(3-(4-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)butyloxy))
phenoxyacetic acid;
E-(4-(3-(3-phenyl-7-propyl-6-bent[4,5]isoxazole)oxy}propyloxy)
cinnamic acid;
E-(3-{3-(3-phenyl-7-propyl-6-bent[4,5]isoxazole}oxy)propyloxy)
cinnamic acid;
3-(3-(3-(3-phenyl-7-propyl-6-bent[4,5]isoxazole)oxy)propyloxy)
phenylpropionic acid;
N-((4-carbomethoxymethyi)benzoyl)-3(3-phenyl-7-propyl-6-benz-[4,7]-
isooxazolyloxy) propylamine ;
2-(4-(3-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propyloxy))
phenoxypropionic acid;
2-(4-(4-(3-phenyl-7-propyl-5-bent-[4,5]-isoxazoloxy)butyloxy))
phenoxypropionic acid;
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3-chloro-4-(3-(7-cyclopropylmethyl-3-phenyl-6-benz-[4, 5]-
isoxazoloxy)propyl-thio)phenylacedc acid;
1-(3-chloro-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-
benz[4,5]isoxazole)oxy)propylthio) phenyl cyclopropane carboxylic
acid;
4-(3-(3-{Ethyl)-7-(phenyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)-3-
chloro-a, a-dimethyl-phenyl propionic acid;
3-Ethoxy-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-bent-[4,5]-
isoxazoloxy)propyloxy)phenylacetate; and
3-chloro-4-(3-(3-phenyl-6-propyl-5-benz-[4,7]-isoxazoIyloxy)-
propylthio) phenylacetic acid.
Preferred examples of the compounds of the instant
invention are:
Methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-bent-j4,5]-isoxazoloxy)-
propylthio)phenylacetate;
3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propylthio)-
phenylacetic acid;
Methyl 3-chloro-4-{3-(3-methoxy-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetate;
3-chloro-4-(3-{3-methoxy-7-propyl-6-bent-[4,5]-isoxazoloxy)
propylthio)-phenylacetic acid;
Methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-bent-[4,5]-isothiazoloxy)-
propylthio)phenyl acetate;
3-chloro-4-(3-{3-ethyl-7-propyl-6-benz-[4,5]-isothiazole)oxy)propylthio
phenylacetic acid;
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' Methyl 3-chloro-4-(3-(3-methyl-7-propyl-6-bent-[4,5]-isoxazoloxy)-
y
propylthio}phenylacetate;
3-chloro-4.-(3-(3-methyl-7-propyl-6-bent-[4,5]-isoxazoloxy}propylthio)-
phenylacetic acid;
Methyl 3-chloro-4-(3-(3,7-dipropyl-b-benz-[4,5]-isoxazoloxy)
propylthio)-phenylacetate;
3-chloro-4-(3-(3,7-dipropyl-b-benz-[4,5]-isoxazoloxy)propylthio)
phenyl-acetic acid;
Methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylthio)phenylacetate S-oxide;
3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propylthio)-
phenylacetic acid S-oxide;
Methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-bent-[4,5]-isoxazoloxy)
propyl-thio)phenylacetate S,S-dioxide;
3-Chloro-4-{3-{3-ethyl-7-propyl-6-bent-(4,5]-isoxazole}oxy)-propylthio
phenylacetic acid S,S-dioxide;
tert-Butyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propylthio)phenyl acetate;
2-methyl-2-(3-chloro-4-(3-(3-phenyl-7-propylbenz[4,5]isoxazol-6-
oxy)propyl)thio)phenyl propionic acid;
Methyl 3-chloro-4-(3-(3-(2,2-dimethylpropyl}-7-propyl-6-benz-[4,5]-
is oxazoloxy)-propylamino)phenylacetate;
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3-Chloro-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-bent-[4,5]-
isoxazoloxy)-propylamino)phenylacetic acid;
3-Chloro-4-(3-(2-phenyl-6-propyl-S-bent-[4,7]-oxazoloxy)
propylthio)phenylacetic acid;
Methyl 3-propyl-4-(3-(3-trifluoromethyl-7-propyl-6-bent-[4,5]-
isoxazoloxy)-propylthio)phenylacetate;
3-propyl-4-(3-(3-trifluoromethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid;
3-chloro-4-(3-(2-propyi-3-trifluoromethyl-6-benz-[4,5]-
isoxazoloxy)propylthio)phenylacetic acid;
3-chloro-4-(3-(3-phenyl-7-cyclopropylmethyl-6-Benz-[4,5]-
isoxazoloxy)-butyloxy)phenylacetic acid;
4-(3-(3-Phenyl-7-propyibenzisoxazol-6-yloxy)propyloxy)-phenylacetic
acid;
4-(3-(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy)propyloxy)-
phenylacetic acid;
3-(4-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)butyloxy)-phenylacetic
acid;
3-(4-(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy)butyloxy)-phenylacetic
acid;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propyloxy}-phenoxyacetic
acid;
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4-(3-(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy}propyloxy)-
phenoxyacetic acid;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)propylthio)-3-
propylphenylacetic acid;
4-(4-(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy)butylthio)-3-
chlorophenyiacetic acid;
4-(4-(1-Phenyl-4-propylbenz[c]pyrazol-5-yloxy}butylthio)-3-
chlorophenylacetic acid;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yIoxy)propylsulfono}-3-
propylphenylacetic acid;
4-(3-(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy)propylsulfono)-3-
chlorophenylacetic acid;
4-(4-{3-Phenyl-7-propylbenzisoxazol-6-yloxy)butylthio}-3-
propylbenzyl-tetrazole;
4-(4-(3-Phenyl-7-propylindol-6-yloxy)butylthio)-3-chlorobenzyl-
tetrazole;
4-{4-{ 1-Phenyl-4-propylindol-5-yloxy)butylthio)-3-chlorobenzyl-
tetrazo1e;
4-(3-(3-Phenyl-7-propylbenzisoxazol-6-yioxy)propylamino}-
phenylacetic acid;
4-(3-(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy)propylamino)-
phenylacetic acid;
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3-(4-(4-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)butyloxy)-phenylacetic
acid;
3-(4-(4~(3-Phenyl-7-propylbenz[c]pyrazol-6-yloxy)butyloxy}-
phenylacetic acid;
3-chloro-4-(3-(2,2-dimethylpropyl)-7-(n-propyl)-6-
benz[4,5]isoxazoloxy)-propylthio)phenylacetic acid;
3-Propyl-4-(3-(3-ethyl-7-propyl-6-benz-(4,5]-isoxazoioxy)-
propyloxy)phenylaceric acid;
4-(3-(3-(Ethyl)-7-propyl-6-benz-[4,5]-isoxazoloxy)butyl)phenylacetate;
3-chloro-4-(7-{n-propyl)-3-(3,3,3-trifluoropropyl)-6-bent[4,5]isoxazol-
oxy)propylthio)phenylacetic acid;
3-chloro-4-(3-(3-trifluoromethyl-7-propyl-6-bent-[4, 5]-
isoxazoloxy)propylamino)phenylacetic acid;
-Chloro-4-(3-(3-phenyl-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propylsulfoxy)phenylacetic acid;
3-fluoro-4-(4-{3-phenyl-7-propyl-6-bent-[4, 5]-isoxazoloxy)-
butyloxy)phenylacetic acid;
3-chloro-4-(3-(2-phenylethyl)-7-propyl-6-bent[4,5]isoxazoloxy)propyl-
thio)phenylacetic acid;
3-Chloro-4-(3-(3-(4-fluorophenyl}-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid;
3-Chloro-4-(3-(3-(4-fluorophenyl)-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylsulfonyl)) phenylacetic acid;
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2,3-Dichloro-4-(3-(3-neo-pental-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid;
2-(3-chloro-4-{3-(3-ethyl-7-propyl-6-bent-[4,5]-
isoxazoloxy)propylthio)) phenylpropionic acid;
3-(4-{3-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propyloxy))
phenylpropionic acid;
3-Chloro-4-(3-(3-{3-fluorophenyl}-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid;
4-{3-(3-phenyl-7-propyl-6-benz[4,5]isoxazole)oxy)propyloxy phenoxy
acetic acid;
(3-(4-(3-phenyl-7-propyl-6-Benz-[4,5]-isoxazoloxy)butyloxy))
phenylacetic acid;
3-(4-{4-(3-phenyl-7-propyl-6-bent-[4,5]-isoxazoloxy)butyloxy))
phenylpropionic acid;
3-chloro-4-(3-(2-methyl-2-phenylpropyl}-7-(n-propyl)-6-benz[4,5]isox-
azoloxy)propylthio)phenylacetic acid;
3-(4-(2-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)ethyloxy))
phenylpropionic acid;
(3-(4-(3-phenyl-7-propyl-6-bent-[4,5]-isoxazoloxy)butyloxy))
phenoxyacetic acid;
E-(4-(3-(3-phenyl-7-propyl-6-bent[4,5]isoxazole)oxy)propyloxy}
cinnamic acid;
3-(3-(3-(3-phenyl-7-propyl-6-bent[4,5]isoxazole)oxy)propyloxy)
phenylpropionic acid;
2-(4-(3-(3-phenyl-7-propyl-6-bent-[4,5J-isoxazoloxy}propyloxy))
phenoxypropionic acid;
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2-(4-(4-(3-phenyl-7-propyl-6-bent-[4,5]-isoxazoloxy)butyloxy))
phenoxypropionic acid;
3-chloro-4-(3-(7-cyclopropylmethyl-3-phenyl-6-Benz-[4, 5]-
isoxazoloxy)propyl-thio)phenylacetic acid;
1-(3-chloro-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-
benz[4,5]isoxazole)oxy)propylthio) phenyl cyclopropane carboxylic
acid; and
4-(3-(3-(Ethyl)-7-(phenyl)-6-Benz-[4,5]-isoxazoloxy)propyloxy)-3-
chloro-oc, oc-dimethyl-phenyl propionic acid.
The compounds of the present invention may have
asymmetric centers and occur as racemates, racemic mixtures, and as
individual diastereomers, with all possible isomers, including optical
isomers, being included in the present invention.
Compounds of the general Formula I may be separated into
diastereoisomerfic pairs of enantiomers by, for example, fractional
crystallization from a suitable solvent, for example methanol or ethyl
acetate or a mixture thereof. The pair of enantiomers thus obtained
may be separated into individual stereoisomers by conventional means,
for example by the use of an optically active acid as a resolving agent.
Alternatively, any enantiomer of a compound of the general
Formula I may be obtained by stereospecific synthesis using optically
pure starting materials of known configuration.
The instant compounds can be isolated in the form of their
pharmaceutically acceptable acid addition salts, such as the salts derived
from using inorganic and organic acids. Examples of such acids are
hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,
trifluoroacetic, propionic, malefic, succinic, malonic and the like. In
addition, certain compounds containing an acidic function such as a '
carboxy or tetrazole, can be isolated in the form of their inorganic salt
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in which the counterion can be selected from sodium, potassium,
lithium, calcium, magnesium and the like, as well as from organic bases.
As previously indicated, the compounds of the present
invention have valuable pharmacological properties. They are useful in
treating or preventing diabetes, treating obesity, lowering triglyceride
levels and prevention of vascular restenosis. They are useful in treating
other disorders where insulin resistance is a component including
ovarian hyperandrogenism (polycyctic ovarian syndrome). They are
also useful in raising high density lipoprotein levels, preventing, halting
or slowing the progression of atherosclerotic cardiovascular diseases
and related conditions and disease events.
The present invention also provides a compound of the
general Formula I or a pharmaceutically acceptable salt thereof for use
as an active therapeutic substance.
The present invention further provides a compound of the
general Formula I, or a pharmaceutically acceptable ester thereof; or
pharmaceutically acceptable salt thereof, for use in the treatment of
hyperglycemia (diabetes) in human or non-human animals.
The present invention further provides a compound of the
general Formula I, or a pharmaceutically acceptable ester thereof; or
pharmaceutically acceptable salt thereof, in combination with known
sulfonylureas, other insulin secretogogues as well as insulin for use in
the treatment of diabetes treating obesity, lowering triglyceride levels,
prevention of vascular restenosis, treating other disorders where insulin
resistance is a component including ovarian hyperandrogenism
(polycyctic ovarian syndrome), raising high density lipoprotein levels,
and preventing, halting or slowing the progression of atherosclerotic
cardiovascular diseases and related conditions and disease events.and
hypertension in human or non-human animals.
In one aspect, the present invention provides a compound of
the general Formula I for use in the treatment of obesity in human or
non-human animals. Said compound can be effectively used in
combination with other known or proposed strategies for the treatment
~ , of obesity or obesity-related disorders; for example, fenfluramine,
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dexfenfluramine, phentiramine and (33 adrenergic receptor agonist r
agents.
The disease diabetes mellitus is characterized by metabolic
defects in production and utilization of glucose which result in the
failure to maintain appropriate blood sugar levels. The result of these
defects is elevated blood glucose or hyperglycemia. Research on the
treatment of diabetes has centered on attempts to normalize fasting and
postprandial blood glucose levels. Treatments have included parenteral
administration of exogenous insulin, oral administration of dnlgs and
dietary therapies. The instant compounds can be effectively used in
combination with known therapies for diabetes including insulin,
sulfonylureas, biguanides (such as metformin), a-glucosidase inhibitors
{such as acarbose) and others.
Two major forms of diabetes mellitus are now recognized.
Type I diabetes, or insulin-dependent diabetes, is the result of an
absolute deficiency of insulin, the hormone which regulates glucose
utilization. Type II diabetes, or non-insulin-independent diabetes, often
occurs in the face of normal, or even elevated levels of insulin and
appears to be the result of the inability of tissues to respond
appropriately to insulin. Most of the Type II diabetics are also obese.
Accordingly, in another aspect the present invention provides a method
of lowering triglyceride levels which comprises administering, to an
animal in need thereof, a therapeutically effective amount of a
compound of the formula I or pharmaceutically acceptable salt or ester
thereof.
In addition the compounds of the present invention lower
or modulate triglyceride levels and/or cholesterol levels and raise HILL
plasma levels and are therefore of use in combating medical conditions
wherein such lowering {and raising) is thought to be beneficial. Thus
they may be used in the treatment of hypertension, obesity,
atherosclerotic disease events, diabetes and related conditions by
administering to an animal in need thereof, a therapeutically effective
amount of a compound of the formula (I) or pharmaceutically
acceptable salt thereof. The compositions are formulated and
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administered in the same general manner as detailed below. They may
also contain other active ingredients known for use in the treatment of
atherosclerotic disease events, diabetes, hypertension, obesity and related
conditions, for example fibrates such as clofibrate, bezafibrate and
gemfibrozil; inhibitors of cholesterol biosynthesis such as HMG-CoA
reductase inhibitors for example lovastatin, simvastatin and pravastatin;
inhibitors of cholesterol absorption for example beta-sitosterol and (acyl
CoA:cholesterol acyltransferase) inhibitors for example melinamide;
anion exchange resins for example choiestyramine, colestipol or a
dialkylaminoalkyl derivatives of a cross-linked dextran; nicotinyl
alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics.
In particular the invention provides methods for preventing
or reducing the risk of developing atherosclerosis, comprising the
administration of a prophylactically effective amount of a compound of
formula I alone or in combination with one or more additional
pharmaceutically active agents, to a mammal, particularly human, who
is at risk of developing atherosclerosis.
Atherosclerosis encompasses vascular diseases and
conditions that are recognized and understood by physicians practicing
in the relevant fields of medicine. Atherosclerotic cardiovascular
disease, coronary heart disease (also known as coronary artery disease
or ischemic heart disease), cerebrovascular disease and peripheral vessel
disease are al/ clinical manifestations of atherosclerosis and are
therefore encompassed by the terms "atherosclerosis" and
"atherosclerotic disease."
The instant invention further provides methods for
preventing or reducing the risk of a first or subsequent (where the
potential exists for recurrence) atherosclerotic disease event, comprising
the administration of a prophylactically effective amount, or more
particularly an HDL-raising amount, of a compound of formula I alone
or in combination with one or more additional pharmaceutically active
agents, to a mammal, particularly human, who is at risk for having an
atherosclerotic disease event. The term "atherosclerotic disease event"
as used herein is intended to encompass coronary heart disease events,
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cerebrovascular events, and intermittent claudication. Coronary heart
disease events are intended to include CHD death, myocardial infarction ,
(i.e., a heart attack), and coronary revascularization procedures.
Cerebrovascular events are intended to include ischemic or hemorrhagic
stroke (also known as cerebrovascular accidents) and transient ischemic
attacks. Intermittent claudication is a clinical manifestation of
peripheral vessel disease. It is intended that persons who have
previously experienced one or more non-fatal atherosclerotic disease
event are those for whom the potential for recurrence of such an event
exists.
Persons to be treated with the instant therapy include those
at risk of developing atherosclerotic disease and of having an
atherosclerotic disease event. Standard atherosclerotic disease risk
factors are known to the average physician practicing in the relevant
fields of medicine. Such known risk factors include but are not limited
to hypertension, smoking, diabetes, low levels of high density
lipoprotein cholesterol, high levels of low density lipoprotein
cholesterol, and a family history of atherosclerotic cardiovascular
disease. Published guidelines for determining those who are at risk of
developing atherosclerotic disease can be found in: National Cholesterol
Education Program, Second report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel Il~, National Institute of Health, National Heart Lung
and Blood Institute, NIH Publication No. 93-3095, September 1993;
abbreviated version: Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults, Summary of the second
report of the national cholesterol education program (NCEP) Expert
Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel 1l), JAMA, 1993, 269,
pp. 3015-23. People identified as having one or more of the above-
noted risk factors, as well as people who already have atherosclerosis,
are intended to be included within the group of people considered to be
at risk for having an atherosclerotic disease event.
4
CA 02244836 1998-07-31
WO 97/28137 PCTlUS97/Ot749
-33-
The active compounds of the present invention may be
orally administered as a pharmaceutical composition, for example, with
an inert diluent, or with an assimilable edible carrier, or they may be
enclosed in hard or soft shell capsules, or they may be compressed into
tablets, or they may be incorporated directly with the food of the diet.
For oral therapeutic administration, which includes sublingual
administration, these active compounds may be incorporated with
excipients and used in the form of tablets, pills, capsules, ampules,
sachets, elixirs, suspensions, syrups, and the like. Such compositions
and preparations should contain at least 0.1 percent of active compound.
The percentage of active compound in these compositions may, of
course, be varied and may conveniently be between about 2 percent to
about 60 percent of the weight of the unit. The amount of active
compound in such therapeutically useful compositions is such that an
effective dosage.will be obtained. The active compounds can also~be
administered intranasally as, for example, liquid drops or spray.
The effective dosage of active ingredient employed may
vary depending on the particular compound employed, the mode of
administration, the condition being treated and the severity of the
condition being treated.
When treating or preventing diabetes mellitus and/or
hyperglycemia or hypertriglyceridemia, or obesity, or when treating,
preventing or slowing the progression of atherosclerosis generally
satisfactory results are obtained when the compounds of the present
invention are administered at a daily dosage of from about 0.1
milligram to about 100 milligram per kilogram of animal body weight,
preferably given as a single daily dose or in divided doses two to six
times a day, or in sustained release form. For most large mammals, the
total daily dosage is from about 1.0 milligrams to about 1000
milligrams, preferably from about 1 milligrams to about 50 milligrams.
In the case of a 70 kg adult human, the total daily dose will generally be
from about 7 milligrams to about 350 milligrams. This dosage regimen
may be adjusted to provide the optimal therapeutic response.
CA 02244836 1998-07-31
WO 97/28137 PCT/US97/OI749
- -34-
.The compositions are formulated and administered in
the same general manner as detailed below. The compounds of the '
instant invention may be used effectively alone or in combination
with one or more additional active agents depending on the desired
target therapy. Combination therapy includes administration of a
single pharmaceutical dosage formulation which contains a
compound of formula I and one or more additional active agents, as
well as administration of a compound of formula I and each active
agent in its own separate pharmaceutical dosage formulation. For
example, a compound of formula I and an HMG-CoA reductase
inhibitor can be administered to the patient together in a single oral
dosage composition such as a tablet or capsule, or each agent
administered in separate oral dosage formulations. Where separate
dosage formulations are used, a compound of formual I and one or
more additional active agents can be administered at essentially the
same time, i.e., concurrently, or at separately staggered times, i.e,
sequentially; combination therapy is understood to include all these
regimens.
An example of combination treatment or prevention of
atherosclerosis may be wherein a compound of formula I is
administered in combination with one or more of the following active
agents:an antihyperlipidemic agent; a lasma HDL-raising agent; an
antihypercholesterolemic agent such as a cholesterol biosynthesis
inhibitor, for example an HMG-CoA reductase inhibitor, an HMG-CoA
synthase inhibitor, a squalene epoxidase inhibitor, or a squalene
synthetase inhibitor (also known as squalene synthase inhibitor); an
acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor such as
melinamide; probucol; nicotinic acid and the salts thereof and
niacinamide; a cholesterol absorption inhibitor such as beta-sitosterol; a
bile acid sequestrant anion exchange resin such as choiestyramine,
colestipol or dialkylaminoalkyl derivatives of a cross-linked dextran; an
LDL (low density lipoprotein) receptor inducer; fibrates such as
clofibrate, bezafibrate, fenofibrate, and gemfibrizol; vitamin B6 (also
known as pyridoxine) and the pharmaceutically acceptable salts thereof -
CA 02244836 2005-03-23
wo 97!28137 . ~ ~~=~ ~ ~ PG°TIUS97l01749
such as .the .HCI salt; vitamin 1312 (also known as cyanocobalamin); anti-
oxidant vitamins such as vitamin C and E and beta carotene; a beta-
blocker; an angiotensin II antagonist; an angiotensin converting enzyme
inhibitor; and a platelet aggregation inhibitor such as fibrinogen
receptor antagonists (i.e., glycoprotein IlblIIIa fibrinogen receptor
antagonists) and aspirin: As noted above, the compounds of formula I
can be administered in combination with more than one additional active
agent, for example, a combination of a compound of formula I with an
HMG-CoA reductase inhibitor {e.g.rlovastatin; simvastatin and
pravastatin) and aspirin; or a compound of formula I with an HMG-CoA
reductase inhibitor and a beta blocker.
Another example of combination therapy can be seen in
treating obesity or obesity-related disorders, wherein the campounds of
formula I may be effectively used in combination with for example,
fenfluramine; dexfenfluramine, phentiramine and X33 adrenergic
receptor agonist agents.
~tiIl another example of combination therapy can be seen in
treating diabetes, and related disorders wherein the compounds of
formula I can be effectively used in combination with for example
sulfonylureas, biguanides, oc-glucosidase inhibitors, other insulin
secretogogues, insulin as well as the active agents discussed above for
treating atherosclerosis.
In accordance with this invention, a pharmaceutically
effective amount of a compound of formula I can be used for the
preparation of a medicament. useful for treating diabetes, treating
obesity, lowering triglyceride levels, raising the plasma level of high
density lipoprotein, and fot° treating, preventing or reducing the risk
of
developing atherosclerosis, and for preventing or reducing the risk of '
having a first or subsequent atherosclerotic disease event in mammals,
particularly in humans.
Additionally, an effective amount of a compound of
formula I and a therapeutically effective amount of one or more active
agents selected from the group consisting of: an antihyperlipidemic
agent; a a m HDL-raising agent; an antihypercholesterolemic agent
* Trade-mark
CA 02244836 2005-03-23
WO 9T128137 : : ~ ~~ ~ p~~~71~1749
_ . _36_
such as -.a cholesterol biosynthesis inhibitor, for example an HMG-CoA
reductase inhibitor, an HMC-CoA synthase inhibitor, a squalene
epoxidase inhibitor, or a squalene synthetase inhibitor (also known as
squalene synthase inhibitor); an acyl-coenzyme A: cholesterol
acyltransferase inhibitor; probucol; nicotinic acid and the salts thereof;
niacinamide; a cholesterol absorption~inhibitor; a bile acid sequestrant
anion exchange resin; a low density lipoprotein receptor inducer;
cloflbrate, fenofibrate, and gemflbrozol; vitamin B6 and _ the
pharmaceutically acceptable salts thereof; vitamixi B 12; an anti-oxidant
vitamin; a beta-blocker, an angiotensin II antagonist; an angiotensin
converting enzyme inhibitor; a platelet aggregation inhibitor; a
fibrinogen receptor antagonist; aspirin; fenfluramines,
dexfenfluramines, phentiramznes, ~3 adrenergic receptor agonists;
sulfonylureas, biguanides, oc-glucosidase inhibitors, other insulin
secretogogues, and insulin can be used together for the preparation of a
medicament useful for the above-described treatments.
The tablets, pills, capsules, and the like may also contain a
binder such as gum tragacanth, acacia, corn starch or gelatin; excipients
such,as dicalcium phosphate; a disintegrating agent such as corn starch,
potato starch, alginic acid; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, lactose or saccharin. When a dosage
unit form is a capsule, it may contain, in addition to materials of the
above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets may
be coated with shellac, sugar or both. t~ -syrup or elixir may contain, in
addition to the active ingredient, sucrose as a sweetening agent, methyl
and propylparabens as preservatives, a dye and a flavoring such as
cherry or orange flavor.
These active compounds may also be administered
parenterally. Solutions or suspensions of these active compounds can be
prepared in water suitably mixed with a surfactant such as hydroxy-
propylcellulose. Dispersions can also be prepared in glycerol, liquid
polyethylene giycois and mixtures thereof irx oils. Under ordinary
* Trade-mark
CA 02244836 1998-07-31
WO 97/28137 PCTliTS9TI(iIT49
- 37 -
conditions of storage and use, these preparations contain a preservative
to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use
include sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be fluid to
the extent that easy syringability exists. It must be stable under the
conditions of manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and fungi. The
carrier can be a solvent or dispersion medium containing, for example,
water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Specific examples of formula i may require the use of
protecting groups to enable their successful elaboration into the desired
structure. Protecting groups may be chosen with reference to Greene,
T.W., et al., Protective Groups in Organic S~mthesis, John Wiley &
Sons, Inc., 1991. The blocking groups are readily removable, i.e., they
can be removed, if desired, by procedures which will not cause cleavage
or other disruption of the remaining portions of the molecule. Such
procedures include chemical and enzymatic hydrolysis, treatment with
chemical reducing or oxidizing agents under mild conditions, treatment
with fluoride ion, treatment with a transition metal catalyst and a
nucleophile, and catalytic hydrogenation.
Examples of suitable hydroxyl protecting groups are:
trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-
nitrobenzyloxycarbonyl, t-butyldiphenylsilyl, t-butyldimethylsilyl,
benzyloxycarbonyl, t-butyloxycarbonyi, 2,2,2-
trichloroethyloxycarbonyl, and allyloxycarbonyl. Examples of suitable
carboxyl protecting groups are benzhydryl, o-nitrobenzyl, p-
nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroailyi, benzyl, 2,2,2-
trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butldiphenylsilyl,
2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-
methoxyphenyl, 4-pyridylmethyl and t-butyl.
CA 02244836 1998-07-31
WO 97/28137 PCT/LTS97/01749
_ 38
The process for making the compounds of the instant
invention is generally depicted in Scheme 1 below:
SCHEME 1
x~ Meo~w~
nngo~w~
~'~' O ~ / Y~~1~ L
O ~ ~~ n
YH
II
I
L = leaving group
2
'-'~ '~ /
I
L
n
~1
IH IV
2
+ l~ y ~ /
I IV
o ~I / w I
n
,
II + III v
L is a leaving group such as halo, preferably bromide, or sulfonyloxy,
preferably mesyloxy or tosyloxy.
The following examples are provided so that the invention
might be more fully understood. They should not be construed as
limiting the invention in any way.
CA 02244836 1998-07-31
WO 97128137 PCTlCTS'97/01749
' -39-
Example 1
,O ~ CI
I ~' II
O ~S~
Methyl 3-chioro-4-{3-(3-ethyl-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylthio)phenylacetate
to A: Preparation of 1-bromo-3-(2-hydroxy-3-propyl-4-
propion~phenox~propane
A solution of 2,4-dihydroxy-3-propylphenyl ethyl ketone
(25.545 grams) in 2-butanone (300 mL) was treated with 1,3-
dibromopropane (48.79 mL) and potassium carbonate (50.859 grams).
The mixture was refluxed for 4 hours. The reaction mixture was
partitioned between isopropyl acetate and pH 4 buffer. The organic was
washed once with water, then dried over magnesium sulfate. The
organic was filtered and evaporated to an oil which was
chromatographed over silica gel with hexane/methylene chloride {2:1 )
to afford the title compound.
NMR (CDCi3) 8 7.62 {d, 1H, J = 8.8 Hz), 6.43 {d, 1H, J = 8.8 Hz),
4.16 (t, 2H, J = 5.8 Hz), 3.60 (t, 2H, J = 6.4 Hz), 2.94 {quart, 2H, 3 =
7.3 Hz), 2.61 (bt, 2H, J = 7.5 Hz).
to B: Preparation of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-
4-propion~riphenoxv)prop i~io~phenviacetate
A solution of 3-chloro-4-dimethylcarbamoylthio-
phenylacetic acid methyl ester (33.038 grams) in dry methanol (350
mL) was treated with a solution of sodium methoxide in methanol
(25wt°7o; 34.15 mL). The solution was refluxed for 2 hours. HPLC
analysis showed the disappearance of the carbamate. The solution was
- allowed to cool to 50°C. 1-bromo-3-(2-hydroxy-3-propyl-4-
W
CA 02244836 1998-07-31
WO 97/28137 PCT/US97/01749
- -40-
propionyl)-phenoxy)propane (Step A; 31.500 grams) was added and the
solution stirred for 1 hour. The reaction was partitioned between '
isopropyl acetate and pH 4 buffer. The organic was washed once more '
with pH 4 buffer, then water. The organic was dried over magnesium
sulfate, filtered and concentrated to an oil. The oil was applied to a
silica gel column packed with hexane/methylene chloride (2:1 ). The
column was eluted with this mobile phase ur<til the product began to
appear in the eluant. The mobile phase was switched to I00%
methylene chloride and elution continued until all the title compound
was recovered.
NMR (Acetone) 8 7.8I (d, 1 H, J = 9.1 Hz), 7.25 (dd, 1 H, J = 8.1, 1.8
Hz), 6.62 (d, 1 H, J = 9.1 Hz), 4.27 (t, 2H, J = 5.9 Hz), 3.64 (s, 3H),
3.25 (t, 2H, J = 7.5 Hz), 3.04 (quart, 2H, J = 7.3 Hz), 2.65 (bt, 2H, J =
7.6 Hz).
step C: Preparation of methyl 3-chloro-4-(3-(2-propyI-3-hydroxy-
4-{ 1-hydroxyiminopropyl)phenoxy)propylthio)-
phenylacetate
A solution of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-4-
propionylphenoxy)propylthio)phenylacetate (Step B; 25.655 grams) in
dry methanol (260 mL) was treated with hydroxylamine hydrochloride
{3.833 grams). Anhydrous sodium acetate (4.524 grams) was added and
the mixture refluxed for 4 hours. The reaction mixture was partitioned
between isopropyl acetate and pH 7 buffer. The organic phase was
washed once with water and dried over magnesium sulfate, filtered and
evaporated to an oil. The title compound was used without further
purification.
NMR (CDCl3) S 7.1 I (dd, I H, J = 8.1, l .8 Hz), 6.42 (d, 1 H, J = 8.9
Hz), 4.09 (t, 2H, J = 5.7 Hz), 3.68 (s, 3H), 3.14 {t, 2H, 3 = 7.2 Hz), 2.83
(quart, 2H, J = 7.7 Hz), 2.66 (bt, 2H, J = 7:7 Hz).
a D: Preparation of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-
4-( 1-acetoxviminoprop,~phenoxv)propvlthio)nhenvlacetate '
CA 02244836 1998-07-31
Wa 97fZ8I37 PCTlzTS97/OI749
_ - -41 -
A solution of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-4-
- (I-hydroxyiminopropyl)phenoxy)propylthio)phenyl acetate (Step C;
' 5.96 grams) in acetic anhydride (50 mL) was stirred for 16 hours. The
solvent was removed in vacuo. The remaining residue was dissolved in
isopropyl acetate and washed with pH 7 buffer. The organic phase was
dried over magnesium sulfate, filtered and evaporated. The title
compound was used without further purification.
NMR (CDCl3) b 7.I1 (dd, 1H, J = 8.0, I.9 Hz), 6.44 (d, 1H, J = 8.8
Hz), 4.10 (t, 2H, J = 5.7 Hz), 3.68 (s, 3H), 3.I3 (t, 2H, J = 7.2 Hz), 2.86
(quart, 2H, J = 7.6 Hz), 2.67 (bt, 2H, J = 7.6 Hz), 2.22 (s, 3H).
to E: Preparation of methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-
benz-f4.51-isoxazoloxv)nropylthio~phenviacetate
A solution of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-4-
(1-acetoxyiminopropyl)phenoxy)propylthio)phenylacetate {Step D; 6.19
grams) in dry pyridine (65 mL) was refluxed for 3 hours. The solvent
was removed in vacuo and the residue partitioned between isopropyl
acetate and O.1N HCI. The organic was washed once more with O.1N
HCI. The organic was dried over magnesium sulfate, filtered and
evaporated to an oil. The crude product was placed on a slica gel
column and eluted with hexane/CH2Cl2 ( i :1 ) until the product appeared
in the eluant. The mobile phase was changed to 100% CH2Cl2 and
elution continued until all the title compound was recovered.
NMR (CDCl3) ~ 7.38 (d, 1H, J = 8.6 Hz), 7.I0 (dd, IH, J = 8.1, 1.8
Hz), 6.87 {d, IH, J = 8.6 Hz), 4.17 (t, 2H, J = 5.8 Hz), 3.68 (s, 3H), 3.16
(t, 2H, J = 7.1 Hz), 2.94 (quart, 2H, J = 7.6 Hz), 2.85 (bt, 2H, J = 7.5
Hz).
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WO 97/2$137 PCT/US97/01749
- - 42 -
lxalriple 2
Ho \ c1
~s ~o
3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propylthio)-
pl~envlacetic acid
A solution of methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-
benz-[4,5]-isoxazoloxy)propylthio)phenylacetate (4.95 grams) in
methanol (95 mL) was treated with a solution of LiOH in water ( I .299
M; I6.50 mL). The solution was refluxed for I hour. The solution
was partitioned between isopropyl acetate and O.1N HCI. The organic
layer was dried over magnesium sulfate, filtered and evaporated to a
solid. The solid was suspended in methylene chloride (18 mL) and
heated to reflux. Cyclohexane {l8mL) was added dropwise while
refluxing. The solution was cooled to 0°C and the title compound
isolated by filtration.
NMR {CDC13 ) ~ 7.3 8 (d, 1 H, J = 8.7 Hz), 7. I 0 (dd, 1 H, J = 8.1, 1.8
Hz), 6.87 (d, IH, J = $.7 Hz), 4.17 (t, 2H, J = 5.8 Hz), 3.57 (s, 2H), 3.16
{t, 2H, J = 7.1 Hz), 2.94 (quart, 2H, J = 7.6 Hz), 2.85 (bt, 2H, J = 7.5
Hz).
example 3
O'
~O \ CI
O I / i\/~ \ I ' N
S p 'O
Methyl 3-chloro-4-(3-(3-methoxy-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetate
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WO 97/28!37 PCT/US97/OI749
- - 43 -
to A: Preparation of methyl 2-hydroxy-3-propyl-4-benzyloxy-
benzoate
A solution of methyl 2,4-dihydroxy-3-propylbenzoate (3.00
grams) in 2-butanone (30 mL) was treated with benzyl bromide (I.70
mL) and potassium carbonate (1.972 grams). The mixture was refiuxed
for 4 hours. The reaction mixture was partitioned between isopropyl
acetate and pH 4 buffer. The organic was washed once with water, then
dried over magnesium sulfate. The organic was filtered and evaporated
to an oil which was chromatographed over silica gel to afford the title
compound.
NMR (CDCl3) ~ 7.67 (d, IH, J = 8.9 Hz), 7.42-7.29 (m, SH), 6.48 (d,
IH, J = 8.9 Hz), 5.12 (bs, 2H), 3.89 (s, 3H), 2.69 (bt, 2H, J = 7.4 Hz).
to B: Preparation of 2-hydroxy-3-propyl-4-benzyloxyphenyl
hvdroxamic acid
A solution of methyl 2-hydroxy-3-propyl-4-benzyloxy
benzoate (Step A; 0.863 grams) in dry methanol (8 mL) was treated
with hydroxylamine hydrochloride (0.299 grams) and a solution of
methanolic sodium methoxide (25 wt%; 0.986 mL). The solution was
refluxed for 8 hours. The reaction was partitioned between isopropyl
acetate and pH 4 buffer. The organic was dried over magnesium
sulfate, filtered and concentrated to a solid. The title compound was
used without further purification.
NMR (CD30D) S 7.45-7.26 (m, 6H), 6.54 {d, 1H, 3 = 8.8 Hz), 5.12
(bs, 2H), 2.67 {bt, 2H, J = 7.4 Hz).
Step C: Preparation of 3-hydroxy-6-benzyioxy-7-propylbenz-[4,5]-
isoxazole
A solution of 2-hydroxy-3-propyl-4-benzyloxyphenyl
hydroxamic acid (Step B; 0.477 grams) in dry THF (5 mL) was treated
with carbonyl di-imidazole (0.513 grams). The solution was stirred at
50° for I4 hours. The reaction was partitioned between isopropyl
acetate and pH 4 buffer. The organic was dried over magnesium
' - sulfate, filtered and evaporated to a solid which was digested in
CA 02244836 2005-03-23
WO 97128137 ~ ,:1 ~~~897I01749
44
refluxing tent-butyl methyl ether. The mixture was allowed to cool to
25°C and the product recovered by filtration. The rifle compound was
used without further purification.
NMR (CD3~D) 8 7.89 (d, 1H, J = 8.8 Hz), 7.47-7.3I (m, SH), 7.18 (d,
iH, J = 8.8 Hz), 5.25 (bs, 2H), 2.80 (bt, 2H,1= 7.4 Hz).
St- ep"D: Prepararion of 3-methoxy-6-benzyloxy-7-propylbenz-[4,5~-
isoxazoIe _. _ __
A solution of 3-hydroxy-6-benzyloxy-7-propylbenz-[4,5]-
isoxazole (Step C; I95 mg) in acetone (3 mL) was treated with methyl
iodide (0.067 mL) and potassium carbonate (100 mg). 'lRhe mixture was
refluxed for 8 hours. The reaction was partitioned between isopropyl
acetate and pH 4 buffer. The organic was dried over magnesium
sulfate, filtered and concentrated to a solid, which was chromatographed
over silica gel to afford the title compound.
NMR (CD3C?D) ~ 7.89 {vbd,1H, 3 = 8.8 Hz), 7.47-7.31 (m, SH), 7.16
(vbd, 1H, J = 8.8 Hz), 5.23 (bs, 2H), 3.97 (s, 3H), 2.79 (vbt, 3 = 7.3 Hz).
Step E:, Preparation of 3-methoxy-6-hydroxy-7-propylbenz-[4,5]-
isoxazole
A solution of 3-methoxy-6-benzyloxy-7-propylbenz-(4,5)-
isoxazole '(Step E; 181 mg) in ethyl acetate (4 mL) was treated with 10%
palladium on carbon catalyst (25 mg). The mixture was shaken under a
hydrogen atmosphere (40 psi) for 3 hours. The mixture was filtered
through Ceiite and concentrated to a solid. The title compound was used
without further purification.
NMIZ (CD30D) ~ 7.70 (d, 1H,1= S.9 Hz), 6.80 (d, 1H, T = 8.9 Hz),
3.93 (s, 3H), 2.69 (bt, 2H, T = 7.6 Hz).
Step F: Preparation of 3-methoxy-6-(3-bromopropyl)oxy-7-
prop~rl-bent-(4.51-isoxazole
Using the method of Example 1, Step A, substituting 3-
methoxy-6-hydroxy-7-propylbenz-(4,5)-isoxazole (Step E) as the
starting material, the ride compound was obtained.
* Trade-mark
CA 02244836 1998-07-31
WO 97/28137 PCTILTS97101749
- 45 -
NMR (CDCl3 ) 8 7.92 (d, 1 H, 3 = 8.9 Hz), 6.90 {d, 1 H, J = 8.8 Hz),
~ 4.22 (t, 2H, J = 5.8 Hz), 4.04 (s, 3H), 3.60 (t, 2H, J = 6.3 Hz), 2.72 (bt,
2H, 3 = 7.5 Hz).
Step G: Preparation of methyl 3-chloro-4-(3-(3-methoxy-7-propyl-
6-bent-14.51-isoxazoloxX,)prop, 1y thio~phenvlacetate
Using the method of Example 1, Step B, substituting 3-
methoxy-6-{3-bromopropyl)oxy-7-propyl-benz-[4,5]-isoxazole as the
starting material, the title compound was obtained.
NMR {CDCl3) 8 7.66 (d, iH, J = 8.9 Hz), 7.10 (dd, 1H, J = 8.1, 1.8
Hz), 6.40 {d, 1H, J = 8.9 Hz}, 4.14 (t, 2H, J = 5.7 Hz), 3.89 (s, 3H), 3.68
(s, 3H}, 3.13 (t, 2H, J = 7.2 Hz}, 2.65 {bt, 2H, J = 7.6 Hz).
xam 1e 4
O'
Ho ( ~ c~
~ /~ N
O ~S ~O ~ U
3-chloro-4-(3-(3-methoxy-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylthio)-phenylacetic acid
1. 2-h dy roxv_-3 _propvl-4-benz~oxyphenvl hydroxamic acid
A solution of 2-hydroxy-3-propyl-4-benzyloxy benzoic acid
methyl ester (0.863 grams) in dry methanol (8 mL) was treated with
hydroxylamine hydrochloride {0.299 grams) and a solution of
methanolic sodium methoxide (25 wt%; 0.986 mL). The solution was
refluxed for 8 hours. The reaction was partitioned between isopropyl
acetate and pH 4 buffer. The organic was dried over magnesium
sulfate, filtered and concentrated to a solid. The product was used
without further purification.
NMR (CD30D} d 7.45-7.26 (m, 6H), 6.54 {d, 1H, J = 8.8 Hz), S.I2
(bs, 2H), 2.67 (bt, 2H, J = 7.4 Hz).
CA 02244836 1998-07-31
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-46- ,
2. ~- vdroxy-6-benzvloxy-7-propel-benzF4 57isoxazole
A solution of 2-hydroxy-3-propyl-4-benzyloxyphenyl
hydroxamic acid (0.477 grams) in dry THF (5 mL) was treated with
carbonyl di-imidazole (0.513 grams). The solution was stirred at 50°
for 14 hours. The reaction was partitioned between isopropyl acetate
and pH 4 buffer. The organic was dried over magnesium sulfate,
filtered and evaporated to a solid which was digested in refluxing tert-
butyl methyl ether. The mixture was allowed to cool to 25°C and the
product recovered by filtration. The product was used without further
purification.
NMR (CD30D) d 7.89 (d, IH, J = 8.8 Hz), 7.47-7.31 (m, 5H), 7.18 (d,
1 H, J = 8.8 Hz), 5.25 (bs, 2H), 2.80 (bt, ZH, J = 7.4 Hz).
3. 3-methoxv-6-benzvloxv-7-propel-benzf4 5lisoxazole
A solution of 3-hydroxy-6-benzyloxy-7-propyl
bent[4,5Jisoxazole (I95 mg) in acetone (3 mL) was treated with methyl
iodide (0.067 mL) and potassium carbonate (100 mg). The mixture was
refluxed for 8 hours. The reaction was partitioned between isopropyl
acetate and pH 4 buffer. The organic was dried over magnesium
sulfate, filtered and concentrated to a solid, which was chromatographed
over silica gel to afford the product.
NMR {CD3OD) d 7.89 (vbd, 1H, J = 8.8 Hz), 7.47-7.31 (m, 5H), 7.16
(vbd, 1H, J = 8.8 Hz), 5.23 (bs, 2H), 3.97 (s, 3H), 2.79 (vbt, J = 7.3 Hz).
4. 3-methoxv-6-hvdroxv-7~,nropvl-benzf4 5lisoxazole
A solution of 3-methoxy-6-benzyloxy-7-propyl Benz-{4,5)-
isoxazole ( 181 mg) in ethyl acetate (4 mL) was treated with 10%
palladium on carbon catalyst (25 mg). The mixture was shaken under a
hydrogen atmosphere (40 psi) for 3 hours. The mixture was filtered
through Celite and concentrated to a solid. The product was used
without further purification.
NMR (CD30D) d 7.70 (d, 1 H, J = 8.9 Hz), 6.80 (d, 1 H, J = 8.9 Hz),
3.93 (s, 3H), 2.69 (bt, 2H, J = 7.6 Hz)
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5. 1-bromo-3-(3-methoxv-7-yronyl-6-benzf4.5~s oxazole)oxv Dronane
A solution of 3-methoxy-6-hydroxy-7-propyl-
benz[4,5]isoxazole (0.112 grams) in 2-butanone (1.5 mL) was treated
with 1,3-dibromopropane {0.215 mL) and potassium carbonate (0.078
grams). The mixture was stirred at 60°C for 16 hours. The reaction
was partitioned between isopropyl acetate and pH 4 phosphate buffer.
The organic was dried over magnesium sulfate, filtered and evaporated
to a residue. The product was purified by silica gel chromatography.
NMR (CDCl3) d 7.92 (d, 1H, J = 8.9 Hz), 6.90 (d, 1H, J = 8.9 Hz),-
4.I2 (t, 2H, J = 5.6 Hz), 4.03 (s, 3H), 3.60 (t, 2H, J = 6.5 Hz), 2.72 (bt,
2H, J = 7.5 Hz).
6. IVlethvI 3-chloro-4-(3-(3-methox ~-~7-propel-6-benzf4.51isoxazole)
oxv)prop, 1y thio~henvl acetate
A solution of 3-chloro-4-dimethylcarbamoylthiophenyl
acetic acid methyl ester (0.109 grams; 0.380 mmol) in dry methanol (2
mL) was treated with a solution of sodium methoxide in methanol
(25wt%; 0.122 mL). The solution was refluxed for 2 hours. LC
analysis showed the disappearance of the carbamate. The solution was
allowed to cool to ambient temperature. 1-bromo-3-(3-methoxy-7-
propyl-6-bent[4,5]isoxazole)oxy propane (0.104 grams; 0.317 mmol)
was added and the solution stirred for I hour. The reaction was
partitioned between isopropyl acetate and pH 4 buffer. The organic was
dried over magnesium sulfate, filtered and concentrated to an oil. The
oil was chromatographed over silica gel to afford the title compound.
NMR (CDC13): 7.66 (d, IH, J = 8.9 Hz); 7.11 {dd, 1H, J = 8.1, 1.9 Hz);
6.39 {d, 1H, 3 = 8.9 Hz); 4.12 (t, 2H, J = 5.7 Hz); 3.89 (s, 3H); 3.68
(s, 3H); 3.58 (s, 2H); 3.13 (t, 2H, J = 7.1 Hz); 2.63 (bt, 2H, J = 7.6
Hz).
7. 3-chloro-4-(3-(3-methoxy-7-propel-6-benzf4.51isoxazole?oxX,)
propvlthio phenyl acetic acid
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A solution of methyl 3-chloro-4.-(3-(3-methoxy-7-propyl-6-
benz[4,5]isoxazole)oxy)propylthio phenyl acetate (0.130 grams; 0.280
mmol) in methanol (2 mL) was treated with a solution of LiOH in
water (1.084 M; 0.387 mL). The solution was refluxed for I hour.
The solution was partitioned between isopropyl acetate and O.1N HCI.
The organic layer was dried over magnesium sulfate, filtered and
evaporated to a solid. The solid was suspended in methylene chloride ( 1
mL) and heated to reflux. Cyclohexane (2 mL) was added dropwise
while refluxing. The solution was cooled to 0°C and the product
isolated by filtration.
NMR (CDCI3): 7.66 (d, I H, J = 8.9 Hz), 7.11 (dd, I H, J = 8.1, 1.9 Hz),
6.39 (d, 1H, 3 = 8.9 Hz), 4.12 (t, 2H, J = 5.7 Hz), 3.89 (s, 3H), 3.58 (s,
2H), 3.I 3 (t, 2H, J = 7.1 Hz), 2.63 (bt, 2H, 3 = 7.6 Hz).
l~xam~pIe 5_
~O ~ C(
l
~S~O
Methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-Benz-[4,5]-isothiazoloxy)-
propylthio)phenyl acetate
Step A: Preparation of 2-chloro-3-(3-propenyl)-4-hydroxy-
henzaldehvde
A solution of 2-chloro-4-(3-propenyl)oxybenzaldehyde
(6.62 grams) in ortho-dichlorobenzene (40 mL) was refluxed for 22
hours. The solvent was removed in vacuo and the derived solid was l
chromatographed over silica gel to afford the title compound.
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_ NMR {CD30D) d 10.28 (s, 1 H), 7.79 {d, 1 H, J = 8.9 Hz), 6.84 (d, 1 H,
. J = 8.9 Hz), 5.90 {m, 1 H), 5.03-4.95 (two overlapping dd, 2H), 3.68 (d,
2H, J = 4.7 Hz).
~p B: Preparation of 2-chIoro-3-propel-4-h,~xvbenzaldeh d~
A solution of 2-chloro-3-(3-propenyl)-4-hydroxy-
benzaldehyde (Step A; 0.923 grams) in methyl tert-butyl ether (10 mL)
was treated with 5% rhodium on alumina (140 mg). The mixture was
shaken under a hydrogen atmosphere (2I psi) for 2 hours. The mixture
was filtered through Celite and evaporated to a solid. The title
compound was used without further purification.
NMR (CD30D) ~ 10.27 (s, I H), 7.64 (d, 1 H, J = 8.8 Hz), 6.81 (d, 1 H,
J = 8.7 Hz}, 2.79 (bt, 2H, 3 = 7.6 Hz).
St, ep C: Preparation of 2-chloro-3-propel-4-benzvloxvbenzaldehvde
Using the method of Example 3, Step A, substituting 2-
chloro-3-(3-propenyI)-4-hydroxybenzaldehyde (Step B) as the starting
material, the title compound was obtained.
NMR (acetone) b 10.35 (s, 1 H), 7.79 (d, 1 H, J = 8.8 Hz}, 7.22 (d, 1 H,
J = 8.8 Hz), 5.31 (bs, 2H), 2.88 (bt, 2H, J = 7.4 Hz).
to : Preparation of 2-methylthio-3-propyl-4-benzyioxy-
benzaidehvde
A solution of 2-chloro-3-propyl-4.-benzyloxybenzaldehyde
(Step C; 0.683 grams) in dry DMF {7 mL) was treated with sodium
methanethiolate (0.166 grams). The solution was stirred at 50°C for 3
hours. The reaction mixture was partitioned between isopropyl acetate
and pH 7 buffer. The organic was washed 3 times with water, then
dried over magnesium sulfate. Filtration and concentration afforded an
oil which was chromatographed over silica gel to afford the title
compound.
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NMR (acetone) 8 10.61 (s, 1H), 7.79 (d, 1H, J = 8.8 Hz), 7.52-7.45
(m, SH), 7.24 (d, I H, J = 8.8 Hz), 5.29 (bs, 2H), 3.05 (bt, ZH, J = 7.6 .
Hz), 2.38 (s, 3H).
Step E: Preparation of 1-(2-methylthio-3-propyl-4-benzyloxy)-
envl-1-propanol
A solution of 2-methylthio-3-propyl-4-benzyloxy-
benzaldehyde {Step D; 324 mg) in dry diethyl ether (3 mL) was added
dropwise to a -78°C solution of 1M ethyl magnesium bromide in diethyl
ether (2.S mL). The reaction was stirred for 1 S minutes, then allowed
to warm to -10°C. The solution was treated with saturated aqueous
ammonium chloride (2 mL), then allowed to warm to 2S°C. The
reaction was partitioned between isopropyl acetate and water. The
organic was dried over magnesium sulfate, filtered and evaporated to an
oiI which was chromatographed over silica gel to afford the desired
product.
NMR (acetone) 8 7.09 {d, 1H, 3 = 8.9 Hz), 5.31 (vbm, IH), 5.13 (bs,
2H), 4.00 (vbs, 1 H), 3.02 {bm, 2H), 2.24 {s, 3H).
Stgp F: Preparation of 2-methylthio-3-propyl-4-benzyloxypropio-
phenone
A -SS°C solution of trifluoroacetic anhydride (0.291 mL)
in dry methylene chloride (2 mL) was treated dropwise with a solution
of dry DMSO (0.292 mL) in methylene chloride (1 mL). The reaction
was stirred for 15 minutes, then treated with a solution of I -(2-
methylthio-3-propyl-4-benzyloxy)phenyl-I-propanol {Step E; 136 mg)
in methylene chloride (2 mL). The solution was stirred for 30 minutes,
then treated dropwise with dry triethylamine (1.15 mL). The mixture
was stirred for 1 hour as it was allowed to warm to 2S°C. The reaction
was partitioned between isopropyl acetate and pH 7 buffer. The organic
layer was dried over magnesium sulfate, filtered and concentrated to an
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oil which was chromatographed over silica geI to afford the title
compound.
IVMR (acetone) d 7.16 (d, 1 H, J = 8.8 Hz), 7.11 (d, 1 H, J = 8.8 Hz),
5.20 (bs, 2H), 3.00 (bt, 2H, T = 7.4 Hz), 2.88 (quart, 2H, J = 7.2 Hz),
2.27 (s, 3H).
Step G: Preparation of 2-methylthio-3-propyl-4-benzyloxypropio-
nhenone oxime
Using the method of Example 1, Step C, substituting 2-
methylthio-3-propyl-4-benzyloxypropiophenone (Step F) as the starting
material, the title compound was obtained.
NMR (major isomer, acetone) 8 9.9I (vbs, I H}, 7.07 {d, 1 H, J = 8.7
Hz), 7.03 (d, 1 H, J = 8.7 Hz), 5.16 (bs, 2H), 3.02 {bt, 2H, 3 = 7.6 Hz),
2.79 (quart, 2H, J = 7.4 Hz), 2.22 {s, 3H}.
a H: Preparation of 3-ethyl-6-benzyloxy-7-propylbenz-[4,5J-
isothiazole
A solution of 2-methylthio-3-propyl-4-benzyloxypropio-
phenone oxime (Step G; 86 mg) in dry pyridine (2 mL) was treated with
acetic anhydride {0.050 mL). The solution was refluxed for 4 hours.
Three-quarters of the solvent was removed in vacuo. The remaining
reaction mixure was partitioned between isopropyl acetate and O.1N
HCI. The organic was washed 3 times more with O.1N HCI, then once
with water. The organic was dried over magnesium sulfate, filtered and
concentrated to an oil. Silica gel chromatography afforded the title
compound.
NMR (acetone) S 7.88 (bd, I H, J = 8.9 Hz), 7.54-7.30 (m, 6H), 5.30
(bs, 2H), 3.04 (b quart, 2H, J = 7.3 Hz), 2.86 (bt, 2H, J = 7.5 Hz).
to J: Preparation of 3-ethyl-6-hydroxy-7-propyl-Benz-[4,5)-
isothiazole
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Using the method of Example 3, Step E, substituting 3-
ethyl-6-benzyloxy-7-propylbenz-[4,5]-isothiazole (Step H) as the starting ,
material, the title compound was obtained.
NMR (acetone) 8 8.93 (vbs, I H), 7.72 (d, 1 H, J = 8.8 Hz), 7.08 (d,
1H, J = 8.8 Hz), 3.03 {quart, 2H, J = 7.4 Hz), 2.80 {bt, 2H, J = 7.7 Hz).
,S~t g~ Preparation of 3-ethyl-6-(3-bromopropyloxy)-7-
DTOV~ibenz-f4.51-isothiazole
Using the method of Example 1, Step A, substituting 3-
ethyl-6-hydroxy-7-propylbenz-[4,5]-isothiazole (Step J} as the starting
material, the title compound was obtained.
NMR (acetone} b 7.90 (d, I H, J = 8.9 Hz), 7.28 (d, 1 H, J = 8.9 Hz},
4.31 (t, 2H, J = 5.6 Hz), 3.75 (t, 2H, J = 6.5 Hz), 3.04 (quart, 2H, J =
7.3 Hz), 2.82 {bt, 2H, J = 7.5 Hz).
tee Preparation of methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-
benz-f4.51-isothiazoloxv)~ropvlthio)phen Iv acetate
Using the method of Example I , Step B, substituting
3-ethyl-6-(3-bromopropyloxy)-7-propylbenz-[4,5]-isothiazole (Step K)
as the starting material, the title compound was obtained.
NMR (acetone) ~ 7.90 {d, I H, J = 8.8 Hz), 7.25 (overlapping d and dd,
2H, Jd = 8.8 Hz}, 4.33 (t, 2H, J = 5.7 Hz}, 3.63 (two overlapping s, 5H),
3.29 (t, 2H, J = 7.4 Hz), 3.04 (quart, 2H, J = 7.6 Hz), 2.83 (bt, 2H, J =
7.5 Hz).
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- example 6
HO ~ CI
I
O v 'S ~O
3-chloro-4-(3-(3-ethyl-7-propyl-6-Benz-[4,5)-isothiazole)oxy)propyl-
thio phenylacetic acid
Using the method of Example 2, substituting methyl 3-
chloro-4-{3-(3-ethyl-7-propyl-6-
benz[4,5]isothiazoloxy)propylthio)phenylacetate (Example 5) as the
starting material, the title compound was obtained.
NMR (acetone) ~ 7.90 (d, 1 H, J = 8.8 Hz), 7.26 (overlapping d and dd,
2H, Jd = 8.8 Hz), 4.33 (t, 2H, J = 5.7 Hz), 3.63 (s, 2H), 3.29 (t, 2H, J =
7.4 Hz), 3.05 (quart, 2H, J = 7.6 Hz), 2.83 (bt, 2H, J = 7.5 Hz).
~x~lnple 7
~O y i
I N
Q
Methyl 3-chloro-4-(3-(3-methyl-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylthio)phenylacetate
k
- Step A: Preparation of 3-methyl-6-hydroxy-7-propylbenz-[4,5]-
isoxazole
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l
A solution of 2,4-dihydroxy-3-propylacetophenone (1.008
grams) in dry methanol (lOmL) was treated with hydroxylamine
hydrochloride (I.803 grams) and anhydrous sodium acetate (2.127
grams). The mixture was refluxed 4 hours. HPLC analysis indicated
the complete disappearance of starting material. The reaction was
partitioned between isopropyl acetate and pH 7 buffer. The organic was
dried over magnesium sulfate, filtered and evaporated to a solid. Acetic
anhydride (l l mL) was added and the solution stirred at ambient
temperature for 14 hours. The solvent was removed in vacuo and the
residue partitioned between isopropyl acetate and pH 7 buffer. The
organic was dried over magnesium sulfate, filtered and concentrated to
a residue. Pyridine {12 mL) was added and the solution refluxed for 3
hours. The solvent was removed in vacuo and the residue partitioned
between isopropyl acetate and 0.1 N HCI. The organic was washed with
0.1 N HCI and dried over magnesium sulfate. The organic was filtered
and concentrated to a residue which was chromatographed over silica
gel to afford the title compound.
NMR {CDCI3 ) 8 7.28 (d, 1 H, J = 8.8 Hz), 6.80 (d, 1 H, J = 8.8 Hz),
5.33 (vbs, 1 H), 2.83 (bt, 2H, J = 7.6 Hz), 2.50 (s, 3H).
~~tey : Preparation of 3-methyl-6-(3-bromopropyI)oxy-7-propyl-
benz-f4.51-isoxazole
Using the method of Example l, step A, substituting 3-
methyI-6-hydroxy-7-propylbenz-[4,5]-isoxazole (Step A) as the starting
material, the title compound was obtained.
NMR (CDCl3) 8 7.38 {d, 1H, J = 9.0 Hz), 6.92 (d, IH, J = 9.0 Hz),
4.20 (t, 2H, J = 5.7 Hz), 3.64 (t, 2H, J = 6.4 Hz), 2.87 (bt, 2H, J = 7.6
Hz), 2.51 (s, 3H).
Step C: Preparation of methyl 3-chloro-4-(3-(3-methyl-7-propyl-6
Benz-f4,51-isoxazoloxvlproDr vlthio) henvlacetate
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Using the method of Example 1, step B, substituting 3-
methyl-6-{3-bromopropyl)oxy-7-propyl-bent-[4,5]-isoxazole (Step C) as
the starting material, the title compound was obtained.
NMR (CDCl3) b 7.35 (d, 1H, J = 8.6 Hz), 7.10 (dd, 1H, J = 8.1, 1.8
Hz), 6.89 (d, 1H, J = 8.6 Hz), 4.17 (t, 2H, J = 5.8 Hz), 3.68 (s, 3H), 3.16
(t, 2H, J = 7.1 Hz), 2.50 (s, 3H), 2.85 (bt, 2H, J = 7.5 Hz).
Example 8
HO ~ C
N
S
3-chloro-4-{3-(3-methyl-7-propyl-6-bent-[4,5]-isoxazoloxy)propylthio)-
phenylacetic acid
Using the method of Example 2, substituting methyl. 3-
chloro-4-(3-(3-methyl-7-propyl-6-benz-[4,5]-
isoxazoloxy)propylthio)phenylacetate (Example 7) as the starting
material, the title compound was obtained.
NMR (CDC13 ) ~ 7.34 (d, 1 H, J = 8.7 Hz), 7.10 (dd, 1 H, J = 8.1, 1.8
Hz), 6.89 (d, 1H, J = 8.7 Hz), 4.17 (t, 2H, J = 5.8 Hz), 3.58 (s, 2H), 3.17
(t, 2H, J = 7.2 Hz), 2.84 {bt, 2H, J = 7.5 Hz), 2.50 (s, 3H).
4
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_ _ _ 56 _
xam 1e 9
~O ~ C
I
'S
Methyl 3-chloro-4-(3-{3,7-dipropyl-6-Benz-[4,5]-isoxazole)oxy)-
propylthio phenyl acetate
to A: Preparation of 2-hydroxy-3-propyl-4-(3-bromopropyloxy)-
phenvl prowl ketone
Using the method of Example 1, step A, substituting 2,4-
dihydroxy-3-propylphenyI propyl ketone as the starting material, the
title compound was obtained.
NMR (CDCl3 ) ~ 7.61 {d, 1 H, J = 8.8 Hz), 6.43 (d, 1 H, J = 8.8 Hz),
4.16 (t, 2H, J = 5.7 Hz), 3.60 (t, 2H, J = 6.4 Hz), 2.87 {t, 2H, J = 7.4
Hz), 2.61 (bt, 2H, J = 7.5 Hz).
step B: Preparation of methyl 3-chloro-4-{3-{2-propyl-3-hydroxy-
4-butvronhenoxv)~rOp, Ithio)nhenvlacetate
Using the method of Example I, step B, substituting 2-
hydroxy-3-propyl-4-(3-bromopropyloxy)phenyl propyl ketone as the
starting material, the title compound was obtained.
NMR (CDCI3} ~ 7.61 (d, IH, J = 9.0 Hz), 7.I1 (dd, IH, 3 = 8.1, I.8
Hz), 6.41 (d, 1 H, J = 8.9 Hz), 4.14 (t, 2H, J = 5.8 Hz), 3.68 (s,3I~), 3.13
(t, 2H, J = 7.6 Hz), 2.87 (t, 2H, J = 7.1 Hz), 2.60 (bt, 2H, J = 7.4 Hz).
~tren C: Preparation of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-
4-( I -hvdroxvlizr~inobut~}phenox~ .~ropvlthio)phen,~c_etate
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r
Using the method of Example 1, step C, substituting methyl
3-chloro-4-(3-(2-propyl-3-hydroxy-4-
butyrophenoxy)propylthio)phenyl-acetate as the starting material, the
title compound was obtained.
NMR (CDC13) 8 7.12 (dd, IH, J = 8.0, 1.8 Hz), 6.43 (d, 1H, J = 8.9
Hz}, 4.09 (t, 2H, J = 5.7 Hz}, 3.69 (s, 3H}, 3.13 (t, 2H, J = 7.3 Hz), 2.79
(bt, 2H, J = 7.9 Hz), 2.65 (bt, 2H, J = 7.6 Hz).
t D: Preparation of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-
4-(1-acetoxyiminobutyl))phenoxy)propylthio phenyl
acetate
Using the method of Example 1, step D, substituting methyl
3-chloro-4-(3-(2-propyl-3-hydroxy-4-(1-hydroxyliminobutyl)phenoxy)-
propylthio)phenylacetate as the starting material, the title compound was
obtained.
NMR {CDC13) 8 7.11 (dd, IH, J - 7.9, 1.8 Hz), 6.43 (d,lH, 3 = 8.8
Hz), 4.09 (t, 2H, J = 5.8 Hz), 3.69 (s, 3H), 3.13 {t, 2H, J = 7.2 Hz), 2.82
(bt, 2H, J = 7.8 Hz), 2.68 (bt, 2H, J = 7.7 Hz).
t E: Preparation of methyl 3-chloro-4-(3-(3,7-dipropyl-6-benz-
f4.Sl-isoxazoloxy~propvlthio)phenvl acetate
Using the method of Example 1, step E, substituting methyl
3-chloro-4-(3-{2-propyl-3-hydroxy-4-(I-acetoxyiminobutyl) phenoxy)
propylthio)phenylacetate as the starting material, the title compound was
obtained.
NMR (CDCl3) S 7.37 {d, 1H, J = 8.7 Hz), 7.10 (dd, 1H, J = 8.1, 1.8
Hz), 6.88 (d, I H, J = 8.7 Hz), 4.17 {t, 2H, J = 5.9 Hz), 3.68 (s, 3H), 3.15
(t, 2H, J = 7.2 Hz), 2.90-2.81 (2 overlapping t, 4H).
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Example 10
HO ~ CI
I
O ~S ~O
3-chloro-4-(3-(3,7-dipropyl-6-benz-[4,5]-isoxazoloxy)propylthio)
phenyl-acetic acid
Using the method of Example 2, substituting methyl 3-
chloro-4-(3-(3,7-dipropyi-6-bent-[4,5]-
isoxazoloxy)propylthiophenylacetate as the starting material, the title
compound was obtained.
NMR (CDCl3 ) 8 7.38 (d, 1 H, J = 8.8 Hz), 7.10 (dd, 1 H, J = 8.1, 1.8
Hz), 6.87 (d, 1H, J = 8.8 Hz), 4.17 (t, 2H, J = 5.8 Hz), 3.57 (s, 2H), 3.16
(t, 2H, J = 7.1 Hz) 2.91-2.81 (2 overlapping t, 4H).
Example 11
,O
I
0
s
c1 o
Methyl 3-chloro-4-(3-(3-ethyl-7-propyI-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetate S-oxide
A 25°C solution of methyl 3-chioro-4-(3-(3-ethyl-7-propyl-
6-benz-[4,5]-isoxazoloxy)propylthio)phenylacetate (Example '1; 57 mg)
in methanol (2 mL) was treated with 80% magnesium
monoperoxyphtalate hexahydrate (49 mg). The mixture was stirred for _
1 hour. The reaction was partitioned between isopropyl acetate and pH
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7 buffer. The organic was washed once with water and dried over
magnesium sulfate. Filtration and concentration afforded a solid which
was purified by chromatography over silica gel to afford the title
compound.
NMR (CDCl3) 8 7.83 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 8.1, 1.8
Hz), 6.82 (d, 1H, J = 8.8 Hz), 4.16 (dtt, 2H), 3.70 (s, 3H), 3.35 (ddd,
I H), 2.98 (ddd, 1 H), 2.92 (quart, 2H, J = 7.5 Hz), 2.79 (bt, 2H, J = 7.6
Hz).
Example 12
HO
SAO
~i
CI O
3-chloro-4-(3-(3-ethyl-7-propyl-6-bent-[4,5}-isoxazoloxy)propylthio)-
phenylacetic acid S-oxide
Using the method of Example 2, substituting methyl 3-
chloro-4-{3-(3-ethyl-7-propyl-6-benz-[4,5]-
isoxazoloxy)propylthio)phenyiacetate S-oxide (Example 1 i ) as the
starting material, the title compound was obtained.
NMR (acetone) ~ 7.81 (d, 1H, J = 8.9 Hz), 7.59 (dd, IH, J = 8.I, 1.8
Hz), 7.04 (d, 1H, J = 9.0 Hz), 4.27 (tt, J = 5.7, 1.l, 1.1 Hz), 3.78 (s,
2H), 3.39 (ddd, 1H), 3.03 {ddd, 1H), 2.94 (quart, 2H, J = 7.8 Hz), 2.82
(bt, 2H, J = 7.9 Hz).
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Exalnpie 13
,O
O
,S~ O
CI O O
Methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-
isoxazoloxy)propyl-thio)phenylacetate S,S-dioxide
A solution of methyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-
ijenz-[4,5]-isoxazoloxy)propylthio)phenylacetate S-oxide (Example 11;
34 mg) in methanol (1 mL) was treated with 80% magnesium
monoperoxyphtalate hexahydrate (33 mg). The solution was stirred at
25°C for 16 hours. The reaction was partitioned between isopropyl
acetate and pH 7 buffer. The organic was washed once with water, then
dried over magnesium sulfate. Filtration and evaporation afforded a
solid which was chromatographed over silica gel to give the title
compound.
NMR (CDCl3 ) 8 8.05 (d, 1 H, J = 8.9 Hz), 7.36 (dd, 1 H, J = 8.1, 1.9
Hz), 6.77 (d, I H, J = 8.9 Hz), 4.12 (t, 2H J = 5.7 Hz), 3.71 (s, 3H), 3.67
(bt, 2H, J = 7.3 Hz), 2.92 (quart, 2H, 3 = 7.4 Hz), 2.80 (bt, J = 7.6 Hz).
Example I4
HO
0
.SAO
CI O O
3-Chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazole)oxy)-propylthio
phenylacetic acid S,S-dioxide -
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Using the method of Example 2, substituting methyl 3-
. chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-
isoxazoloxy)propylthio}phenylacetate S,S-dioxide (Example 13) as the
starting material, the title compound was obtained.
NMR {CDCl3) S 8.09 (d, 1H, J = 8.8 Hz), 7.38 {dd, IH, J = 8.I, 1.9
Hz), 6.80 (d, 1 H, J = 8.8 Hz), 4.13 (t, 2H J = 5.6 Hz), 3.69 (s, 2H), 3.65
(bt, 2H, J = 7.2 Hz), 2.93 {quart, 2H, J = 7.5 Hz), 2.80 (bt, J = 7.6 Hz).
E~ple l 5
i~o
o w S~o w o
ci
tert-Butyl 3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy}-
propylthio)phenyl acetate
A solution of 3-chloro-4-(3-(3-ethyl-7-propyl-6-bent-[4,5]-
isoxazoloxy)propylthio)phenylacetic acid (Example 2; 0.073 grains) in
dry toluene (1.0 mL} was treated with dimethylformamide bis-tert-butyl
acetal (0.780 mL}. The solution was heated at 70°C for 24 hours. The
reaction was partitioned between isopropyl acetate and pH 4 buffer.
The organic layer was dried over magnesium sulfate and filtered.
Concentration afforded a solid which was chromatographed over silica
gel to afford the title compound.
NMR (CDCl3) 8 7.38 (d, iH, J = 8.8 Hz), 7.10 (dd, 1H, J = 8.1, 1.8
Hz), 6.87 (d, 1 H, J = 8.8 Hz), 4.17 (t, 2H, J = 5.8 Hz), 3.43 (s, 2H), 3. I 6
(t, 2H, J = 7.1 Hz), 2.94 (quart, 2H, J = 7.6 Hz), 2.85 {bt, 2H, J = 7.5
Hz), 1.40 (s overlapping with downfield peak of t, 12H total).
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Example 16
HO / CI
I
~s~o
3-Chloro-4-(3-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid
Step 1A
A solution of 3-chloro-4-dimethylcarbamoylthiophenyl acetic acid
methyl ester (10.028 grams; 34.848 mmol) in dry MeOH (90 mL) was
treated with a solution of sodium methoxide (4.37 M; 11.16 mL;
48.788 mmol). The reaction was refluxed for 2 hours. The reaction
mixture was cooled to 20° C and transferred to a dropping funnel. The
dropping funnel was placed atop a flask containing a solution of
dibromopropane (14.15 rnL; 139.392 mmol) in dry MeOH (50 mL).
The contents of the dropping funnel were added to the flask dropwise,
and the solution stirred for 2 hours. The reaction mixture was
partitioned between isopropyl acetate and pH 4 buffer. The layers were
separated and the organic washed once with water. The organic was
dried over magnesium sulfate, filtered and concentrated. Silica gel
chromatography afforded 3-chloro-4-(3-bromopropyl)thiophenyl acetic
acid methyl ester.
Step I
Commercially available 4-allyloxy-2-hydroxybenzophenone (15 g) was
rearranged by heating under reflux in ortho-dichlorobenzene (60 mL)
for 26 hours. The product was isolated by dilution of the reaction .
mixture with 5 volumes hexanes to give a crystalline product as fine
needles. .
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' Characteristic NMR Resonances; 1H NMR 400MHz (CDC13); 7.62-7.59
' (m, 2H), 7.56-7.52 (m, 2H), 7.49-7.44 {m, 2H), 7.40 (d, 1H, J=8.9 Hz),
6.34 (d, I H, J=8.8 Hz), 6.02 (ddt, 1 H, J=17.21, 10.1, 6.2 Hz}, 5.72 {s,
1H, phenol OH), 5.14-5.24 (m, 2H}, 3.53 (d with fine splitting, 2H,
3=6.2 Hz).
Step 2
A solution of 2,4-dihydroxy-3-(2-propenyl)benzophenone (3 g) was
reduced under ~ 1 atm H~ in ethyl acetate (100 mL) over 10% Pd/C
catalyst (0.3 grams) for 3 hours. The product was purified by
crystallization from methanol/water. The product is obtained as small
yellow plates.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCI3); 7.61-7.59
(m, 2H), 7.55-7.51 {m, 1 H), 7.48-7.44 (m, 2H), 7.33 (d, I H, J=8.8 Hz),
6.29 (d, 1 H, J=8.8 Hz), 5.51 (s, 1 H, phenol OH), 2.66 (dd, 2H, J=7.6,
9.3 Hz), 1.61 (sext, 2H, J=7.7 Hz), 0.99 (t, 3H, J=7.3 Hz).
Step 3
The 2,4-dihydroxy-3-propylbenzophenone ( 2.5 g, 1.0 Eq, 9.8 mmol)
was converted to the oxime with NH20H-HCl (2.7 g, 4.0 Eq, 39 mmol)
and NaOAc ( 3.21 g, 4.0 Eq, 39 mmol) as in Example 7 Step A. The
oxime was purified by elution from a silica gel column (180 g E. Merck
40-63 a ) with 97 : 3 Toluene : EtOAc. The product oxime (1.82 g) was
further treated as in Example 7 Step A with acetic anhydride (I5 mI)
and subsequent reflux in pyridine (15 ml). The cooled reaction mixture
was poured into 2 N Hcl and EtOAc. The aqueous phase was extracted
with EtOAc and washed with sat'd aq NaHCO3, followed by sat'd aq
NaCl. The EtOAc extracts were dried over Na2SO4 and reduced i. vac.
The residue was taken up in refluxing toluene (50 mI}. The product
benzisoxazole is obtained as colorless crystals upon cooling to RT.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.92-7.89
(m, ZH), 7.57 {d, IH, J=8.5 Hz), 7.55-7.49 (m, 3H), 6.86 (d, 1H, J=8.6
Hz}, 5.14 (s, 1H, phenol OH), 2.90 (dd, 2H, J=8.9, 7.6 Hz), 1.76 {sext,
2H, J=7.5 Hz), 1.01 {t, 3H, J=7.3 Hz).
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x
MS CI NH3 M+1 254.I
Step 4
The hydroxy-3-phenylbenzisoxazole ( 50 mg, 1.0 Eq, 0.195 mmol) was
dissolved in DMF ( 0.4 ml ) with the bromide (73 mg, 1.i Eq, 0.22
mmol) and CsC03 ( 62 rng, 1.0 Eq, 0.195 mmol ). The suspension was
stirred 3 Hrs at RT. The mixture was poured into 0.2 N HCl and
EtOAc. The aqueous phase was extracted with EtOAc and the EtOAc
extracts washed with sat'd aq NaCl. The extracts were dried over
MgS04 and reduced i. vac. The product was purified by elution from a
silica gel column (4 g E. Merck 40-63 w ) with toluene : hexanes
EtOAc 60 : 37 : 3.
Characteristic NMR Resonances; I H NMR 400MHz (CDCl3); 7.9I -7.93
(m, ZH), 7.64 (d, 2H, J=8.7 Hz), 7.51-7.53 {m, 3H), 7.30 (d, 1 H, 1.8
Hz), 7.28 (d, 1H, J=8.1 Hz), 7.12 (dd, 1H), 6.96 {d, iH, J=8.8), 4.21 (t,
2H, J=5.9 Hz), 3.68 (s, 3H), 3.54 (s, 2H), 3.17 (t, 2H, J=7.1 Hz), 2.92
(dd, ZH), 2.20 (pent, 2H), 1.72 (sext, 2H, J=7.5 Hz), 0.97 (t, 3H, J= 7.3
Hz).
MS ESI M+1 510.1.
Step 5
The ester ( 43.8 mg, I Eq, 0.086 mmol ) was dissolved in
approximately 1 ml 2 : 1 dioxane : H20. 1.5 M Aqueous LiOH (120 u1,
2.0 Eq, 0.180 mmol) was added dropwise at RT and the mixture stirred
3/4 Hr. The reaction mixture was diluted into 0.2 N HCl and EtOAc.
The aqueous phase was extracted with EtOAc and the EtOAc extracts
washed with sat'd aq NaCl. The extracts were dried over MgSO~ and
reduced i. vac.
The crude acid can be purified by crystallization from methanol.
Characteristic NMR Resonances; 1H NMR 400MHz {CDCI3); ); 7.92
(m, 2H), 7.64 (d, 1 H, J=8.8 Hz), 7.52 (m, 3H), 7.3 (m, 2H), 7. i 3 (dd,
1H, 3=1.9, 8.1 Hz), 6.96 {d, 1H, J=8.8 Hz), 4.21 (t, ZH, J=5.8 Hz), 3.58
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(s, 2H), 3.18 (t, 2H, J=7.2 Hz), 2.9I (dd, 2H, J=6.5, 7.7 Hz), 2.2 (pent,
- 2H, J=5.8 Hz), 1.71 (seat, 2H, J=7.5 Hz), 0.97 (t, 3H, J=7.4Hz).
MS ESI M+1 496./.
Example 17
,O
O~
F3
N
Methyl 3-propyl-4-(3-(3-trifluoromethyl-7-propyl-6-bent-[4,5)-
isoxazoloxy)-propylthio)phenylacetate
t A: Preparation of methyl 4-alloxvnhenvlacetate
A solution of methyl 4-hydroxyphenylacetate (3.2 grams)
in 2-butanone (70 mL) was treated with allyl bromide (2.0 mL) and
potassium carbonate (3.5 grams). The mixture was refluxed overnight.
The reaction mixture was cooled to room temperature and partitioned
between isopropyl acetate and pH 4 buffer. The organic layer was
separated, washed with water, dried over MgS04, and concentrated.
Column Chromatography (silica gel 60, 50% methylene chloride in
hexane) gave the tittle compound.
1H NMR( 400MHz, CDC13): 8 7.I6 (d, 2H, J = 8.7 Hz), 6.85 (d, 2H, J =
8.7 Hz), 6.04 (m, i H), 5.4-5.2 (m, 2H), 4.5 (m, 2H), 3.66 (s, 3H), 3.54
(s, 2H).
a B: Preparationof meth,~llvl-4-hydroxyphenylacetate
A solution of methyl 4-alloxyphenylacetate (3.1 grams) in
dry ortho-dichlorobenzene (50 mL) was refluxed for 25 hours. The
solvent was removed under reduced pressure, and the residue was
:, purified by chromatography ( silica gel, 50% methylene chloride in
hexane) to afford the tittle compound.
Y
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1H NMR( 400MHz, CDCI3): 8 7.01 (m, 2H}, 6.71 (d, 1 H, J = 7.4 Hz),
5.27 (s, 1 H), S. I2 {m, 2H), 3.67 (s, 3H), 3.52 (s, 2H), 3.35 (m, ZH}.
,step C: Preparation of methyl 3-pron~vl-4-_hydroxy"phenylacetate
A solution of rnethyi 3-propyl-4-hydroxyphenylacetate
(1.7i grams) and palladium (10 wt.% on activated carbon) (0.27 grams)
in ethyl acetate {30 mL) was hydrogenated at 50 PSI for 2 hours. The
reaction mixture was filtered and concentrated to afford the tittle
compound.
1H NMR( 400MHz, CDCl3): 8 6.99 (d, 1H, J = 2.2 Hz), 6.95 (dd, 1H, J
= 8.1, 2.2 Hz), 6.67 (d, 1H, J = 8.1 Hz), 4.83 (s, IH), 3.66 (s, 3H), 3.51
(s, 2H), 2.53 (t, 2H, 3 = 7.6 Hz), 1.61 (hex, 2H, J = 7.5 Hz), 0.95 (t, 3H,
J = 7.3 Hz).
a D: Preparation of methyl 3-propyl-4-{3-(3-trifluoromethyl-7-
propvl-6-benz-f4 51-isoxazoloxv)-propvlthio)phenvlacetate
A solution of methyl 3-propyl-4-hydroxyphenylacetate
(0.10 grams), I-bromo-3-(3-trifluorornethyl-7-propyl-6-bent-[4,5)-
isoxazoloxy)phenoxypropane (0.2I grams) and potassium carbonate
(0.07 grams) in 2-butanone (4 mL). The mixture was refluxed
overnight. The reaction mixture was cooled to room temperature and
partitioned between isopropyl acetate and pH 4 buffer. The organic
layer was separated, washed with water, dried over MgS04, and
concentrated. Column Chromatography (silica gel 60, 50% methylene
chloride in hexane) gave the tittle compound.
1H NMR( 400MHz, CDCl3): 8 7.53 (d, IH, J = 8.8 Hz), 7.03 (d, 1H, 3 =
8.9 Hz), 7.01 (m, 2H), 6.78 (d, I H, J = 8.3 Hz), 4.30 {t, 2H, J = 6.1 Hz),
4.16 (t, 2H, J = 6.0 Hz), 3.65 (s, 3H), 3.52 (s, 2H), 2.87 (t, 2H, J = 7.5
Hz), 2.53 (t, 2H, J = 7.6 Hz), 2.32 (quint, 2H, J = 6.1 Hz), 1.66 (hex,
2H, J = 7.6 Hz), 1.55 (hex, 2H, J = 7.5 Hz), 0.91 (t, 3H, J = 7.3 Hz),
0.87 (t, 3H, J =7.3 Hz).
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- xaxxlple 18
C F3
HO ~ ( ~ N
ono ~ o
3-propyI-4-(3-(3-trifluoromethyi-7-propyi-6-benz-14.51-isoxazoloxy)-
p~o~vlthiolphenvlacetic acid
A solution of methyl 3-propyl-4-(3-(3-trifluoromethyl-7-
propyl-6-benz-[4,5]-isoxazoloxy)-propylthio)phenylacetate (0.08 grams)
in methanol (3 mL} was treated with a solution of LiOH in water (1.0
M, 0.32 mL). The solution was refluxed for 1 hour. The solution was
partitioned between isopropyl acetate and 0.2 N HCI. The organic layer
was separated, washed with water, dried over MgS04, and concentrated
to afford the tittle compound.
1H NMR( 400MHz, CDCl3}: 8 7.53 {d, IH, J = 8.8 Hz), 7.05 (d, IH, J =
8.8 Hz), 7.02 (m, 2H), 6.79 (d, 1H, J = 8.3 Hz), 4.29 (t, 2H, J = 6.1 Hz),
4.16 (t, 2H, J = 6.0 Hz), 3.54 (s, 2H), 2.88 (t, 2H, J = 7.5 Hz), 2.52 {t,
2H, J = 7.6 Hz), 2.33 (quint, 2H, J = 6.1 Hz), l .67 (hex, 2H, J = 7.6 Hz),
I.54 (hex, 2H, J = 7.5 Hz), 0.90 (t, 3H, J = 7.3 Hz), 0.86 (t, 3H, J =7.3
Hz).
Example 19
HO
I
O ~ SAO
CI
2-methyl-2-(3-chloro-4-(3-(3-phenyl-7-propylbenz[4,5]isoxazol-6-
oxy)propyl)thio)phenyl propionic acid .
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1. 2-methyl-2-(3-chloro-4-dimethyl carbamoyIthio)phen~l pro , ionic
acid methyl ester
A -78° C solution 2-(3-chloro-4-dimethyIcarbamoylthio)-
phenyl propionic acid methyl ester (0.378 grams; 1.25 mmol) in dry
THF (2 mL) was treated with a solution of lithium
bis(trimethylsilyl)amide (1.0M; 1.50 mL; 1.50 mmol). The reaction
was stirred for 1 hour at -78° C, then allowed to warm to -10° C
and
stirred for 30 minutes. The solution was re-cooled to -78° C and
treated
dropwise with a solution of methyl iodide (0.094 mL; 1.50 mmol) in
dry THF (0.5 mL). The reaction was stirred at -78° C for 30 minutes,
then warmed to -10° C and stirred for an additional 30 minutes. The
reaction mixture was partitioned between isopropyl acetate and pH 4
buffer. The layers were separated and the organic washed once with
water. The organic was dried over magnesium sulfate, filtered and
concentrated to an oil. Silica geI chromatography afforded 2-methyl-2-
(3-chloro-4-dimethyl carbamoylthio)phenyl propionic acid methyl ester.
NMR (CDCI3): 7.54 (d, 1H, J = 8.2 Hz): 7.48 (d, 1H, J = 2.1 Hz); 7.24
(dd, 1H, J = 8.1, 2.0 Hz); 3.65 (s, 3H); 3.12 (vbs, 3H); 3.04 (vbs, 3H);
1.56 (s, 6H).
2. 2-methyl-2-(3-chloro-4-(3-bromopropvl)thiolphenyl propionic acid
meth, 1 ester
A solution of 2-methyl-2-(3-chloro-4-
dimethylcarbarnoylthio)-phenyl propionic acid methyl ester (0.403
grams; 1.27 mmol) in dry MeOH (4 mL) was treated with a solution of
sodium methoxide (4.37 M; 0.407 rnL; 1.78 mmol). The reaction was
refluxed for 2 hours. The reaction mixture was cooled to 20° C and
transferred to a dropping funnel. The dropping funnel was placed atop
a flask containing a solution of dibromopropane (0.516 mL; 5.08
mmol) in dry MeOH (2 mL). The contents of the dropping funnel were
added to the flask dropwise, and the solution stirred fox 2 hours. The -
reaction mixture was partitioned between isopropyl acetate and pH 4
buffer. The layers were separated and the organic washed once with
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r
water. The organic was dried over magnesium sulfate, filtered and
concentrated. Silica gel chromatography afforded 2-methyl-2-(3-
chloro-4-(3-bromopropyl)thio)phenyl propionic acid methyl ester.
NMR (CDCl3); 7.36 (d, iH, J = 2.1 Hz); 7.26 (d, 1H, J = 8.3 Hz); 7.19
(dd, 1H, J = 8.2, 2.0 Hz); 3.66 (s, 3H); 3.55 (t, 2H, J = 6.3 Hz); 3.09
(t, 2H, J = 7.0 Hz); 2.18 (pent, 2H, J = 6.6 Hz).
3. 2-meth-2S3-chloro-4 ~3-(3Tnhenyl-7-prowl-6-benzf4.51
isQxazole)oxypro~yl)thio)phenvl propionic acid meth~ester
A solution of 2-methyl-2-(3-chloro-4-(3-
bromopropyl)thio)phenyl propionic acid methyl ester (0.053 grams;
0.145 mmol) in dry DMF ( 1 mL) was treated with 3-phenyl-6-hydroxy-
7-propylbenz[4,5]isoxazole (0.044 grams; 0.174 mmol). Cesium
carbonate (0.057 grams; 0.174 mmol) was added and the reaction was
stirred for 7 hours. The reaction mixture was partitioned between
isopropyl acetate and pH 4 buffer. The layers were separated and the
organic washed twice with water. The organic was dried over
magnesium sulfate, filtered and concentrated. Silica gel
chromatography afforded 2-methyl-2-(3-chloro-4-(3-(3-phenyl-7-
propyl-6-bent[4,5] isoxazole)oxypropyl)thio)phenyl propionic acid
methyl ester.
NMR (CDCl3): 7.92 (dd, 2H, J = 7.8, 2.6 Hz); 7.63 (d, 1H, J = 8.8 Hz);
7.55-7.48 (mutt, 4H); 7.39 (d, 1 H, 3 = 2. I Hz); 7.28 (d, 1 H, J = 8.4
Hz); 7.23 {dd, I H, J = 8.7, 2.1 Hz); 6.95 (d, 1 H, J = 8.6 Hz); 4.20 (t,
2H, J = 5.7 Hz); 3.18 (t, 2H, J = 7.1 Hz); 2.92 (bt, 2H, J = 7.5 Hz);
0.96 {t, 3H, J = 7.4 Hz).
4. 2-methyl-2-f3-chloro-4-(3-(3-phenyl-7-propylbenzf4.5],isoxazol-6-
oxX)propyl)thio~phen3rl propionic acid
A solution of 2-methyl-2-(3-chloro-4-(3-(3-phenyl-7-
propylbenz[4,5]isoxazol-6-oxy)propyl)thio)phenyl propionic acid
methyl ester (0.038 grams; 0.071 mmol) in isopropanol (1 mL) was
refluxed. A solution of potassium hydroxide (1.00 M; 0.212 mL;
Y
0.212 mmol) in water was added dropwise and refluxing continued for
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4 hours. The reaction mixture was partitioned between isopropyl acetate
and 0.1 N HCl. The layers were separated and the organic was dried
over magnesium sulfate, filtered and concentrated. Trituration with
cyclohexane/methylene chloride (3:1 ) afforded 2-methyl-2-(3-chloro-4-
(3-(3-phenyl-7-propyl-6-bent[4,5]isoxazole) oxypropyl)thio)phenyl
propionic acid
NMR (CDC13): 7.91 (dd, 2H, J = 7.8, 2.6 Hz); 7.63 (d, 1H, J = 8.8 Hz);
7.53-7.47 (mutt, 4H); 7.40 {d, 1 H, J = 2. I Hz); 7.28 (d, 1 H, J = 8.4
Hz); 7.21 {dd, 1 H, J = 8.7, 2.1 Hz); 6.95 (d, 1 H, J = 8.6 Hz); 3.63 {s,
3H); 4.21 (t, 2H, J = 5.7 Hz); 3.18 {t, 2H, J = 7.1 Hz); 2.90 (bt, 2H, J
= 7.5 Hz); 0.98 (t, 3H, J = 7.4 Hz).
Example 20
F3
HO
l I ~/'~ N
S
CI
3-chloro-4-(3-(2-propyl-3-trifluoromethyl-6-bent-[4,5]-
isoxazoloxy)propylthio)phenylacetic acid
to A: Preparation of 2.4-dihvdrox~~ro_pyl-
trifluoroaceto~henone
A solution of 2-propylresorcinol (5.0 grams) and
trifluoroacetic anhydride (9.6 mL) in 1,2-dichloroethane (30.0 mL) was
treated with aluminum chloride(4.38 grams). This mixture was stirred
overnight. The reaction mixture was partitioned between methylene
choride and water. The organic phase was dried over sodium sulfate
and filtered. The solvent was evaporated and the resulting solid was
recrystalized using methylene chloride and cyclohexane (l : l ). to give the
titled compound.
NMR {CDCl3) 8 7.59 (d, I H), 6.24 {d, 1 H), 5.92 (s, 1 H), 2.63 (t, 2H),
I.74 {s, 1H), 1.58 (m, 2H), 0.98 (t, 3H). .
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_ _ 7i _
Y
,~'~P B: Preparation of 3-trifluoromethyl-7-propyl-6-hydroxy-
benzisoxazole
A mixture of 2,4-dihydroxy-3-propyl-
trifluoroacetophenone(2.5 grams), sodium acetate (4.18 grams),
hydroxylamine hydrochloride (3.59 grams) and methanol (80 mL) was
refluxed overnight. The solvent was then evaporated and the resulting
solid was partitioned in ethyl acetate and pH 7 buffer. The organic
phase was seperated and washed with brine. The organic phase was
dried over sodium sulfate and the solvent was evaporated to give a oil.
The oil was then dissolved in acetic anhydride. The solution was stirred
for two hours, then the acetic anhydride was evaporated in vacuo. The
residue was partitioned between ethyl acetate and pH 7 buffer and the
organic phase was dried over sodium sulfate. The organic phase was
evaporated to give an oil. This was dissolved in pyridine and refluxed
overnight. The solvent was evaporated in vacuo to give an oil which
was chromatographed on silica gel using ethyl acetate and hexane (1:4)
to give the titled compound.
NMR (CDCl3} 8 7.45 (d, 1H), 5.92 (d, IH}, 5.42 (bs, 1H), 2.89 {t, 2H),
1.74 (m, 2H), 0.98 {t, 3H).
TE C: Preparation of methyl 3-chloro-4-(3-{7-propyl-3-
trifluoromethyl-5-benz- [4,5]-isoxazoloxy)propylthio)
phenvlacetic acid
A solution of 3-trifluoromethyl-7-propyl-6-hydroxy-
benzisoxazole (2.5 grams) in 2-butanone (30 mL} was treated with I,3-
dibromopropane (4.8 mL) and potassium carbonate (5.0 grams). The
mixture was refluxed for 4 hours. The reaction mixture was partitioned
between isopropyl acetate and pH 4 buffer. The organic was washed
once with water, then dried over magnesium sulfate. The organic was
filtered and evaporated to an oil which was flitered through a silica gel
plug using methyiene chloride and hexane (1:2} to give 3-
trifluoromethyl-7-propyl-5-(3-brornopropyloxy}-benzisoxazole. A
solution of 3-chloro-4-dimethylcarbamoylthio-phenylacetic acid methyl
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ester (0.33 grams) in dry methanol (3.5 mL) was treated with a solution
of sodium methoxide in methanol (25wt%; 0.34ImL). The solution
was refluxed for 2 hours. HPLC analysis showed the disappearance of
the carbamate. The solution was allowed to cool to 50°C. 3-
trifluoromethyl-7-propyl-6-(3-bromopropyloxy)-benzisoxazole (0.31
grams) was added and the solution stirred for 1 hour. The reaction was
partitioned between isopropyl acetate and pH 4 buffer. The organic was
washed once more with pH 4 buffer, then water. The organic was dried
over magnesium sulfate, filtered and concentrated to an oil. The oil was
applied to a silica gel column packed with hexane/methylene chloride
(2:1 ). The column was eluted with this mobile phase until the product
began to appear in the eluant. The mobile phase was switched to 100%
methylene chloride and elution continued until all the product was
recovered.
NMR (CDC13) S 7.52 (d, 2H), 7.30 (d, 1H), 7.27 (d, IH), 7.I2 (d, 1H),
7.08 (d, I H), 4.21 (t, 2H), 3.68 (s, 3H), 3.54 (s, 2H), 3.I5 (t, 2H), 2.89
(t, 2H), 2.I9 (m, 2H), 1.68 (m, 2H), 0.94 (t, 3H).
Step D: Preparation of 3-chloro-4-(3-(2-propyl-3-trifluoromethyl-
6-bent-f4.51-isoxazoloxy)prop 1v thio)phenylacetic acid
A solution of methyl 3-chloro-4-(3-(2-propyl-3-
trifluoromethyl-6-benz-[4,5]-isoxazoloxy)propylthio)phenylacetic acid
(0.1 i3 grams) in methanol {I.5 mL) was treated with a solution of
lithium hydroxide in water (1.01 M; 0.362 mL). The reaction was
refluxed 1 hour. The reaction mixture was partitioned between
isopropyl acetate and O.IN HCl. The organic was dried over
magnesium sulfate, filtered and concentrated to a solid. The solid was
suspended in methylene chloride/cyclohexane {1:1; 2 mL). The
mixture was refluxed briefly and cooled to 0°C. The title compound
was isolated by filtration.
NMR (CDC13) S 7.53(d, 2H), 7.3I (d, 1H), 7.27 {d, 1H), 7.12 (d, iH),
7.02 (d, 1H), 4.2I (t, 2H), 3.57 (s, 2H), 3.16 (t, 2H), 2.89 (t, 2H), 2.I9
(m, 2H), 1.67 (m, 2H), 0.93 (t, 3H).
ESI-MS: m/e = 488 (m+1 ).
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_ _ - 73 _
H3C
O
Methyl 3-chloro-4-(3-(3-(2,2-dimethylpropyl}-7-propyl-6-Benz-[4,5]-
isoxazoloxy)-propylamino)phenylacetate
St_ ep A: Preparation of 3-chloro-4-acetamidophenylacetic acid
Acetic anhydride (152 mL, I.6 moles) was added dropwise
to a rapidly stirring mixture of 4-aminophenylacetic acid ( 195 grams,
1.3 moles) in acetic acid (600 mL) and water (250 mL) at room
temperature. After a slight exotherm, the dark brown solution was
stirred for one hour at room temperature. The solution was diluted
with ethanol {500 mL) and water (250 mL), and a suspension of
Calcium hypochlorite (340 grams, 2.3 moles) in water {I L plus SOOmL
rinse) was added portionwise. The temperature rose to SOoC and the
mixture was stirred for 16 hours at room temperature. The mixture
was poured into ice-water (8 L) and extracted with ethyl acetate (3x
2L). The combined extracts were washed with saturated brine, dried
over magnesium sulfate and concentrated in vacuo to a small volume.
Hexane was added and the resulting precipitate filtered, washed with
hexane and dried to give the title compound(180 grams) as a brown
solid
NMR (CDCl3 + 10% CD30D): 8 2.12 (s, 3H); 3.45 (s, 2H); 7.I0 (dd,
2H)); 8.02 (dd, 1 H).
Step B: Preparation of methyl 3-chloro-4-aminonhenylacetate-HCl
A solution of 3-chloro-4-acetamidophenylacetic acid (180
grams, 0.79 moles) in methanol {2 L), was treated with concentrated
_ HCl (200 mL} and the resulting solution refluxed for 6 hours and then
stirred at room temperature for 16 hours. The mixture was
Example 2I
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concentrated in vacuo to about one-half its volume and ether (4 L) was
added. The resulting precipitate was filtered, washed with ether and
dried to give the title compound (173 grams) as a tan solid NMR,
(CD30D): S 3.70 (s, 2H); 3.73 (s, 3H); 7.35 (d, 1H); 7.43 (d, 1H); 7.56
(s, I H).
Step? C: Preparation of methyl 3-chloro-4-(3-
bromopropylamino)phenylacetate
Magnesium oxide (10 grams, 250 mmoIes), was added to a
solution of 1,3-dibromopropane (139 grams, 70 mL, 700 mmoles) in
dimethylacetamide (150 mL). A solution of methyl 3-chloro-4-
aminophenylacetate~HCl (23.6 grams, 100 mmoles) in dimethylacetmide
(200 mL) was added dropwise over 30 minutes and the mixture stirred
at 80oC for 6 hours. The cooled mixture was partitioned with
methylene chloride and water. The aqueous phase was extracted with
methylene choride and the combined organic phases washed with brine,
dried over magnesium sulfate and concentrated in vacuo to an oil. The
crude product was chromatographed on a silica gel column eluting with
hexane:ethyl acetate (9: i ). The product was further purified by a
second silica gel chromatography in methylene chloride:hexane (2:3) to
give the title compound as an oil. NMR, (CDC13): 8 2.15 (qnt, 2H);
3.35 (q, ZH); 3.47 (s,2H); 3.49 (t, 2H); 3.67 (s, 3H); 6.63 {d, 1 H); 7.03
(dd, 1 H); 7.17 (d, 1 H).
Step D: Preparation of 3-chloro-4-(3-(3-(2,2-dimethylpropyl)-7-
propyl-6-benz-[4,5]-isoxazoloxy)-propylamino)-
~henvlacetate
A solution of methyl 3-chloro-4-(3-bromopropylamino)-
phenylacetate (4.55grams, 14.19 mmoles) and 3-{2,2-dimethylpropyl)-
6-hydroxy-7-propylbenz-[4,5]-isoxazole (3.5I grams, 14.19 mmoles) in
2-butanone (50 mL) was treated with potassium carbonate (2.35 grams,
17.0 mmoles). The mixture was refluxed for 8 hours, stirred at room _'
temperature for 16 hours and filtered. Evaporation in vacuo followed
by flash chromatography on silica gel in hexane:ethyl acetate (9: I )
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r
afforded the title compound as a white solid. NMR, (CD30D): S 0.94
(t, 3H); 1.04 (s, 9H); 1.70 (m, 2H); 2.15 (m, 2H); 2.83 (s, 2H); 2.90 (t,
2H); 3.45 (t, 2H); 3.48 (s, 2H); 3.66 (s, 3H); 4.22 {t, 2H); 6.71 (d, 1 H);
6.99 (d, 1 H); 7.07 (d, 1 H}; 7.15 (d, 1 H); 7.52 (d, 1 H).
Example 22
H ~ CI
I
O
N
H
3-Chloro-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-benz-[4,5]-
isoxazoloxy~-propylamino)phenvlacetic acid
To a solution of methyl 3-chloro-4-(3-(3-(2,2-
dimethylpropyl)-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propylamino)phenylacetate (4.24 grams, 8.71 mmoles) in methanol (90
mL) was added a solution of lithium hydroxide (IM, 17.42 mL, 17.42
mmoles}, and the resulting mixture stirred at 60oC for 2.5 hours. The
solurion was evaporated in vacuo and the residue diluted with water and
ethyl acetate. The pH was brought to 5.0 with 1 M hydrochloric acid
and organic phase separated. The aqueous phase was extracted 3 times
with ethyl acetate and the combined organic extracts dried over
magnesium sulfate and evaporated in vacuo to give the title compound as
a white crystalline solid.(mp = 115-1 l6oC.; Mass spec = 473, 475, calc
= 473) NMR, (CD30D); 8 0.96 (t, 3H); I.03 (s, 9H); I.71 (m, 2H);
2.15 {m, 2H); 2.83 (s, 2H); 2.90 (t 2H}; 3.44 (s, 2H}; 3.45 (t, 2H); 4.22
(t, 2H}; 6.72 (d, 1H); 7.01 (d, i H); 7.03 (d, 1 H); 7.07 (d, 1 H); 7. I 6 (d,
1H); 7.50 (d, 1H).
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Example 23
HO / O O
I
O
3-{4-(3-(2,2-dimethylpropyl)-7-propyl-6-benz-[4,5J-isoxazoloxy)-
butoxy)phenylacetic acid
1A
A solution of 2,4-dihydroxy-3-propylphenyl ethyl ketone
(25.545 grams) in 2-butanone (300 mL) was treated with 1,3-
dibromopropane (48.79 mL) and potassium carbonate (50.$59 grams).
The mixture was refluxed for 4 hours. The reaction mixture was
partitioned between isopropyl acetate and pH 4 buffer. The organic was
washed once with water, then dried over magnesium sulfate. The
organic was filtered and evaporated to an oil which was
chromatographed over silica gel with hexane/rnethylene chloride {2:1 }
to afford the title compound.
to 1
The ester was obtained from the Fischer esterification of
the commercially available acid in methanol. The 3-
hydroxyphenylacetic acid (25g) was dissolved in methanol (i00 ml) with
approximately 0.4 lizl H2S04 conc. The mixture was heated 16 Hrs
under reflux. The mixture was cooled and reduced l. vac. The residue
was taken up in ethyl acetate and washed with sat'd aq NaHC03,
followed by sat'd aq NaCl. The EtOAc extracts were dried over MgS04
and reduced l. vac. The ester was used without further purification.
Characteristic NMR Resonances; ~H NMR 400MHz (CDCl3); 7.15 (t,
1 H, J=7.7 Hz), 6.80 (t, 1 H, J=8.1 Hz), 6.75 (brd s, 1 H), 6.72 (dd, 1 H,
J=2.6, 8.1 Hz), 3.68 (s, 3H), 3.56 (s, 2H). '
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St, ~p 2
The ester ( 4.0 g, 1 Eq, 0.024 mol ) was dissolved in DMF
( 30 ml } with 1,4-dibromobutane ( 14.4 ml, 5 Eq, 0.121 mol ) and
CsC03 ( 8.3 g, 1.05 Eq, 0.025 mol ). The suspension was stirred 1.5
Hrs at RT. The mixture was poured into 0.2 N HCl and EtOAc. The
aqueous phase was extracted with EtOAc and the EtOAc extracts washed
three times with water, followed by sat'd aq NaCI. The extracts were
dried over MgS04 and reduced i. vac.
The product was purified by elution from a silica gel column (150 g E.
Merck 40-63 ~ ) with 9 : 1 Hexanes : EtOAc. The bromide is obtained
as an oil.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.21 (t,
1H, J=7.9 Hz), 6.86-6.76 (m, 3H), 3.97 (t, 2H, J=6.0 Hz), 3.67 (s, 3H),
3.58 (s, 2H), 3.47 {t, 2H, J=6.6 Hz), 2.02-2.09 (complex m, 2H), 1.89-
1.96 (complex m, 2H).
Step 3
The hydroxybenzisoxazole ( 41 mg, 1.0 Eq, 0.165 mmol)
was dissolved in DMF ( 0.5 ml ) with the bromide ( 52 mg, 1.05 Eq,
0.174 mmol ) and CsC03 ( 59 mg, 1.1 Eq, 0.182 mmol ). The
suspension was stirred 16 Hrs at RT. The mixture was poured into 0.2
~T HCl and EtOAc. The aqueous phase was extracted with EtOAc and the
EtOAc extracts washed with sat'd aq NaCI. The extracts were dried
over Na2S04 and reduced i. vac. The product was purified by elution
from a silica gel column ( 10 g E. Merck 40-63 ~ } with 98 : 2 toluene
EtOAc. The product is obtained as an oil.
Characteristic NMR Resonances; 1H NMR 400MHz (CDC13); 7.34 (d,
1H, J=8.7 Hz), 7.21 (t, IH, J=7.9 Hz), 6.88 (d, IH, J=8.7 Hz}, 6.85-6.78
(m, 3H), 4.11 (t, 2H, J=5.7 Hz), 4.03 (t, 2H, J=5.7 Hz), 3.67 (s, 3H),
3.57 (s, 2H), 2.86 (dd, 2H, J=8.9, 7.5 Hz), 2.79 (s, 2H), 1.99 (m, 4H),
1.69 (next, 2H, J=7.5 Hz), 1.03 (s, 9H), 0.95 (t, 3H, J=7.4 Hz).
MS ESI CH3CN / NH4C02 aq. M+1 468.5.
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~t~p 4
The ester { 60 mg, 1 Eq, 0.13 mmol ) was dissolved in
approximately 3 ml 2 : 1 dioxane : H20. I.5 VI Aqueous LiOH ( I70 mI,
2.0 Eq, 0.25 mmol ) was added dropwise at RT and the mixture stirred
1 Hr. The reaction mixture was diluted into 0.2 ~T HCI and EtOAc. The
aqueous phase was extracted with EtOAc and the EtOAc extracts washed
with sat'd aq NaCI. The extracts were dried over Na2S04 and reduced i.
vac. The product is obtained as an oii.
Characteristic NMR Resonances; IH NMR 400MHz (CDC13); 7.34 (d,
1 H, 3=8.6 Hz), 7.24 (t, 1 H, J=7.7 Hz), 6.88 (d, 1 H, J=8.7 Hz), 6.85-6.79
(m, 3H), 4.10 (t, 2H, J=5.7 Hz), 4.03 (t, 2H, J=5.7 Hz), 3.59 {s, 2H),
2.85 (dd, 2H, J=8.9, 7.5 Hz), 2.79 (s, 2H), 1.99 (m, 4H), 1.67 (sext, 2H,
J=7.5), 0.94 (t, 3H, J=7.4 Hz).
MS ESI CH3CN / NH4C0~ aq. M+1 454.5.
Example 24
HO
I
O ~O O
CI
~, -Ph
O'N
3-chIoro-4-(3-(3-phenyl-7-cyclopropylmethyl-6-benz-[4,5]-
isoxazoloxy)-butyloxy)phenylacetic acid
Step A: Preparation of 7-cyclopropylmethyl-3-phenyl-6-
hvdroxybenz-f4.51-isoxazole _
A solution of 2,4-dihydrobezophenone {2.14 grams) in
DMF {20 mL) was treated with potassium carbonate (1.45 grams). This
mixture was heated to 40oC and stirred for 0.5 hours. To this mixture
was added allyl bromide (3.6 grams), then the reaction was stirred
overnight. The mixture was diluted with ethyl acetate and washed with
1 M HCI solution and brine. The organic phase was dried over sodium
sulfate and filtered. The solvent was removed in vacuo and the resulting
oiI was filtered through a plug of silica gel using methylene chloride and '
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r
hexane ( I :2) to give 4-allyloxy-2-hydroxybenzophenone. This was then
dissolved in 1,2-dichiorobenzene and refluxed for 24 hours. The
solvent was evaporated in vacuo and the resulting oil was filtered
through a plug of silica gel using methylene chloride and hexane (I:1) to
give 3-allyl-2,4-dihydrobezophenone. 3-allyl-2,4-dihydrobezophenone
{1.0 grams) was dissolved in methanol (20 mL) and treated with
hydroxylamine hydrochloride (1.35 grams) and sodium acetate (I.6
grams) and refluxed overnight. The solvent was evaporated in vacuo
and the resulting solid was partitioned in ethyl acetate and pH 7 buffer.
The organic phase was dried over sodium sulfate and filtered. The
solvent was removed to give a solid. This was stirred in acetic
anhydride for 2 hours and then the solvent was remove in vacuo to give
an oil. The oil was dissolved in pyridine and refluxed overnight. The
solvent was evaporated in vacuo and the residue was filtered through a
pad of siliga gel using methylene chloride and hexane (I:I) to give 7-
allyl-3-phenyl-6-hydroxybenz-[4,5]-isoxazole. To a solution of 7-allyl-
3-phenyl-6-hydroxybenz-[4,5]-isoxazole (0.5 grams) in 2 mL of ethyl
ether was added diazomethane (i5 mL of a 0.70M soIn. in Et20) under
nitrogen followed by the addition of palladium acetate (cat., 2 mg). The
reaction mixture was stirred at ambient temperature for 30 min until
gas evolution had ceased. The ether was evaporated in vacuo, and the
residue was purified on a silica gel flash chromatography column eluted
with 10% EtOAc:hexane. Evaporation of the purified fractions and
solvent removal in vacuo afforded the product.
NMR (CDCl3) 8 7.91 (d, 2H), 7.58 (d, 1H), 7.53 (m, 3H), 6.89 (d, 1H),
5.64 (s, 1 H), 2.91 (d, 2H), 1.24 (m, 1 H), 0.54 (m, ZH), 0.37 (d, 2H).
STEP B: Preparation of 3-chloro-4-(3-(3-phenyl-7-
cyclopropylinethyl-6-bent-[4,5]-isoxazoloxy)-
butyIoxy)phenvlacetlc acid
A solution of 7-cyclopropylinethyl-3-phenyl-6-
hydroxybenz-[4,5]-isoxazole (0.25 grams) in 2-butanone (3.0 mL) was
treated with 1,3-dibromopropane (0.48 mL) and potassium carbonate
' ~ (0.50 grams). The mixture was refluxed for 4 hours. The reaction
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' -80-
mixture was partitioned between isopropyl acetate and pH 4 buffer. The
organic was washed once with water, then dried over magnesium
sulfate. The organic was filtered and evaporated to an oil which was
flitered through a silica gel plug using methylene chloride and hexane
(1:2) to give 7-cyclopropylmethyl-3-phenyl-6-(3-
bromopropyloxy)benz-[4,5]-isoxazole. A solution of 3-chloro-4-
hydroxyphenylacetic acid methyl ester (42.0 mg) in DMF {I.0 mL) was
treated with potassium carbonate (26 mg) and this mixture was stirred
for 0.5 hours. Then 7-cyclopropylmethyl-3-phenyl-6-(3-
bromopropyloxy)benz-[4,5]-isoxazole was added and the mixture was
stirred over night. The reaction mixture was partitioned between ethyl
acetate and 1 M HCl solution. The organic was dried over sodium
sulfate and filtered. The solvent was removed in vacuo and the residue
was chromatographed on silica gel using methlene chloride and hexane
(1:1) to give an oil. A solution of methyl 3-chloro-4-(3-(3-phenyl-7-
cyclopropylmethyl-6-benz-[4,5]-isoxazoloxy)-butyloxy)phenylacetic acid
(0.04 grams) in methanol (I.5 mL) was treated with a solution of
lithium hydroxide in water {1.01 M; 0.1 mL). The reaction was
refluxed I hour. The reaction mixture was partitioned between
isopropyl acetate and O.1N HCL The organic was dried over
magnesium sulfate, filtered and concentrated to a solid. The solid was
suspended in methylene chloride/cyclohexane (1:1; 2 mL). The
mixture was refluxed briefly and cooled to 0°C. The title compound
was isolated by filtration.
NMR (CDCi3) S 7.93(d, 2H), 7.65 (d, IH), 7.53 {m, 3H), 7.28 (s, 1H),
7.01 (d, 1 H), 6.98 (d, I H), 6.87 (d, 1 H), 4.18 (t, 2H), 4.08 (t, 2H), 3.55
(s, 2H), 2.88 (d, 2H), 2.08 {m, 4H), 0.41 (m, ZH), 0.30 (m, 2H).
ESI-MS: m/e = 506 (m+I).
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_ _ _81 _
exam In a 25
HO / CI
O ~ (~~ ' ~ O
S~
O
3-chloro-4-(3-{2-phenyl-6-propyl-5-benz-[4,7]-oxazoIoxy)propylthio)
phenylacetic acid
to A: Preparation of 1-propen~v-4-benzvloxy benzene:
5.0 grams (25.0 mmole, 1.0 eq.) of 4-benzyloxyphenol was
dissolved in 100 ml of N,N-dimethylformamide. I0.4 grams (75.0
mmole, 3.0 eq.) of potassium carbonate and 3.25 mI (37.5 mmole, 1.5
eq.) of ailyl bromide were added to the reaction and it was stirred at
80°C for 3 hours and at room temperature for another I36 hours. The
reaction mixture was diluted with water and extracted 3x with 60 mI of
ethyl acetate. The combined organics were dried over sodium sulfate,
filtered, evaporated and pumped on high vacuum overnight. The title
compound (4.3 grams, 72% yield) was isolated by recrystallization from
methanol.
NMR (400 MHz, CDCl3} ~ 7.36 (m, SH}, 6.88 (m, 4H), 6.04 (m, 1H),
5.39 (d, 1H}, 5.24 (d, IH), 5.01 (s, 2H), 4.44 (d, 2H).
to B: Preparation of 2-propenyl-4-benz~loxvohenol:
7.5 grams (31.3 mmole, I.0 eq.) of product from step A
was dissolved in 35 ml of 1,2-dichloroethane and heated to reflux for 24
hours. The reaction mixture was directly chromatographed after
cooling to give 6.8 grams (91 % yield) of the title compound.
NMR (300MHz, CDC13) 8 7.36 {m, SH), 6.77 {d, I H), 6.74 (m, 2H),
6.00 (m, 1H), 5.18 (dm, 2H), 4.99 {s, 2H), 4.58 {s, 1H), 3.39 (dd, 2H).
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S~e~ C Preparation of 2-propylhydroquinone:
6.8 grams (28.4 mmole, 1.0 eq.) of product from step B
was dissolved in 60 ml of methanol. 680 mg of 10% palladium on
carbon (0.64 mmole, 0.023 eq.) was added and the stirring suspension
was evacuated and charged with hydrogen. After I6 hours the catalyst
was filtered over celite and the filtrate evaporated. The title compound
{4.3 grams) was recovered by recrystallization from
dichloromethane/hexanes.
NMR (400 MHz, CD30D) b 6.56 {d, 1 H), 6.51 (d, I H), 6.43 (dd, 1 H),
2.48 (t, 2H), 1.58 (m, 2H), 0.96 (t, 3H).
Step D: Preparation of I.4-dimethox~r-2-prop",vl benzene:
1.0 gram (6.6 mmole, 1.0 eq.) of product from step C was
dissloved in 30 ml of freshly distilled THF. The solution was cooled to
0°C and 0.65 gram of 61 % sodium hydride (16.5 mmole, 2.5 eq) and
1.25 ml (20.1 mmole, 3.0 eq.} of iodomethane were added. The
reaction was stirred at 0°C for 16 hours under nitrogen atmosphere.
The reaction was quenched with saturated aqueous ammonium chloride
and extracted 3x with dichloromethane. The organic was dried over
sodium sulfate, filtered and evaporated. The recovered crude material
was chromatographed to give 0.96 gram of the title compound as a clear
liquid.
NMR (400 MHz, CDCl3} S 6.74 (d, IH), 6.71 (d, IH), 6.66 (dd, 1H),
3.76 (s, 3H), 3.74 (s, 3H), 2.55 (t, 2H), 1.60 {m, 2H), 0.96 (t, 3H).
.~teu E: Preparation of 2.5-dimethoxv-4-pronvl benzophenone~
0.254 gram (1.4 mmole, 1.0 eq.) of product from step D
was dissolved in 7 ml of 1,2-dichloroethane, after which 0.20 ml of
benzoyl chloride and 0.225 gram aluminum (III) chloride ( 1.7 mmole,
1.2 eq. each} were added. Stirred at room temperature under nitrogen
atmosphere for 75 minutes, then quenched with aqueous potassium ,
carbonate. Diluted further with water and extracted 3x with
dichioromethane. The combined organics were dried over sodium
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_ _83_
a
sulfate, filtered and evaporated. The resulting crude material was
chromatographed to give 0.38 gram {95% yield) of the title compound.
NMR (400 MHz, CDCl3) 8 7.80 (dd, 2H), 7.53 (dt, 1 H), 7.42 {t, 2H),
6.88 (s, 1H), 6.78 (s, 1H), 3.77 (s, 3H), 3.62 (s, 3H), 2.62 (t, ZH), 1.64
(m, 2H), 0.97 (t, 3H).
to F: Preparation of 2.5-dihvdroxy-4-prowl benzophenone:
0.37 gram (1.3 mmole, 1.0 eq.) of product from step E was
dissolved in 5 m1 of dichloromethane. The solution was stirred under
nitrogen atmosphere at -78°C and 3.2 m1 of 1.0 M boron tribromide
solution in hexanes (3.2 mmole, 2.5 eq.) was added dropwise over a 5-8
minute span. The reaction was allowed to slowly warm, and after 3
hours ice was added to the reaction mixture. After an additional 30
minutes some water was added and the mixture was diluted with
dichloromethane. The layers were separated and the organic was
washed twice more with water, dried over sodium sulfate, filtered and
evaporated to give the title compound (0.33 gram, 100% yield) without
further purification.
NMR (400 MHz, CDCl3) b 11.65 (s, 1H), 7.65 (dd, 2H), 7.55 (dt, 1H),
7.46 (t, 2H), 6.92 {s, 1 H), 6.84 (s, 1 H), 4.34 (s, 1 H), 2.59 (t, 2H), 1.67
(m, 2H), 0.98 (t, 3H).
to G: Preparation of 2.5-dih,~y-4-propyl benzoxime:
0.22 gram (0.88 mmole, 1.0 eq.) of product from step F
was dissolved in 2.5 ml of 100% ethanol. 0.61 gram of hydroxylamine
hydrochloride and 0.72 gram of sodium acetate (8.8 mmole, 10 eq.
each) were then added and the reaction was heated to reflux under
nitrogen atmosphere for 16 hours. The reaction was cooled to room
temperature and diluted with water and ethyl acetate. The layers were
separated and the organic layer was washed twice more with water, then
dried over sodium sulfate, filtered and evaporated to give 0.23 gram
(97% yield) of the title compound without further purification.
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NMR (400 MHz, CDCI3) $ 7.40 (m, SH), 6.88 (s, 0.25H}, 6.78 (s,
0.75H), 6.37 (s, 0.25H), 6.19 (s, 0.75H), 2.58 (t, O.SH), 2.50 (t, 1.5H),
1.62 (m, 2H), 0.99 {t, 0.75H}, 0.98 (t, 2.25H).
Step H: Preparation of 2-phenyl-5-hydroxy-6-propyl bent-[4,7]-
9xazole:
0.23 gram (0.83 mmole, 1.0 eq.) of product from step G
was dissolved in 0.75 ml of acetonitrile and 0.25 ml of N,N-
dimethylacetamide. Under a nitrogen atmosphere 0.085 m1 (0.91
mmole, 1.1 eq.) of phosphorus oxychloride was added and the reaction
stirred for 30 minutes. Water and ethyl acetate were added, as was solid
sodium acetate (ca. 0.3 gram}. The layers were separated and the
organic was washed with saturated aqueous sodium chloride solution,
then dried over sodium sulfate, filtered and evaporated. The crude was
purified by column chromatography to give 0.12 gram (57% yield) of
the title compound. Structure comfirmed by NMR, MS, and NOE
difference spectroscopy.
NMR (500 MHz, DMSO-d6) 8 9.39 (s, iH), 8.11 (m, 2H), 7.56 (m,
3H), 7.42 (s, 1 H), 7.10 (s, I H), 2.62 (t, 2H), 1.61 (m, 2H), 0.91 (t, 3H).
MS[ESI]: m/e 254.1 (M+I).
t I: Preparation of methyl 3-chloro-4-(3-bromopropylthio)
~henvI acetate:
10.0 grams (34.7 mmole, I.0 eq.) of 3-chloro-4-
dimethylcarbamoylthio-phenylacetic acid methyl ester was dissolved in
IS ml anhydrous methanol, then 8.3 ml of 25% w/w (38.2 mmole, 1.1
eq.) sodium methoxide in methanol was added and the reaction heated to
reflux for one hour. In a separate flask, 14.1 ml (I39 mmole, 4.0 eq.)
of 1,3-dibromopropane was dissolved in 15 ml of anhydrous methanol,
which was then cooled by an ice bath. The sodium thiolate solution was
cooled to room temperature, then added dropwise via cannula to the
stirring dibromopropane. After 30 minutes at 0°C and one hour at
room temperature, the reaction was quenched by adding saturated
aqueous ammonium chloride followed by water. The aqueous was
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r
extracted twice with ethyl acetate. The combined organics were washed
with water (2x) and saturated sodium chloride (lx). The organic Iayer
was dried over sodium sulfate, filtered and evaporated. The recovered
crude material was purified by silica gel chromatography to give 8.1
gram (71 % yield) of the title compound.
NMR (500 MHz, CDCI3) 8 7.34 (d, 1H), 7.30 (d, 1H), 7.17 (dd, 1H),
3.72 (s, 3H), 3.59 (s, 2H), 3.57 (t, 2H), 3.10 (t, 2H), 2.20 (quint, 2H).
J Preparation of methyl 3-chloro-4-(3-(2-phenyl-6-propyl-5-
benz-14.71-oxazoloxxl propvlthio) phenyl acetate:
20.0 mg of product from step H (79 p.mole, I.0 eq.) was
dissolved in 0.75 mi of N,N-dimethylformamide. 27.0 mg of cesium
carbonate (83 p,mole, 1.05 eq.) and 26.7 mg {79 p,mole, 1.0 eq.) of
product from step I were then added, and the reaction stirred at 65°C
for 2 hours. The reaction mixture was diluted with water, acidified
with dilute aqueous HCl and extracted with ethyl acetate. The organic
was dried over sodium sulfate, filtered and evaporated, then purified by
silica gel chromatography to give 26.5 mg (66% yield) of the title
compound.
NMR {500 MHz, CDC13) 8 8.23 (m, 2H), 7.52 (m, 3H), 7.37-7.30 (m,
3H), 7.20 (s, 1 H), 7.I 5 (dd, 1 H), 4.34 (t, 2H), 3.72 {s, 3H), 3.58 (s, 2H),
3.21 (t, 2H), 2.74 (t, 2H), 2.23 (m, 2H), 1.70 (m, ZH), 1.00 {t, 3H).
f~: Preparation of 3-chloro-4-(3-(2-phenyl-6-propyl-5-benz-
14.71-oxazoloxv)propylthio) phenylacetic acid:
24.6 mg {48.2 ,mole, 1.0 eq.) of the product from step J
was dissolved in 0.6 ml of a 1:l mixture of tetrahydrfuran and
methanol. Then 0.35 ml of 0.25N lithium hydroxide (87.5 pmole, 1.8
eq.) was added and the reaction stirred for 16 hours. Then the reaction
was heated to 80°C for 20 minutes, but this failed to push the reaction
to
completion. The reaction mixture was diluted with water, acidified with
i
- dilute HCI, and extracted with ethyl acetate. The organic was dried over
sodium sulfate, filtered and evaporated. The recovered crude was
purified by silica gel chromatography that utilized an acetic acid
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modified mobile phase, giving 16.4 mg (69% yield) of the title .
compound.
NMR (500 MHz, CDC13) $ 8.24 (m, 2H}, 7.54 {m, 3H}, 7.46 (d, 1H),
7.42 (d, 1 H), 7.33 {s, 1 H), 7.24 (dd, I H), 6.81 (s, 1 H), 3.85 (t, 2H},
3.64
{s, 2H), 3.23 (t, 2H), 2.70 {t, 2H), 2.29 (m, 2H), 1.66 (m, 2H}, 0.97 (t,
3H).
MS[ES)7: m/e 496.2 (M+I).
Example 26
HOOC
SAO
Cf ~ /
i~
~-N
3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-j4,5]-isoxazoloxy)-but-2-en-
thio}phenylacetic acid
STEP A: Preperation of I-bromo-4-(3-ethyl-7-propyl-6-benz-
[4,5]-isoxazoloxy)but-2-ene
Using the method found in example 1 step A, substituting 2-
hydroxy-3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy as the starting
material and substituting 1,4-dibromobut-2-ene in place of 1,3-
dibromopropane, the titled compound was obtained. This compound
purified by filtering it through a plug of silica gel, using I00% hexane
and then 20% ethyl acetate/ hexane to remove the excess 1,4-
dibromobut-2-ene.
NMR (CDCl3 ) 8 7.37 (d, 1 H, J = 8.7 Hz); 6.85 (d, 1 H, J = 8.7 Hz}; 6.03
{m, 2H}; 4.63 (d, 2H, J = 5.78 Hz); 3.99 (d, 2H, J = 7.2 Hz); 2.93 (q,
2H, J = 7.65 Hz); 2.86 {t, 2H, J = 6.27 Hz); 1.67 (m, 2H); 1.40 (t, 3H, J
= 7.61 Hz); 0.948 (t, 3H, J = 7.4 Hz).
STEP B: Preparation of Methyl 3-chloro-4-(4-(3-ethyl-7-propyl-6-
benz-[4,5]-isoxazoloxy)-but-2-en-thio)phenylacetate
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y
Using the method in example 1 step B, substituting 1-
bromo-4-(3-ethyl-7-propyl-6-Benz-[4,5]-isoxazoloxy)but-2-ene as the
starting material, the titled compound was obtained. This compound
was taken forward without further purification.
STEP C: Preparation of 3-chloro-4-{4-(3-ethyl-7-propyl-6-benz-
[4,5]-isoxazoloxy)-but-2-en-thio)phenylacetic acid
Using the method in example 2 step A (19632PV2},
substituting Methyl 3-chloro-4-(4-(3-ethyl-7-propyl-6-benz-[4,5]-
isoxazoloxy}-but-2-en-thio}phenylacetate as the starting material, the
titled compound was obtained.
NMR (CDCl3) S 7.33 {d, 1H, J = 8.63 Hz); 7.29 (s, 1H); 7.20 {d, 1H, J =
8.13); 7.06 (d, 1H, J = 8.09 Hz}; 6.80 (d, IH, J = 8.63 Hz); 5.87 {m,
2H); 4.55 (d, 2H, J = 4.4 Hz); 3.60 (d, 2H, J = 5.62 Hz); 3.56 (s, 2H);
2.93 (q, 2H, J = 7.6 Hz); 2.81 (t, 2H, J = 7.4 Hz); 1.64 (m, 2H, J = 7.49
Hz); 1.41 (t, 3H, J = 7.61 Hz); 0.91 (t, 3H, J = 7.41 Hz}.
ESI: Mass spec: m/e = 460 {M+1 ).
Example 27
HO_ v 0 \ /
N
~ \ ~ O
O
4-(3-(3-ethyl-7-propyl-6-bent[4,5]isoxazole)oxy)propyloxy phenoxy
acetic acid
1. Methyl p-H,~yphenoxy acetate
A solution of p-hydroxyphenyl acetic acid (4.602 grams;
27.368 mmol) in dry methanol (80 mL) was treated with con. H2S04
- (0.50 mL). The solution was stirred at 55° C for 2 hours. The
reaction
was partitioned between isopropyl acetate and aqueous sodium
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- 8g - ,
bicarbonate solution. The organic was dried over magnesium sulfate, '
filtered and evaporated to afford the title compound as a solid.
NMR (acetone): 6.75 (apparent quart, 4H, J = 9.5 Hz); 4.60 (s, 2H);
3.71 (s, 3H).
2. Methvl 4-(3-f3-ethyl-7-propel-6-benzf4 Slisoxazole~oxy) propvloxY
phenoxv acetate
A solution of methyl p-hydroxyphenoxy acetate (0.530
grams; 2.909 mrnol) in dry methyl ethyl ketone (6 mL) was treated
with 3-ethyl-6-(3-bromopropyl)oxy-7-propyIbenz[4,5]isoxazole (0.790
grams; 2.424 mmol) and potassium carbonate (0.422 grams; 3.055
mmol). The mixture was refluxed for 12 hours. The reaction mixture
was cooled to ambient and partitioned between isopropyl acetate and pH
4 buffer. The organic was washed with water, then dried over
magnesium sulfate, filtered and evaporated in vacuo to an oil. Silica gel
chromatograhy afforded the title compound.
NMR (CDCl3): 7.38 (d, 1H, J = 8.6 Hz); 6.90 (d, 1H, J = 8.5 Hz); 6.83
{apparent s, 4H); 4.57 (s, 2H); 4.21 (t, 2H, J = 5.9 Hz); 4.12 (t, 2H, J
= 5.8 Hz); 3.78 (s, 3H); 2.94 (quart, 2H, J = 7.4 Hz); 2.84 (bt, 2H, J =
7.9 Hz). -
3. 4-(3-(3-ethyl-7-prowl-6-benz~4 Slisoxazole)oxy)nrop~loxy phenoxy
acetic acid
A solution of methyl 4-(3-(3-ethyl-7-propyl-6-
benz[4,5]isoxazole) oxy)propyloxy phenoxy acetate (0.358 grams;
0.837 mmol) in methanol (4 mL) was treated with a solution of LiOH in
water (1.299 M; 0.770 mL; 1.00 mmol). The solution was refiuxed
for 2 hours. The reaction was partitioned between isopropyl acetate and
0.1 N HCI. The organic was dried over magnesium sulfate, filtered and
evaporated to an oil which was digested in cyclohexane/methylene
chloride (1:1; 3 mL). Removal of volatiles under high vacuum
afforded the title compound as a glass
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r
NMR (acetone): 7.68 (d, 1 H, J = 8.6 Hz); 7. I 2 (d, 1 H, J = 8.7 Hz);
- 6.88 (AB dd, 4H); 4.62 (s, 2H); 4.32 (t, 2H, J = 5.6 Hz); 4.20 (t, 2H, J
= 5.6 Hz); 2.94 (quart, 2H, J = 7.5 Hz); 2.85 (bt, 2H, J = 7.5 Hz).
l xample 28
D 'S'CH3
ht ~ ~ CI
1
O
N-Methylsulfonvl 3-chloro-4-(3-(3-ethyl-7-~ropvl-6-berzf4 51
isoxazole)oxy)prop~lthio~henyl acetamide
I. 3-chloro-4-(3-(3-ethyl-7-prowl-6-berzf4 5lisoxazole)oxv)
~ropylthio phenyl acetamide
A solution of 3-chloro-4-(3-(3-ethyl-7-propyl-6-benz[4,5]isoxazole)
oxy)propylthio phenyl acetic acid (L-165,461) (0.204 grams; 0.455
mmol) in dry methylene chloride (3 mL) was treated with dry DMF (5
~L). Oxalyl chloride (0.048 mL; 0.546 mmol} was added dropwise and
the solution stirred for 14 hours. All volatiles were removed in vacuo
and the derived residue dissolved in dry THF {10 mL). Concentrated
ammonia (i mL) was added dropwise and the mixture stirred for 3
hours. The reaction was partitioned between isopropyl acetate and
water. The organic was washed once more with water, then dried over
magnesium sulfate. Filtration and evaporation afforded the title
compound as a solid.
NMR (CDCl3): 7.59 (d, IH, J = 8.7 Hz); 7.40 {two overlapping d, 2H,
J = 8.0, 1.9 Hz); 7.15 (dd, 1 H, J = 8.1, 1.8 Hz}; 7.09 (d, 1 H, J = 8.8
Hz); 6.91 (vbs, I H); 6.29 (vbs, 1H); 4.20 (t, 2H, J = 5.9 Hz); 3.48 (s,
- 2H); 3.27 (t, 2H, 3 = 7.2 Hz); 2.95 {quart, ZH, J = 7.4 Hz);
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2. N-Methylsulfonvl 3-chloro-4-(3-(3-ethyl-7-propyl-6-benzf4 51
isoxazole)oxv)propvlthio phenyl acetamide
A solution of 3-chloro-4-(3-(3-ethyl-7-propyl-6-
benz[4,5]isoxazole) oxy)propylthio phenyl acetamide (L,-783,573)
(0.069 grams; 0.154 mmol) in dry toluene (2 mL) was treated with
methanesulfonyl chloride (0.013 mL; 0.162 mmol) and 80°1o sodium
hydride (0.005 grams; 0. i 62 mmol). The mixture was stirred at 80° C
for 14 hours. The reaction mixture was partitioned between isopropyl
acetate and 0.1 N HCI. The organic was dried over magnesium sulfate,
filtered and concentrated to an oil which was chromatographed over
silica gel to afford the title compound.
NMR (CDCl3): 7.59 (d, 1 H, J = 8.6 Hz); 7.43 (d, I H, J = 8.1 Hz);
7.41 (d, 1 H, J = 1.9 Hz); 7.27 {dd, 1 H, J = 8.0, 2.0 Hz); 7.09 (d, 1 H, J
= 8.5 Hz); 4.30 (t, 2H, J = 5.8 Hz); 3.72 (s, 2H); 3.27 (t, 2H, J = 7.0
Hz); 3.22 (s, 3H); 2.94 (quart, 2H, J = 7.2 Hz); 2.88 (bt, 2H, J = 7.6
Hz).
Example 29
HO2C I ~ OMe
O~
OMe
3,5-dimethoxy-4-(3-(3-(Ethyl)-7-(propyl)-6-bent-[4,5]-
isoxazoloxy)propyloxy)phenyl acetic acid
Step A: Preparation of Methyl-3,5-dimethoxy-4-hydroxyphenyl
acetate
A solution of 3,5-dimethoxy-4-hydroxyphenyl acetic acid
{424mg) in methanol (2mL) was treated with excess ,
trimethylsilyldiazomethane (2M in hexanes) at room temperature for -
30min. The reaction was then treated with solid magnesium sulfate -
filtered and concentrated to yield the title compound (450mg). NMR -
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Y
(CDCl3); 8 8.20 (s,lH), 6.49 (s,2H), 3.72 (s,6H), 3.59 (s,3H), 3.52
- (s,2H).
Step B: Preparation of Methyl-3,5-dimethoxy-4-(3-(3-(Ethyl)-7-
(propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)phenyl acetate
The procedure from Example 76 Step C was followed using
methyl-3,5-dimethoxy-4-hydroxyphenyl acetate (108mg) and3-bromo-
I-{3-(Ethyl)-7-(propyl)-6-Benz-[4,5]-isoxazoloxy)propane (156mg) to
afford a colorless oil (88mg). NMR (CDCl3); 8 7.41 (d,2H), 6.99
{d,2H), 6.45 (s,2H), 3.76 (s,6H), 3.71 (s,3H), 3.55 (s,3H), 1.43 {t,3H),
0.92 (t,3H).
Step C: Preparation of 3,5-dimethoxy-4-(3-(3-(Ethyl)-7-(propyl)-
6-benz-[4,5]-isoxazoloxy)propyloxy)phenyl acetic acid
Methyl-3,5-dimethoxy-4-(3-(3-{Ethyl)-7-(propyI)-6-benz-
[4,5]-isoxazoloxy)propyloxy)phenyl acetate (80mg) was hydrolyzed
according to the procedure found in Example 30 Step B to give the
desired compound (68mg) as a colorless solid. NMR (CDCl3); ~ 7.41
{d,2H), 6.98 (d,2H), 6.45 (s,2H), 3.76 (s,6H), 3.58 (s,3H), 1.43 (t,3H),
0.92 (t,3H).
Example 30
H02C. I ~ CI
O~O
CI
3,5-dichloro-4-(3-(3-(Ethyl)-7-{propyl)-6-bent-[4,5]-
isoxazoloxy)propyloxy)phenyl acetic acid
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Step A: Preparation of Methyl 3,5-dichloro-4-hydroxy benzoate
A solution of 2,4-dichloro-4-hydroxybenzoic acid (414 mg)
in ether (2mL) was trated with excess trimethylsilyl diazomethane (2M
in hexanes). After 1 hour at room temperature the reaction was
concentrated to yield an amber oil. The oil was chromatographed on
silica gel to yield the title compound ~(220mg). NMR (CDC13); 8 7.80
(s,2H), 3.85 (s,3H).
Step B: Preparation of Methyl-3,5-dichloro-4-(3-(3-{Ethyl)-7-
(propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)benzoate
The title compound was prepared according to Example 76
Step C using methyl 2,4-dichloro-4.-hydroxy benzoate (l l2mg) and 3-
bromo-I-(3-(Ethyl)-7-{propyl)-6-bent-[4,5J-isoxazoloxy)propane
(165mg) to afford a slightly pink colored solid (220mg). NMR
(CDCl3}; 8.0 (s,2H), 7.42 (d2H), 6.96 (d,2H}, 3.91 (s,3H), 1.42 {t,3H),
0.94 (t,3H).
Step C: Preparation of 3,5-dichloro-4-(3-(3-(Ethyl}-7-(propyl)-6-
benz-[4,5]-isoxazoloxy)propyloxy)-benzoic acid
Methyl-2,5-dichloro-4-(3-(3-(Ethyl)-7-(propyl)-6-benz-
[4,5J-isoxazoloxy)propyloxy)-benzoate (281mg} was hydrolyzed to give
the title compound following the procedure of example 32 Step D as a
colorless solid (227mg). NMR (CDCl3}; 8 790 (s,2H), 7.42 (d,2H), 6.95
(d,2H), 3.90 (s,3H), 1.41 (t,3H}, 0.94 (t,3H).
Step D: Preparation of Methyl-3,5-dichloro-4-(3-(3-(Ethyl)-7-
(propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy}phenyl acetate
The title compound was prepared from 2,5-dichloro-4-{3-
(3-(Ethyl)-7-(propyl}-6-benz-[4,5]-isoxazoloxy)propyloxy)-benzoic acid
(202mg) following the procedure from Example 77, Step C, to give a
clorless solid (177mg). NMR (CDCl3); 8 7.42 (d,2H), 7.21 (s,2H), 6.96
{d,2H), 3.76 {s,3H), 3.54 (s,2H), I.42 (t,3H), 0.97 (t,3H).
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Step E: Preparation of 3,5-dichloro-4-(3-(3-(Ethyl)-7-
{propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)phenyl acetic
acid
Methyl-2,5-dichloro-4-(3-(3-(Ethyl)-7-(propyl)-6-benz-
[4,5]-isoxazoloxy)propyloxy)phenyl acetate (37mg) was hydrolyzed
according to the procedure found in Example 30 Step B to give a
colorless solid (30mg). NMR (CDCl3); S 7.41 (d,2H), 7.20 {s,2H), 6.95
(d,2H0, 3.59 (s,2H0, 1.42 (t,3H), 0.95 (t, 3H).
Example 31
H02C ~ Me
i~
o~
Me
3,5-dimethyI-4-(3-(3-{Ethyl)-7-(propyI)-6-benz-[4,5]-
isoxazoloxy)propyloxy)phenyl acetic acid
Step A: Preparation of Methyl-3,5-dimethylbenzoate
A solution of 3,5-dimethyl-4-hydroxybenzoic acid ( 1.0g) in
ether (5mL) and methanol(5mL) was treated with excess
trimethylsilyldiazomethane. After stirring 30min at room temperature
the reaction was treated with magnesium sulfate, filtered and
concentrated to a brown solid. The title compound was obtained by
purification on silica gel to give a colorless solid (670mg}. NMR
(CDC13); S 7.75 (s,2H), 3.85 (s,3H), 2.30 (s,6H).
Step B: Preparation of Methyl-3,5-dimethyl-4-{3-(3-(Ethyl)-7-
(propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)benzoate
The title compound was prepared following the procedure
for example 17, Step D, using methyl-3,5-dimethylbenzoate (500mg)
and 3-bromo-1-(3-(Ethyl)-7-(propyl)-6-bent-[4,5]-isoxazoloxy)propane
(890mg) as starting materials to give after silicagel chromatography
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l.Ig of a waxy solid. NMR (CDCl3); S 7.80 (s,2H), 7.42 (d,2H), 6.95 '_
(d,2H), 3.85 (s,3H), 2.26 (s,3H},1.40 (t,3H), 0.96 (t,3H).
Step C: Preparation of Methyl-3,S-dimethyl-4-{3-(3-(Ethyl)-
7-(propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)phenyl
acetate
Methyl-3,5-dimethyl-4-(3-(3-(Ethyl)-7-(propyl}-6-benz-
[4,5]-isoxazoloxy)propyloxy)benzoate (200mg) was hydrolyzed
according to the procedure found in Example 77, Step C to give a waxy
colorless solid {180mg). This material was then treated according to
Example 77, Step C to give a colorless oil (88mg). NMR {CDCI3); 8
7.41 (d,2H), 7.20 (s,2H), 6.94 (d,2H}, 3.80 (s,3H), 3.52 (s,3H), 1.41
{t,3H), 0.95 (t,3H).
Step D: Preparation of 3,5-dimethyl-4-(3-(3-(Ethyl}-7-
{propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)phenyl acetic
acid
3,S-dimethyl-4-(3-(3-(Ethyl)-7-(propyI}-6-Benz-[4,5]-
isoxazoloxy)propyloxy)phenyl acetate {77mg} was hydrolyzed
aaccording to Example 30 Step B to give the desired compound (53mg}.
NMR (CDC13); 8 7.41 (d,2H), 7.22 (s,2H), 6.94 (d,2H), 3.51 {s,3H),
1.42 (t,3H), 0.96 (t,3H).
Exam 1p a 32
H02C ! \
~~N
\ O
O O
4-(3-(3-{Ethyl}-7-(propyl)-6-benz-[4,5]-isoxazoloxy}-propyloxy)-phenyl
propionic acid
Step A: Preparation of 3-{4-hydroxyphenyl)propionate:
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In a 0°C ice bath, 3-(4-hydroxyphenyl)propionic acid
- {313.3 mg; 1.9 mmol), was dissolved in 3 ml of ether. Added to this
' solution was about 6 mL of diazomethane dissolved in ether {0.32
mmoL/ mL). Allowed to stir for 5 minutes, vented the excess
diazomethane with nitrogen to a colorless solution and concentrated in
vacuo to afford a light yellow oil. Isolated 340.0 mg of the title
compound and used without further purification. NMR: 8 7.07 (d,2H);
6.76 (d,2H); 3.68 (s,3H); 2.89 (t,2H); 2.62 (t,2H);
Step B: Preparation of 3-ethyl-6-hydroxy-7-propylbenz-j4,5]-
isoxazole
The title compound was prepared by following the
procedures from Example 7 Step A substituting commercially available
2,4-dihydroxy-3-propylpropiophenone, as a colorless solid. NMR 7.42
(d,2H), 6.98 (d,2H), 2.95 (q,2H}, 2.84 (t,2H), 1.76 (m,2H), 1.42 (t,3H),
1.0 (t,3H).
Step C: Preparation of 3-ethyl-6-(3-bromopropyl)oxy-7-
propylbenz-[4,5]-isoxazole
Following the procedure of Example 7 Step B and
substituting 3-ethyl-6-hydroxy-7-propylbenz-j4,5]-isoxazole, the title
compound was prepared as a colorless solid. NMR: 8 7.40 (d,lH); 6.92
(d,lH); 4.22 (t,2H}; 3.69 (t,2H); 2.99 (q,2H); 2.84 (t,2H); 2.38
(m,2H); 1.41 (t,3H); 0.95 (t,3H)
Step D: Preparation of Methyl 4-(3-(3-(Ethyl)-7-(propyi)-6-benz-
[4,5]-isoxazoloxy)propyloxy}-phenyl propionate
A mixture of 3-(4-hydroxyphenyl)propionate (73.7 mg;
0.409 mmol), (3-(3-(Ethyl}-7-(propyl)-6-bent-[4,5]-isoxazoloxy
bromide (146.7 mg; 0.45 mmol), cesium carbonate. (139.7 mg; 0.43
mmol) and about 2.0 mi dry dimethylformamide was stirred and heated
for 16 hours. It was concentrated in vacuo, diluted with water arid
- extracted with ethyl acetate. The organic layer was washed with water,
dried (Na2S04), concentrated and chromatographed (silica gel, 30%
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ethyl acetate in hexane) to yield 118.7 mg of the title compound as a
light yellow oil. NMR: b 7.20 (d, l H); 7.12 (d,2H); 6.92 (d, l H); 6.83
(d,2H); 4.28 (t,2H); 3.99 (t,2H); 3.69 (s,3H); 2.98 {q,2H); 2.90
(m,4H); 2.6I (m,2H); 2.32 (m,2H); 1.70 (m,2H); 1.43 (t,3H); 0.93
(t,3H)
Step E: Preparation of 4-(3-(3-(Ethyi)-7-(propyl)-6-benz-[4,5]-
isoxazoloxy)-propyloxy)-phenyl propionic acid
A solution of 4-(3-(3-(Ethyl)-7-(propyl)-6-bent-[4,5]-
isoxazoloxy)propyloxy)-phenyl (32.3 mg; 0.071 mmol), 1M LiOH {aq)
(124 ~.L)and methanol (2.0 mL) was heated at 60°C for 16 hours. The
mixture was diluted with ethyl acetate and acidified to pH 5-6 with 1 M
HCI, washed with water (2 times), brine (1 time) and dried over sodium
sulfate and concentrated to afford 29.4 mg of the title compound. . MS
412 (M+H), NMR: S 7.41 (d, l H); 7.13 (d,2H); 6.94 (d, l H); 6.87
(d,2H); 4.28 (t,2H); 4.20 (t,2H); 2.93 (m,6H); 2.66 (m,2H); 2.33
(m,2H); 1.68 (m,2H); 1.44 (t,3H); 0.95 (t,3H)
EXAMPLE 33
MO ~ CI
O
3-chloro-4-(3-phenylinethyl-7-(n-propyl)-6-
benz[4,5]isoxazoloxy)propyl-thio)phenylacetic acid
Step A Prepararion of 1,3-dihydroxy-4-phenylacetyl-2-(n-propyl)-
benzene
Using the procedure in Example 51, step I, phenylacetic
acid and 2-(n-propyl)resorcinol were condensed in triflic acid to form
1,3-dihydroxy-4-phenylacetyl-2-(n-propyl)benzene.
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NMR (CDCI3): d 7.64 {d, 1H); 7.24 - 7.38 (m, 5H); 6.35 (d, 1H); 5.36
(s, 1 H); 4.23 (s, 2H); 2.61 (t, 2H); 1.56 (m, 2H); 0.98 (t, 3H).
Step B Preparation of 6-hydroxy-3-phenylinethyl-7-(n-propyl)-
benz[4,5}isoxazole
Using the procedures in Example 51. steps 2 and 3, 1,3-
dihydroxy-4-phenylacetyl-2-{n-propyl)benzene was converted into 6-
hydroxy-3-phenylinethyl-7-(n-propyl)benz[4,5}isoxazole.
NMR (CDCI3): d 7.2I - 7.37 (m, SH); 7.03 (d, 1H); 6.68 (d, IH); 5.2
(bs, 1H); 4.26 (s, 2H); 2.85{t, 2H); 1.72 (m, 2H); 1.00 (t, 3H).
Step C Preparation of methyl 3-chloro-4-(3-phenylinethyl-7-(n-
propyl)-6-bent[4,5}isoxazoloxy)propylthio)phenylacetate
Using the procedure in Example 16, step 4, 6-hydroxy-3-
phenylmethyl-7-(n-propyl)benz[4,5}isoxazole and methyl 3-chloro-4-(3-
bromopropylthio)phenylacetate were heated in DMF with Cs2C03 to
prepare methyl 3-chloro-4-{3-phenylmethyl-7-(n-propyl)-6-benz[4,5}-
isoxazoloxy)propylthio)phenylacetate
NMR (CDC13): d 7.22 - 7.35 (m, 5H); 7.12 (m, 2H); 6.79 (d, 1H); 4.29
{s, ZH); 4.13 (t, 2H); 3.7I (s, 3H); 3.55 (s, 2H); 3.15 (t, 2H); 2.86 (t,
2H); 2.16 (m, 2H); 1.69 {m, 2H); 0.95 (t, 3H).
Step D Preparation of 3-chloro-4-(3-phenylmethyl-7-(n-propyl)-6-
bent[4,5}isoxazoloxy)propylthio)phenylacetic acid
Using the procedure in Example 2, methyl 3-chloro-4-(3-
phenylmethyl-7-(n-propyl)-6-bent[4,5}isoxazoloxy)propylthio)phenyl
acetate was saponified with LiOH to form 3-chloro-4.-(3-phenylmethyl-
7-(n-propyl)-6-bent[4,5}isoxazoloxy)propylthio)phenylacetic acid
NMR (DMSOd6): d 7.43 (d, 1H); 7.20 - 7.39 {m, 4H); 7.13 (dd, iH);
7.04 (d, 1 H); 4.30 {s, 2H); 4.16 (t, 2H); 3.30 (s, 2H); 3.12 (t, 2H); 2.77
(t, 2H); 2.04 (m, 2H); 1.59 {m, 2H); 0.87 (t, 3H).
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_9g_
EXAMPLE 34
ci
( °rv
° i s~ o ~ o
3-chloro-4-(3-(2,2-dimethylpropyl)-7-(n-propyl)-6-
benz[4,5]isoxazoloxy)-propylthio)phenylacetic acid
Step A Preparation of 1,3-dihydroxy-4-(3,3-dimethylbutyryl)-2-
(n-propyl )benzene
Using the procedure in Example S I , step 1, 3,3-dimethyl-
butyric acid and 2-(n-propyl)resorcinol were condensed in triflic acid to
form 1,3-dihydroxy-4-(3,3-dimethylbutyryl)-2-(n-propyl)benzene
NMR (CDCl3 ): d 7.53 {d, I H); 6.32 (d, 1 H); 2.86 (s, 2H); 2.62 (t, 2H);
1.59 {m, 2H); I.06 (s, 9H); 0.98 (t, 3H).
Step B Preparation of 3-(2,2-dimethylpropyl)-6-hydroxy-7-(n-
propyl)benz[4,5]isoxazole
Using the procedures in Example 51, steps 2 and 3,
1,3-dihydroxy-4-(3,3-dimethylbutyryl)-2-(n-propyl)benzene was
converted into 3-(2,2-dimethylpropyl)-6-hydroxy-7-(n-
propyl)benz[4,5]isoxazole
NMR (CDCl3): d 7.29 (d, IH); 6.80 {d, IH); 5.30 (vbs, IH); 2.87 (t,
2H); 2.80 (s, 2H); I.75 (m, 2H); 1.04 (s, 9H); I.00 (t, 3H).
Step C Preparation of methyl 3-chloro-4-(3-{2,2-dimethylpropyl)-
7-(n-propyI)-6-bent[4,5] isoxazoloxy)propylthio)-phenylacetate
Using the procedure in Example I6, step 4, 3-(2,2-
dimethyl-propyl)-6-hydroxy-7-(n-propyi)benz[4,5]isoxazole and methyl
3-chloro-4-(3-bromopropylthio)phenylacetate were heated in DMF with
Cs2C03 to prepare methyl 3-chloro-4-(3-(2,2-dimethylpropyl)-7-(n-
propyl)-6-bent[4,5]isoxazoloxy)propylthio)phenylacetate
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r
NMR {CDCl3}: d 7.37 (d, 1H); 7.25 - 7.33 {m, 2H); 7.12 (dd, 1H); 6.90
(d, I H); 4.19 (t, 2H); 3.70 (s, 3H); 3.55 {s, 2H}; 3.18 (t, 2H); 2.89 (t,
2H); 2.81 (s, 2H); 2.20 (m, 2H); 1.71 {m, 2H); 1.05 (s, 9H); 0.96 (t,
3H}.
Step D Preparation of 3-chloro-4-(3-(2,2-dimethylpropyl)-7-(n-
propyl}-6-bent[4,5]isoxazoloxy)propylthio)phenylacetic acid
Using the procedure in Example 2, methyl 3-chloro-4-(3-
(2,2-dimethylpropyl)-7-(n-propyl)-6-
benz[4,5]isoxazoloxy)propylthio}phenyl acetate was saponified with
LiOH to form 3-chloro-4-(3-(2,2-dimethyl-propyl)-7-(n-propyl)-6-
benz[4,5]isoxazoloxy)propylthio)phenylacetic acid
NMR (CDCl3): d 7.36 (d, 1H); 7.26 - 7.35 (m, 2H}; ?.i3 (dd, IH), 6.89
(d, 1H); 4.I9 (t, 2H); 3.60 (s, ZH}; 3.17 (t, ZH); 2.86 (t, 2H); 2.81 (s,
2H); 2.19 (m, 2H); 1.70 (m, 2H); 1.04 (s, 9H); 0.95 (t, 3H).
Exile 35
H02C
~O~O
2-methyl-4-(3-(3-(Ethyl)-7-(propyl)-6-bent-[4,5]-
isoxazoloxy)propyloxy)-phenyl propionic acid
Step A: Preparation of Preparation of Methyl-2-methyl-4-(3-(3-
{Ethyl)-7-(propyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)-phenyl
propi onate
A solution of Methyl 4-(3-(3-(Ethyl)-7-(propyl)-6-benz-
[4,5]-isoxazoloxy)propyloxy)-phenyl propionate from Example 32 Step
C (16.5mg, 0.36 mmoL) in THF (0.5mL) at -78°C, under nitrogen was
trated with KHMDS (0.08mL, 0.5 M in toluene)and stirred for 30min.
- Excess methyl iodide was then added and the reaction stirred 30 min
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longer then warmed to RT. After 45 min the reaction was treated with -
IM ammonium chloride and extracted with ethyl acetate (x2), dried .
over anhydrous sodium sulfate, filtered and concentrated. The title
compound was obtained after purification by silica gel chromatography
to give a colorless oil {l2mg, 76%} NMR {CDCl3}; 8 7.41 (d,2H), 7.09
(d, 2H), 6.95 (d, ZH), 6.83 (d,2H}, 3.65 (s,3H), 1.43 (t,3H), 1.I6 (d,2H),
0.90 (t,3H}.
Step B: Preparation of 2-methyl-4-(3-(3-(Ethyl}-7-(propyl)-6-benz-
[4,5]-isoxazoloxy)propyloxy)-phenyl propionic acid
A solution of methyl-2-methyl-4-(3-{3-(Ethyl)-7-(propyl)-
6-benz-[4,5]-isoxazoloxy}propyloxy}-phenyl propionate (11.5 mg, Step
A) was dissolved in MeOH (0.5mL)and 1M LiOH (O.lOmL} was added.
The resulting solution was warmed to 50°C for 2 hours, cooled and
concentrated. The residue was partitioned between ethyl acetate and 1 M
HcI. The organic fraction was removed, dried and concentrated to give
the title compound as a colorless oil (I0.7 mg) NMR (CDCI3); 8 7.40
(d,2H), 7.1 I (d,2H), 6.95 (d,2H}, 6.85 {d,2H), 1.43 (t,3H), 1.18 {d,2H),
0.95 (t,3H).
example 36
HO O
o'~"'o 0
~3-Propyl-4-(3-(3-ethyl-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propyloxy)phenylacetic acid
Step A: Preparation of methyl 3-propyl-4-(3-(3-ethyl-7-propyl-6-
benz-[4,5]-isoxazoloxy)-propyloxy)phenylacetate
Using the method of Example 17, Step D, 1-bromo-3-(3-
ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)phenoxypropane as the starting
material, the title compound was obtained.
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1H NMR{ 400MHz, CDCl3 ): ~ 7.37 (d, 1H, J = 8.6 Hz), 7.01 {m, 2H),
' 6.90 (d, 1 H, J = 8.5 Hz}, 6.78 (d, 1 H, J = 8.3 Hz), 4.24 {t, 2H, J = 6.1
Hz), 4.15 (t, 2H, J = 6.0 Hz), 3.65 {s, 3H}, 3.52 (s, 2H), 2.94 (quart, 2H,
J = 7.6 Hz), 2.82 (t, 2H, J = 7.7 Hz), 2.53 (t, 2H, J = 7.7 Hz), 2.29
(quint, 2H, 3 = 6.0 Hz), 1.66 (hex, 2H, J = 7.5 Hz), 1.57 (hex, 2H, J =
7.6 Hz), 1.41 {t, 3H, J = 7.6 Hz), 0.89 (m, 6H).
Step B: Preparation of 3-propyl-4-{3-{3-ethyl-7-propyl-6-benz-
[4,5]-isoxazoloxy)-propyloxy}phenylacetic acid
Using the method of Example 18, methyl 3-propyl-4-(3-(3-
ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)- propyloxy)phenylacetate as
the starting material, the title compound was obtained.
1H NMR{ 400MHz, CDC13 ): 8 7.37 (d, 1H, J = 8.6 Hz), 7.0I (m, 2H),
6.90 (d, 1 H, J = 8.5 Hz), 6.78 (d, 1 H, J = 8.3 Hz}, 4.24 (t, 2H, 3 = 6. I
Hz), 4.15 (t, 2H, J = 6.0 Hz), 3.52 (s, 2H), 2.94 (quart, 2H, 3 = 7.6 Hz),
2.82 (t, 2H, J = 7.7 Hz), 2.53 (t, 2H, J = 7.7 Hz}, 2.29 (quint, 2H, J =
6.0 Hz}, 1.66 {hex, 2H, J = 7.5 Hz), I.57 (hex, 2H, J = 7.6 Hz), 1.41 (t,
3H, J = 7.6 Hz), 0.89 (m, 6H).
ESI: MS m/e = 440 (M+1 )
,example 37
~o
~~
N
i ~
~ ~
d
4-(3-(3-(Ethyl)-7-propyl-6-benz-[4,5]-isoxazoloxy)butyl)phenylacetate
Step A: Preparation of methyl 4-(4-hydroxybutyn-1-
yl)phenylacetate
To a solution of methyl 4-bromophenylacetate (229 mg, I.0
mmole) and 3-butyn-1-of (151 p.L, 2.0 mmole) in triethylamine (4.0
mL) was added cuprous bromide (18 mg, 0.12 mmole) and
tetra(triphenylphosphine)palladium (46 mg, 0.04 mmole}, and the
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mixture refluxed under a nitrogen atmosphere for lhr 20 min. The
mixture was evaporated in vacuo and the residue partitioned with water
and ether. The organic phase was washed with brine, dried over
magnesium sulfate and concentrated in vacuo to an oil. Flash
chromatography on silica gel in 7:3 hexane:ethyl acetate afforded the
title compound (175 mg) as an oil NMR (CDCI3): 8 I.69 (s, 1H); 2.71
(t, 2H); 3.63 (s, 2H); 3.71 (s, 3H); 3.83 {t, 2H); 7.22 (d, 2H); 7.38 (d,
2H).
Step B: Preparation of methyl 4-{4-hydroxybutyl)phenylacetate
A solution of methyl 4-(4-hydroxybutyn-1-yl)phenylacetate
(178 mg, 0.82 mmole) and 10% palladium on carbon (30 rng) in ethanol
(2 mL) were stirred under a balloon of hydrogen for 3 days at room
temperature. The mixture was filtered and the filtrate concentrated in
vacuo to give the title compound {181 mg) as an oil. NMR (CDCl3): S
1.52 (s, I H); 1.64 (m, 2H); I .7 l (m, 2H); 2.65 (t, 2H); 3.61 (s, 2H);
3.68 (t, 2H); 3.71 ( s, 3H); 7.15 (d, 2H); 7.21 (d, 2H).
Step C: Preparation of methyl 4-(4-methansulfonyloxybutyl)-
phenylacetate
To a solution of methyl 4-(4-hydroxybutyl)phenylacetate
(170 mg, 0.77 mmole) in methylene chloride {2 mL) was added
methansulfonyl anhydride (146 mg, I.06 mmole), pyridine (187 p.L,
2.3I mmole) and 4-dimethylaminopyridine (5 mg, 0.04 mmole) and the
mixture stirred at room temperature for 2 hours. The mixture was
concentrated in vacuo and the residue dissolved in ethyl acetate and
washed with 1N HCI, water, brine, dried over magnesium sulfate and
concentrated in vacuo to give the title compound (187 mg) as an oil.
NMR (CDCI3): 8 1.77 (m, 4H); 2.66 (t, 2H); 3.00 (s, 3H); 3.62 (s, 2H);
3.71 (s, 3H); 4.25 (t, 2H); 7. l 5 (d, 2H); 7.22 (d, 2H).
Step D: Preparation of methyl 4-(3-(3-(ethyl)-7-propyl-6-bent-
[4,5)-isoxazoioxy)butyI)phenylacetate
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A suspension of sodium hydride (15 mg, 0.36 mmole) in
DMF (1.5 mL) was treated with 3-ethyl-6-hydroxy-7-propylbenz-[4,5]-
isoxazoie (68 mg, 0.33 mmole) and the mixture stirred at room
temperature for 10 minutes under a nitrogen atmosphere. A solution of
methyl 4-(4-methansulfonyloxybutyl}phenylacetate (100 mg, 0.33
mmole) in DMF (0.5 mL) was added and the mixture stirred at 80oC
for 5 hours. The cooled reaction mix was dissolved in ethyl acetate and
washed with water (twice), brine, dried over magnesium sulfate and
concentrated in vacuo to an oil. The crude product was purified by thin
layer chromatography on silica gel eluting with hexane:ethyl acetate
(4:1 ) to give the title compound (80 mg) as an oil. NMR (CDCl3): 8
0.97 {t, 3H); 1.44 {t, 3H); 1.7I (m, 2H); 1.87 (m, 4H); 2.71 (t, 2H); 2.88
(t, 2H); 2.97 {q, 2H); 3.62 (s, 2H); 3.71 (s, 3H); 6.89 (d, 1 H); 7. I 8 (d,
2H); 7.22 (d, 2H); 7.39 (d, 1 H).
Step E: Preparation of 4-{3-(3-(ethyl)-7-propyl-6-bent-[4,5]-
isoxazoloxy)butyl)phenylacetate
To a solution of methyl 4-{3-(3-{ethyl)-7-propyl-6-benz-
[4,5]-isoxazoloxy)butyl)phenylacetate (80 mg, 0.195 mmole) in
methanol {2 mL) was added a solution of iithiurri hydroxide {1M, 390
~t.L), and the resulting solution stirred at 60oC for 2 hours. The
solution was concentrated in vacuo and the residue partitioned with ethyl
acetate and 1 NHCI. The aqueous phase was washed with ethyl acetate
and the combined organic extracts washed with water, brine, dried over
magnesium sulfate and concentrated in vacuo to afford the title
compound (76 mg) as an oil. NMR (CDCl3): 8 0.968 (t, 3H); 1.44 (t,
3H); 1.71 {m, ZH); 2.87 {m, 4H); 2.7I (t, 2H); 2.88 (t, 2H); 2.97 (q,
2H); 3.65 {s, 2H); 4.07 (t, 2H); 6.89 (d, 1H); 7.I9 (d, 2H}; 7.23 {d, ZH);
7.39 (d, 1H). Mass spec, m/e = 396 {m + 1).
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EXAMPLE 38
CI CF3
H02
S~
3-chloro-4-(7-(n-propyl)-3-(3,3,3-trifluoropropyl)-6-benz[4,5]isoxazol-
oxy)propylthio)phenylacetic acid
Step A Preparation of I,3-dihydroxy-2-(n-propyl)-4-(4,4,4-
trifluoro-butyryl)benzene
Using the procedure in Example 51, step 1, 4,4,4-
trifluoro-butyric acid and 2-(n-propyl)resorcinol were condensed in
triflic acid to form 1,3-dihydroxy-2-(n-propyl)-4-(4,4,4-
trifluorobutyryl)benzene
NMR (CDCl3): d 7.52 (d, IH); 6.38 (d, 1H}; 5.42 (s, 1H); 3.22 (t, 2H);
2.62 (t, 2H); 2.59 (m, 2H); 1.58 (m, 2H); 0.98 (t, 3H).
Step B Preparation of 6-hydroxy-7-(n-propyl)-3-(3,3,3-trifluoro-
propyl)benz(4,5]isoxazole
Using the procedures in Example 51, steps 2 and 3, 1,3-
dihydroxy-2-(n-propyl)-4-(4,4,4-trifluorobutyryl)benzene was
converted into 6-hydroxy-7-(n-propyl)-3-(3,3,3-
trifluoropropyl)bent[4,SJisoxazo1e
NMR (CDC13): d 7.31 (d, IH); 6.84 (d, IH); 5.31 (vbs, 1H); 3.18 (m,
2H); 2.86 (t, 2H}; 2.70 (m, 2H); 1.74 (m, 2H}; 0.99 (t, 3H).
Step C Preparation of methyl 3-chloro-4-(7-(n-propyl)-3-(3,3,3-
trifluoropropyl)-6-bent[4,5]isoxazoloxy)propylthio}-phenylacetate
Using the procedure in Example 16, step 4, 6-hydroxy-7-
(n-propyl)-3-(3,3,3-trifluoropropyI)bent[4,5]isoxazo1e and methyl 3-
chloro-4-(3-bromopropylthio)phenylacetate were heated in DMF with
Cs2C03 to prepare methyl 3-chloro-4-(7-(n-propyl)-3-(3,3,3-
trifluoropropyl)-6-bent[4,SJisoxazoloxy)propylthio)phenylacetate
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NMR (CDCl3): d 7.38 (d, 1H); 7.25 - 7.33 (m, 2H); 7.13 (dd, 1H); 6.93
(d, IH); 4.21 (t, 2H); 3.71 (s, 3H); 3.56 (s, 2H); 3.19 (m, 4 H); 2.89 {t,
2H); 2.72 (m, 2H); 2.21 (m, 2H); 1.70 (m, 2H); 0.95 (t, 3H).
Step D Preparation of 3-chloro-4-(7-(n-propyl)-3-(3,3,3-trifluoro-
propyl)-6-bent[4,5]isoxazoloxy)propyithio)phenylacetic acid
Using the procedure in Example 2, methyl 3-chloro-4-(7-
{n-propyl)-3-(3,3,3-trifluoropropyl)-6-
benz[4,5]isoxazoloxy)propylthio)-phenylacetate was saponified with
LiOH to form 3-chloro-4-(7-(n-propyl)-3-(3,3,3-trifluoropropyl)-6-
benz[4,5]isoxazoloxy)propylthio)phenylacetic acid.
NMR {CDCl3): d 7.39 (d, 1H); 7.26 - 7.34 {m, 2H); 7.13 (dd, 1H); 6.92
(d, 1 H); 4.20 (t, 1 H); 3.60 (s, 2H); 3.19 (m, 2H); 2.87 (t, 2H); 2.7 I (m,
2H); 2.20 (m, 2H); 1.69 (m, 2H); 0.95 (t, 3H).
EXAMPLE 39
\ /
ci
~~ N
~S~O ~ O
3-chloro-4-(3-(4-chlorophenylmethyl)-7-(n-propyl)-6-
benzj4,5]isoxazol-oxy)propylthio)phenylacetic acid
ci
Step A Preparation of 4-(4-chlorophenylacetyl)-1,3-dihydroxy-2-
(n-propyl)benzene
Using the procedure in Example 51, step 1, 4-
chlorophenyl-acetic acid and 2-(n-propyl)resorcinol were condensed in
triflic acid to form 4-(4-chlorophenylacetyl)-1,3-dihydroxy-2-(n-
propyl)benzene.
NMR (CDCl3): d 7.60 (d, 1H); 7.31 (d, 2H); 7.20 (d, 2H); 6.35 {d, 1H);
4.I9 (s, 2H); 2.61 (t, 2H); 1.59 (m, 2H); 0.96 (t, 3H).
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Step B Preparation of 3-(4-chlorophenylmethyl)-6-hydroxy-7-(n-
propyl)benz[4,5]isoxazole -
Using the procedure in Example 51, step 4-(4-
chlorophenyl-acetyl)-1,3-dihydroxy-2-(n-propyl}benzene.was converted
into 3-(4-chlorophenylmethyl)-6-hydroxy-7-(n-
propyl)benz[4,5]isoxazole
NMR (CDCl3): d 7.27 (q, 4H); 7.03 (d, 1H); 6.71 (d, 1H}; 5.14 (bs,
1H); 4.24 (s, 2H); 2.85 (t, 2H); 1.73 {m, 2H); 1.00 {t, 3H).
Step C Preparation of methyl 3-chloro-4-(3-(4-chlorophenyl-
methyl)-7-(n-propyl)-6-benz[4,5]isoxazoloxy)propylthio)phenylacetate
Using the procedure in Example 16, step 4, 6-hydroxy-3-
(4-chlorophenyhnethyl)-7-(n-propyi)benz[4,5]isoxazole and methyl 3-
chloro-4-(3-bromopropylthio)phenylacetate were heated in DMF with
Cs2C03 to prepare methyl 3-chloro-4-(3-(4-chlorophenylmethyl)-7-(n-
propyI)-6-bent[4,5]-isoxazoIoxy)propylthio)phenyl acetate
NMR (CDCl3): d 7.23 - 7.32 (m, 6H); 7.I2 (dd, 1H); 7.10 (d, 1H); 6.71
(d, 1 H); 4.25 (s, 2H); 4.15 (t, 2H); 3.7 I (s, 3H); 3.54 (s, 2H); 3.15 (t,
2H); 2.86 {t, 2H); 2.17 (m, 2H); 1.69 (m, 2H); 0.95 (t, 3 H).
Step D Preparation of 3-chIoro-4-(3-(4-chlorophenylmethyl)-7-(n-
propyI)-6-bent[4,5]isoxazoloxy)propylthio)phenylacetic acid
Using the procedure in Example 2, methyl 3-chloro-4-(3-
(4-chlorophenylmethyl)-7-(n-propyl)-6-Benz[4,5]isoxazoloxy)-
propylthio)-phenyl acetate was saponified with LiOH to form 3-chloro-
4-(3-(4-chlorophenylmethyl)-7-(n-propyl)-6-bent[4,5]isoxazoloxy)-
propyl-thio)phenylacetic acid
NMR (DMSOd6)): d 7.46 (d, 1H); 7.34 - 7.41 (q, 4H); 7.27 - 7.34 (m,
2H); 7.13 (dd, 1 H); 7.04 (d, 1 H); 4.31 (s, 2H); 4.17 (t, ZH); 3.29 (s, 2H);
3.14 (t, 2H); 2.78 (t, 2H); 2.04 (m, 2H); I.59 (m, 2H); 0.86 (t, 3 H).
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Example 40
~o ~ ct
0
cH3
3-Chloro-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-benz-[4,5}-
isoxazoloxy)propyl- N-methylamino)phenylacetate
Step A: Preparation of Methyl 3-Chloro-4-(3-(3-(2,2-
dimethylpropyl)-7-propyl-6-benz-[4,5]-isoxazoloxy)propyl-N-
methylamino)phenylacetate
Sodium cyanoborohydride (10.5 mg, 0.16 mmoIe) was
added in portions to a solution of methyl 3-chloro-4-{3-(3-(2,2-
dimethylpropyl)-7-propyl-6-bent-[4,5]-
isoxazoloxy)propylamino)phenylacetate (obtained as the product in
Example 21, 50 mg, 0.102 mmole), 37°/o formaldehyde (92 ~.L, 1.02
mmole) and bromocresol green solution (0.04%, 1 drop) in acetonitrile
( 1 mL) at room temperature. The mixture was stirred for 1 hour
during which time acetic acid was added to maintain an acid pH {yellow
indicator color). The mixture was diluted with ethyl acetate and washed
with ice-cold 2.5M sodium hydroxide {2x), water (2x), brine, dried
over magnesium hydroxide and concentrated in vacuo to give the title
compound {S I mg) as gum. NMR (CD3OD); 8 0.904 (t, 3H); 1.03 (s,
9H); I.63 {m, 2H); 2.07 (m, 2H); 2.77 {s, 2H); 2.82 {t, 2H); 2.82 {s,
3H); 3.27 {t, 2H); 3.57 (s, 2H); 3.67 {s, 3H); 4.17 (t, 2H); 7.01 (d, 1H);
7.14 (m, 2H); 7.27 (s, 1H); 7.49 (d, 1H).
Step B: Preparation of 3-Chloro-4-(3-(3-{2,2-dimethylpropyl)-7-
propyl-6-bent-[4,5]-isoxazoloxy)propyl-N- methylamino(phenylacetate)
Using the method of Example 22, substituting methyl 3-
chloro-4-{3-(3-{2,2-dimethylpropyl)-7-propyl-6-bent-[4,5]-
isoxazoloxy)propyl-N-methylamino)phenylacetate as starting material,
- the title compound was obtained. NMR {CD30D); S 0.9 l (t, 3H); 1.03
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(s, 9H); e .64 (m, 2H); 2.06 (m, 2H); 2.77 (s, 2H); 2.82 (t, 2H); 2.82 (s,
3H); 3.26 (t, 2H); 3.52 (s, 2H); 4.17 {t, 2H); 7.01 (d, 1H); 7.15 {s, 2H);
7.29 (s, 1H); 7.49 (d, 1H}. Mass spec, m/e = 488 (m + 1).
Example 41
H
~N
~O w O
3,5-Dipropyl-4-(3-(3-ethyl-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propyloxy)phenylacetic acid
Step A: Preparation of methyl 3-ally!-4-allyloxyphenylacetate
A solution of methyl 3-ally!-4-hydroxyphenylacetate (4.I0
g)(Example 17, Step B), ally! bromide (2.30 mL) and potassium
carbonate (3.95 g) in 2-butanone (40 mL} was refluxed for four hours.
The mixture was pardoned between 0.2N HCl and ethyl acetate. The
organic layer was dried over magnesium sulfate, felted, concentrated in
vacuo. Column Chromatography (silica gel 60, 50% methylene chloride
in hexane} gave the tittle compound.
1H NMR( 400MHz, CDCl3): 8 7.04 (m, 2H), 6.76 (d, 1H, J = 8.2 Hz),
6.08-5.92 (m, 2H), 5.41-5.01 (m, 4H), 4.49 (m, 2H), 3.66 (s, 3H), 3.52
(s, 2H), 3.37 (d, 2H, 3 = 6.7 Hz).
Step B: Preparation of methyl 3,5-diallyl-4-hydroxyphenylacetate
Using the method of Example 17, Step B, methyl 3-ally!-4-
allyloxyphenylacetate as the starting material, the title compound was
obtained.
1H NMR( 400Mhz, CDCI3 ): S 6.90 (s, 2H), 5.98-5.94 (m, 2H), 5.14 (m,
SH), 3.66 (s, 3H), 3.49 (s, 2H), 3.37 (d, 4H, J = 6.5 Hz)
Step C: Preparation of methyl 3,5-dipropyl-4-hydroxyphenylacetate
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Using the method of Example 17, Step C, methyl 3,5-
diallyl-4-hydroxyphenylacetate as the starting material, the title
compound was obtained.
1H NMR( 400MHz, CD3COCD3): ~ 6.88 (s, 2H), 4.62 {s,lH), 3.68 (s,
3H), 3.S I {s, 2H), 2.54 (t, 4H, J = 7.6 Hz), 1.62 (hex, 4H, J = 7.5 Hz),
0.98 (t, 6H, 3 = 7.4 Hz).
Step D: Preparation of methyl 3,5-dipropyl-4-(3-(3-ethyl-7-propyl-
6-benz-[4,5]-isoxazoloxy)-propyloxy)phenylacetate
Using the method of Example 17, Step D, methyl 3,5-
dipropyl-4-hydroxyphenylacetate and I-bromo-3-(3-ethyl-7-propyl-6-
benz-[4,5]-isoxazoloxy)phenoxypropane as the starting material, the title
compound was obtained.
1H NMR( 400MHz, CDCI3 ): 8 7.39 (d, i H, J = 8.5 Hz), 6.94 (d, 1 H, J =
8.6 Hz), 6.90 (m, 2H), 4.3I (t, 2H, J = 5.9 Hz), 3.94 (t, 2H, J = 5.9 Hz),
3.66 (s, 3H), 3.51 (s, 2H), 2.95 (quart, 2H, J = 7.5 Hz), 2.85 (t, 2H, J =
7.3 Hz), 2.52 (m, 4H), 2.28 (quint, J = 6.5 Hz), 1.7I-1.52 (m, 6H), 1.40
(t, 3H, 3 = 7.3 Hz), 0.94 (t, 3H, J = 7.3 Hz), 0.84 (t, 6H, J = 7.4 Hz).
Step E: Preparation of 3,5-dipropyl-4-(3-(3-ethyl-7-propyl-6-benz-
[4,5]-isoxazoloxy)-propyloxy)phenylacetic acid
Using the method of Example 18, methyl 3,5-dipropyl-4-
(3-(3-ethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)-propyloxy)phenylacetate
as the starting material, the title compound was obtained.
1H NMR{ 400MHz, CDCl3 ): S 7.39 (d, l H, J = 8.5 Hz), 6.94 {d, IH, J =
8.6 Hz), 6.90 (m, 2H), 4.31 (t, 2H, J = 5.9 Hz), 3.94 (t, 2H, J = 5.9 Hz),
3.51, (s, 2H), 2.95 (quart, 2H, J = 7.5 Hz), 2.85 (t, 2H, J = 7.3 Hz), 2.52
(m, 4H), 2.28 (quint, J = 6.5 Hz), 1.71-1.52 (m, 6H), 1.40 (t, 3H, J =
7.3 Hz), 0.94 (t, 3H, J = 7.3 Hz), 0.84 (t, 6H, J = 7.4 Hz).
ESI: MS m/e = 482 (M+I )
f
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-.110 -
Example 42
HO Fs .
O~
F
3-fluoro-4-(3-(7-propyl-3-trifluoromethyl-6-bent-[4, S]isoxazoloxy)-
propyloxy)phenylacetic acid
STEP A: Preparation of Methyl 3-fluoro-4-(3- bromopropyloxy)-
phenylacetate
A solution of methyl 3-fluoro-4-hydroxyphenylacetate
(25.545 grams) in 2-butanone (300 mL) was treated with 1,3-
dibromopropane (48.79 mL) and potassium carbonate (50.859 grams).
The mixture was refluxed for 4 hours. The reaction mixture was
partitioned between isopropyl acetate and pH 4 buffer. The organic was
washed once with water, then dried over magnesium sulfate. The
organic was filtered and evaporated to an oil which was
chromatographed over silica gel with hexanelmethylene chloride (2:1 )
to afford the title compound. This compound was taken forward
without further purification.
STEP B: Preparation of 3-trifluoromethyl-7-propyl-6-hydroxybenz-
[4, 5]-isoxazole
Using the method and materials in example 20 steps A and
B the titled compound was obtained.
STEP C: Preparation of Methyl 3-fluoro-4-(3-(7-propyl-3-
trifluoromethyl-6-bent-[4, 5]-isoxazoloxy)propyloxy)phenylacetate
Using the method in example I7 step I7 substituting methyl
3-fluoro-4-(3-bromopropyloxy)phenylacetate and 3-trifluoromethyl-7-
propyl-6-hydroxybez-[4, SJ-isoxazole as the starting materials, the titled ,
compound was obtained. -
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' NMR {CDCl3) 8 7.54 (d,lH, J = 8.79 Hz); 7.07 (d, 1H, J = 8.83 Hz);
7.02 (d, 1 H, J = I 0.25 Hz); 6.92 (m, 2H); 4.29 {t, 2H, J = 5.97 Hz); 4.23
{t, 2H, J = 5.98 Hz); 3.67 (s, 1H); 3.53 (s, 2H); 2.88 (t, 2H, J = 7.49 Hz);
2.33 {m, 2H, J = 6.03 Hz); 1.65 {m, 2H); 0.91 (t, 3H, J = 7.41 Hz).
STEP D: Preparation of 3-fluoro-4-{3-(7-propyl-3-trifiuoromethyl-6-
benz-[4, 5)-isoxazoloxy)propyloxy)phenylacetic acid
Using the method in example 2 step A, substituting Methyl
3-fluoro-4-(3-(7-propyl-3-trifluoromethyl-6-bent-[4, 5]-
isoxazoloxy)propyloxy)phenylacetate as the starting material, the titled
compound was obtained.
NMR (CDC13) 8 7.53 (d, l H, J = 8.42 Hz); 7.07 (d, 1 H, 3 = 8.82 Hz};
7.0I (d, I H, 3 = 10. I 8 Hz); 6.93 (m, 2H); 4.29 (t, 2H, J = 5.94 Hz); 4.23
(t, 2H, J = 6.06 Hz); 3.56 (s, 2H); 2.87 (t, 2H, J = 7.40 Hz); 2.33 (m,
2H, J = 5.98 Hz); 1.66 (m, 2H); 0.91 (t, 3H, J = 7.41 Hz}.
ESI: Mass spec: m/e = 456 (M+I ).
Example 43
Hooc
3-chloro-4-(3-(3-trifluoromethyl-7-propyl-6-bent-[4, 5)-
isoxazoloxy)propylamino)phenylacetic acid
STEP A: Preparation of 3-trifluoromethyl-7-propyl-6-hydroxybenz-[4,
5]-isoxazole
Using the method and materials in example 20 steps A and
B the titled compound was obtained.
STEP B: Preparation of Methyl 3-chloro-4-(3-bromopropylamino)-
phenylacetate
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Magnesium oxide (10 grams, 250 mmoles),
was added to a solution of 1,3-dibromopropane {I39 grams, 70 mL, 700 _
mmoles} in dimethylacetamide (150 mL). A solution of methyl 3-
chioro-4-aminophenylacetate-HCl (23.6 grams, 100 mmoles) in
dimethylacetmide {200 mL} was added dropwise over 30 minutes and
the mixture stirred at 80oC for 6 hours. The cooled mixture was
partitioned with methylene chloride and water. The aqueous phase was
extracted with methylene choride and the combined organic phases
washed with brine, dried over magnesium sulfate and concentrated in
vacuo to an oil. The crude product was chromatographed on a silica gel
column eluting with hexane:ethyl acetate {9:1 ). The product was further
purified by a second silica geI chromatography in methylene
chloride:hexane (2:3) to give the title compound as an oil. NMR,
(CDC13): 8 2.15 (qnt, 2H); 3.35 (q, 2H); 3.47 (s,2H); 3.49 (t, 2H}; 3.67
(s, 3H}; 6.63 (d, 1 H); 7.03 (dd, 1 H); 7.17 (d, 1H).
STEP C: Methyl 3-chloro-4-{3-{3-trifluoromethyl-7-propyl-6-benz-
[4, 5]-isoxazoloxy)propylamino}phenylacetate
Using the method in example 17 step D substituting
Methyl 3-chloro-4-(3-bromopropylamino}phenylacetate and 3-
trifluoromethyl-7-propyl-6-hydroxybenz-[4, 5]-isoxazole as the starting
materials, the titled compound was obtained.
NMR {CDCl3) S 7.54 (d,lH, J = 8.10 Hz); 7.18 (s, 1H); 7.03 (m, 2H);
6.64 (d, 1 H, J = 8.34 Hz); 4.39 (bs, 1 H); 4.20 (t, 2H, J = 5.86 Hz); 3.66
(s, 3H); 3.47 (s, 2H}; 3.42 (t, 2H, J = 6.83 Hz}; 2.92 (t, 2H, J = 7.58 Hz);
2.18 (m, 2H); 1.69 (m, 2H); 0.95 {t, 3H, J = 7.41 Hz).
STEP D: 3-chloro-4-(3-(3-trifluoromethyl-7-propyl-6-bent-[4, 5]-
isoxazoloxy)propylamino)phenylacetic acid
A solution of Methyl 3-chloro-4-{3-(3-trifluoromethyl-7-
propyl-6-bent-[4, 5]-isoxazoloxy)propylamino)-phenylacetate (Step C,
0.113 grams) in methanol (1.5 mL) was treated with a solution of
lithium hydroxide in water (1.01 M; 0.362 mL). The reaction was
refluxed 1 hour. The reaction mixture was partitioned between '
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isopropyl acetate and O.IN HCl. The organic was dried over
magnesium sulfate, filtered and concentrated to a solid. The solid was
suspended in methyiene chloride/cyclohexane (1:1; 2 mL). The
mixture was refluxed briefly and cooled to 0°C. The title compound
was isolated by filtration..
NMR (CDC13) 8 7.54 (d,lH, J = 8.10 Hz); 7.18 (s, 1H); 7.03 (m, ZH);
6.64 (d, 1 H, J = 8.34 Hz); 4.19(t, 2H, J = 5.86 Hz); 3.50 {s, 2H); 3.43 (t,
2H, J = 6.83 Hz); 2.92 (t, 2H, J = 7.58 Hz); 2.18 (m, 2H); 1.69 (m, 2H);
0.95 (t, 3H, J = 7.41 Hz).
ESI: Mass spec: m/e = 471 (M+1 ).
Example 44
HOO I j \ I ~N
O~O O
3-Isobutyl-4-{3-(3-neo-pental-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propyloxy)phenyiacetic acid
Step A: Preparation of methyl 4-methallyloxyphenylacetate
Using the method of Example l 7, step A, methallyl
bromide as the starting material, the title compound was obtained.
iH NMR( 400MHz, CDCl3 ): 8 7.16 (d, 2H, J = 8.5 Hz), 6.86 (dd, 2H, J
= 8.6, 2.1 Hz), 5.06 {s, IH), 4.97 (s, 1H), 4.39 (s, 2H), 3.66 (s, 3H),
3.54 {s, 2H), 1.80 {s, 3H).
Step B: Preparation of methyl 4-hydroxy-3-methaiiylphenylacetate
Using the method of Example 17, step B, methyl 4-
methallyloxyphenylacetate as the starting material, the title compound
was obtained.
1H NMR( 400MHz, CDCl~ ): 8 7.03 (dd, 1 H, J = 8.I, 2.2 Hz), 6.98 (d,
1H, J = 2.5 Hz), 6.98 (d, 1H, J = 8.2 Hz), 5.18 (s, IH), 4.90 (s, 1H),
4.82 (s, IH), 3.66 (s, 3H), 3.52 (s, 2H), 3.33 (s, 2H).
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Step C: Preparation of methyl 4-hydroxy-3-isobutylphenylacetate
Using the method of Example i 7, step C, methallyl
bromide as the starting material, the title compound was obtained.
1H NMR{ 400MHz, CDCl3 ): 8 6.95 (m, 2H), 6.66 (d, 2H, J = 8.2 Hz),
3.70 (s, 3H), 3.54 (s, 2H), 2.43 (d, 2H, J = 7.5 Hz), I.91 (m, IH), 0.92
(d, 6H, J = 7.6 Hz).
Step D: Preparation of methyl 3-isobutyl-4-(3-(3-neo-pental-7-
propyl-6-benz-[4,5]-isoxazoIoxy)-propyloxy)phenylacetate
Using the method of Example I7, step D, methyl 4-
hydroxy-3-isobutylphenylacetate and 1-bromo-3-(3-neo-pental-7-
propyl-6-benz-[4,5]-isoxazoloxy)phenoxypropane as the starting
material, the title compound was obtained.
1H NMR{ 400MHz, CDCI~ ): 8 7.34 (d, 1H, J = 8.7 Hz), 7.04 (dd, 1H, J
= 8.3, 2.2 Hz), 6.97 (d,lH, J = 2.2 Hz), 6.90 (d, 1H, J = 8.7 Hz), 6.78
(d, I H, J = 8.2 Hz), 4.24 (t, 2H, J = 6. I Hz), 4.14 (t, 2H, J = 5.9 Hz),
3.66 (s, 3H), 3.51 (s, 2H), 2.83 {t, 2H, J = 7.4 Hz), 2.78 (s, 2H), 2.42 (d,
2H, J = 7.0 Hz), 2.30 (quint, 2H, J = 6.0 Hz), 1.83 {m, I H), I .64 (m,
2H), 1.02 (s, 9H), 0.91 (t, 3H, J = 7.4 Hz), 0.82 {d, 6H, J = 6.7 Hz).
Step E: Preparation of 3-isobutyl-4-(3-(3-neo-pental-7-propyl-6-
benz-[4,5]-isoxazoloxy)-propyloxy)phenylacetic acid
Using the method of Example 18, the product of step D was
saponified to give the title compound.
1H NMR( 400MHz, CDC13 ): 8 7.34 (d, 1 H, J = 8.7 Hz), 7.04 (dd, 1 H, J
= 8.3, 2.2 Hz), 6.97 (d, I H, J = 2.2 Hz), 6.90 (d, 1 H, J = 8.7 Hz), 6.7 8
(d, I H, J = 8.2 Hz), 4.24 (t, 2H, J = 6. I Hz), 4.14 (t, 2H, J = 5.9 Hz),
3.5I (s, 2H), 2.83 (t, 2H, J = 7.4 Hz), 2.78 (s, 2H), 2.42 (d, 2H, J = 7.0
Hz), 2.30 (quint, 2H, J = 6.0 Hz), 1.83 (m, 1 H), 1.64 (m, 2H), I .02 {s,
9H), 0.91 (t, 3H, J = 7.4 Hz), 0.82 (d, 6H, J = 6.7 Hz).
ESI: MS m/e = 496 (M+1 )
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_ - -lI5-
example 45
HO
i
I
O O.S,.~
O
3-Propyl-4-(3-(3-neo-pental-7-propyl-6-Benz-[4,5]-isoxazoloxy)
propylthio)phenylacetic acid S,S-dioxide
Step A: Preparation of methyl 3-propyl-4-(3-(3-neo-pental-7-
propyl-6-benz-[4,5]-isoxazoloxy)propylthio)phenylacetate S,S-dioxide
Using the method of Example 13, methyl 3-propyl-4-(3-(3-
neo-pental-7-propyl-6-benz-[4,5]-isoxazoloxy)propylthio)phenylacetate
as the starting material, the title compound was obtained.
1H NMR( 400MHz, CDC13 }: S 7.96 (d, 1H, J = 8.6 Hz), 7.33 (d, 1H, J =
8.6 Hz), 7.32 {m, 2H), 6.92 (d, 1H, J = 8.7 Hz), 4.12 (t, 2H, J = 5.9 Hz),
3.69 (s, 3H), 3.66 (s, 2H), 3.35 (t, 2H, J = 7.5 Hz), 2.94 (t, 2H, J = 7.9
Hz), 2.78 (2H, J = 8.0 Hz), 2.27 {m, 2H), 1.74-I.58 (m, 4H), 1.02 (s,
9H), 0.98 (t, 3H, J = 7.4 Hz), 0.98 (t, 3H, J = 7.3 Hz)
Step B: Preparation of 3-propyl-4-(3-(3-neo-pental-7-propyl-6-
benz-[4,5]-isoxazoloxy)propylthio)phenylacetic acid S,S-dioxide
Using the method of Example I4, methyl 3-propyl-4-(3-(3-
neo-pental-7-propyl-6-bent-[4,5]- isoxazoloxy)propylthio}phenyiacetate
S,S-dioxide as the starting material, the title compound was obtained.
1H NMR( 400MHz, CDCl3 ): 8 7.96 {d, 1H, J = 8.6 Hz), 7.33 (d, 1H, J =
8.6 Hz), 7.32 (m, 2H), 6.92 (d, I H, J = 8.7 Hz), 4. I 2 (t, 2H, J = 5.9 Hz),
3.66 (s, 2H), 3.35 (t, 2H, J = 7.5 Hz), 2.94 (t, 2H, J = 7.9 Hz), 2.78 (2H,
3 = 8.0 Hz), 2.27 {m, 2H), I.74-1.58 (m, 4H), 1.02 {s, 9H), 0.98 (t, 3H,
J = 7.4 Hz), 0.98 (t, 3H, J = 7.3 Hz)
" ESI: MS m/e = 530 (M+1)
r
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~~le 46
~o ~ ca
0
s
02
-Chloro-4-(3-(3-phenyl-7-propyl-6-bent-[4,5]-isoxazoloxy}-
propylsulfoxy)phenylacetic acid
Step 1
The acid prepared in Example 16 Step 5 ( 19.2 mg, 1.0 Eq,
0.04 mmol ) was dissolved in methylene chloride { 0.3 ml ) with
mCPBA (85%, 18.2 mg, 2.3 Eq, O.I 1 mmol ). At a 1/4 Hr the mixture
was, diluted with EtOAc and sodium bisulfate 10% aq. The EtOAc
extract was washed again with sodium bisulfate IO% aq, followed by
NaCI sat'd aq. The EtOAc extracts were dried over MgSO4 and reduced
to an oil a. vac.
The product was purified by elution from a reversed phase RP-8 col {E.
Merck 40-63 w ) with 65 : 35 CH3CN : H20 0.1 % TFA. The ester is
obtained as a glass.
Analytical HPLC 75 : 25 CH3CN : H20 0.1 % TFA, E. Merck RP-8 5~
4 X 250 mm, 1 mi/min. UV 210, RT 7.73 min.
Characteristic NMR Resonances; IH NMR 400MHz (CDCl3); 8.09 (d,
1 H, J = 8.1 Hz), 7.90 (m, 1 H), 7.62 (d, I H, J = 8.7 Hz), 7.52 (m, 4H),
7.38 (dd, 1 H, J = 8.2, 1.6 Hz), 6.89 (d, 1H, J = 8.8 Hz), 4.17 (t, 2H, J =
5.8 Hz}, 3.70 {s, 2H), 3.67 (m, 2H}, 2.87 (t, 2H, J = 7.4 Hz), 2.28 (m,
2H), I.67 (next, 2 H, 7.5 Hz}, 0.93 (t, 3H, J = 7.36 Hz}.
MS ESI M+1 = 528.3. MW = 527.I
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Example 47
F
HOOC
O
3-fluoro-4-(4-(3-phenyl-7-propyl-6-bent-[4, 5]-isoxazoloxy)-
butyloxy)phenylacetic acid
STEP A: Preparation of Methyl 3-fluoro-4-(4-bromobutyloxy)-
phenylacetate
A solution of methyl 3-fluoro-4-hydroxyphenylacetate and
1,4-dibromobutane (Step A; 0.552 grams) in 2-butanone {6 mL) was
treated with 3-propyl-2,4-dihydroxypropiophenone (0.299 grams).
Potassium carbonate (0.217 grams) was added and the mixture refluxed
for 4 hours. The reaction was partitioned between isopropyl acetate and
pH 4 phosphate buffer. The organic was dried over magnesium sulfate,
filtered and evaporated to a residue which was chromatographed over
silica gel to give the product.
NMR (CDC13) S 7.08 (d, 1H); 6.91 (m, 2H); 4.05 (t, 2H); 3.69 (s,
3H);3.52 (s, 2H); 3.48 (t, 2H); 2.06 (m, 2H); i .97 (m, 2H).
STEP B: Preparation of 3-phenyl-7-propyl-6-hydroxybenz-[4, 5]-
isoxazoie
Using the method and materials in example I 6 steps 1 A, I ,
2, and 3 the titled compound was obtained.
STEP C: Preparation of Methyl 3-fluoro-4-{4-(3-phenyl-7-propyl-6-
benz-[4, 5]-isoxazoloxy)butyloxy)phenylacetate
Y
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Using the method in example 23 step 3 substituting Methyl
3-fluoro-4-(4-bromobutyloxy)phenylacetate as the starting material, the
titled compound was obtained.
NMR (CDCl3 ) $ 7.92 (m, 2H); 7.64 (d, 1 H, J = 8.70 Hz); 7.51 {m,
3H); 6.97 (m, 4H); 4.12 (m, 4H); 3.67 (s, 3H);3.53 (s, 2H); 2.90 (t, 2H,
3 = 7.35 Hz); 2.02 (m, 4H); 1.71 (m, 2H); 0.96 (t, 3H,J = 7.36 Hz).
STEP D: Preparation of 3-fluoro-4-(4-(3-phenyl-7-propyl-6-benz-[4,
Sj-isoxazoloxy)butyloxy)phenylacetic acid
Using the method in example 23 step 4 substituting Methyl
3-fluoro-4-(4-(3-phenyl-7-propyl-6-benz-[4, 5)-isoxazoloxy)butyloxy)-
phenylacetate as the starting material, the titled compound was obtained.
NMR (CDCI3) ~ 7.93 (m, 2H); 7.65 (d, 1H, 3 = 8.70 Hz); 7.51 (m,
3H); 6.98 (m, 4H); 4.12 (m, 4H); 3.58(s, 2H); 2.90 {t, 2H, J = 7.35 Hz);
2.02 (m, 4H); 1.71 (m, 2H); 0:99 (t, 3H, J = 7.36 Hz).
ESI: Mass spec: m/e = 479 (M+1 ).
Exam In a 48
C F3
HO ~ /
\\N
O ~ / \ ~ i
O O ~O
2
C~
3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benz-[4, 5]-
isoxazoloxy)propyl-thio)phenylacetic acid S, S-dioxide
STEP A: Preparation of Methyl 3-chloro-4-(3-(7-propyl-3-
trifluoromethyI-6-bent-[4, 5]-isoxazoloxy)propyl-thio)phenylacetate
Using the method and materials in example 20 step A, B
and C the titled compound was obtained.
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' -119-
STEP B: Preparation of Methyl 3-chloro-4-(3-(7-propyl-3-
' trifluoromethyl-6-bent-[4, 5]-isoxazoloxy)propyl-thio)phenylacetate S,
S-dioxide
Using the method in example 13 substituting Methyl 3-
chloro-4-(3-(7-propyl-3-trifluoromethyl-6-bent-[4, 5]-
isoxazoloxy)propyl-thio)phenylacetate as the starting material and using
2 equivalents of the oxidating agent, the titled compound was obtained.
This compound was filtered through a pad of silica gel using ethyl ether
and hexane ( 1: l ) as the mobile phase, and taken forward without further
purification.
STEP C: Preparation of 3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-
benz-[4, 5]-isoxazoloxy}propyl-thio}phenylacetic acid S, S-dioxide
Using the method in example 2 step A, substituting Methyl
3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-bent-[4, 5]-
isoxazoIoxy)propyl-thio}phenylacetate S, S-dioxide as the starting
material, the titled compound was obtained.
NMR (CDCl3) 8 8.09 (d, IH, 3 = 8.15 Hz); 7.51 (m, 2H); 7.39 (d, 1H, J
= 5.38 Hz); 6.97 (d, IH, J = 8.87 Hz); 4.18 (t, 2H, J= 5.86 Hz); 3.71 (s,
2H); 3.64 (t, 2H, 3 = 7.49 Hz); 2.85 (t, 2H, J = 7.41 Hz); 2.30 (m, 2H);
1.64 (m, 2H}; 0.91 (t, 3H, J = 7.36 Hz).
ESI: Mass spec: m/e = 520 (M+1 ).
Bxam~le 49
CF
HO ~
\\N
O ~ ~ %~ ~ ~ O
-S O
O
CI
3
3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benz-[4, 5]-
isoxazoloxy)propyl-thio)phenylacetic acid S-oxide
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- I20 -
STEP A: Preparation of Methyl 3-chloro-4-{3-(7-propyl-3-
trifluoromethyl-6-Benz-[4, 5]-isoxazoloxy)propyl-thio)phenylacetate S-
oxide
Using the method in example 1 I substituting Methyl 3-
chloro-4-(3-(7-propyl-3-trifluoromethyl-6-bent-[4, 5]-
isoxazoloxy)propyl-thio)phenylacetate as the starting material, (Example
20, step C) the titled compound was obtained. This compound was
filtered through a pad of silica gel using ethyl ether and hexane (1:1) as
the mobile phase, and taken forward without further purification.
STEP B: Preparation of 3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-
benz-[4, 5]-isoxazoloxy)propyl-thio)phenylacetic acid S-oxide
Using the method in example 2 substituting Methyl 3-
chloro-4-(3-(7-propyl-3-trifluoromethyl-6-bent-[4, 5]-
isoxazoloxy)propyl-thio)phenyiacetate S-oxide as the starting material,
the titled compound was obtained.
NMR (CDCl3) b 7.85 (d, 1H, J = 8.02 Hz); 7.52 {d, 2H, J = 8.79 Hz);
7.43 (d, I H, J = 6.43 Hz); 7.35 {s, 1 H); 6.99 (d, I H, J = 8.87 Hz); 4.18
(m, 2H); 3.68 (s, 2H); 3.38 (m, 1H); 3.02 (m, 1H}; 2.84 (t, 2H, J = 7.49
Hz}; 2.44 (m, I H); 2.18 (m, 1 H); i .63 (m, 2H); 0.91 (m, 3H}.
ESI: Mass spec: m/e = 504 {M+1 }.
EXAMPLE 50
H02C \ CI
SAO
3-chloro-4-(3-{2-phenylethyl)-7-propyl-6-benz[4,5]isoxazoloxy)propyl-
thio)phenylacetic acid
Step A Preparation of 1,3-dihydroxy-4-(3-phenylpropionyl)-2-(n- '
propyl)benzene
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' Using the procedure in Example 5 i , step 1, 3-
phenylpropionic acid and 2-(n-propyl}resorcinol were condensed in
triflic acid to form 1,3-dihydroxy-4-(3-phenylpropionyl)-2-(n-
propyl)benzene.
NMR (CDCl3): d 7.20 (d, 1H); 7.19 - 7.33 (m, 5H}; 6.33 (d, 1H); 5.28
(s, 1 H); 3.24 {t, 2H); 3.04 (t, 2H); 2.63 (t, 2H); 1.57 (m, 2H); 0.99 (t,
3H).
Step B Preparation of 6-hydroxy-3-(2-phenylethyl}-7-(n-
propyl)benz-[4,5]isoxazole
Using the procedures in Example 51, steps 2 and 3, 1,3-
dihydroxy-4-(3-phenylpropionyl)-2-(n-propyl)benzene was converted
into 6-hydroxy-3-(2-phenylethyl)-7-(n-propyl)benz[4,5]isoxazole.
NMR (CDCI3): d 7.2I - 7.32 (m, 5H); 7.18 (d, 1H); 6.77 (d, 1H); 5.32
(vbs, 1 H); 3.22 (m, 2H); 3.14 (m, 2H); 2.77 {t, 2H); 1.74 (m, 2H); 1.00
(t, 3H).
Step C Preparation of methyl 3-chloro-4-(3-(2-phenylethyl)-7-
propyl-6-Benz[4,5]isoxazoioxy}propylthio)phenylacetate
Using the procedure in Example 16, step 4, 6-hydroxy-3-
(2-phenylethyl)-7-(n-propyl)benz[4,5]isoxazole and methyl 3-chloro-4-
(3-bromopropylthio}phenylacetate were heated in DMF with Cs2C03 to
prepare methyl 3-chloro-4-(3-(2-phenylethyl}-7-propyl-6-benz[4,5]-
isoxazoloxy)propylthio)phenylacetate.
NMR (CDCl3): d 7.21 - 7.35 (m, 8H); 7.13 (dd, 1H); 6.87 (d, 1H); 4.19
(t, 2H); 3.71 (s, 3H); 3.57 (s, 2H); 3.12 - 3.27 (m, 6H); 2.88 (t, 2H);
2.20 (m, 2H), i.70 (m, 2H); 0.95 (t, 3H).
Step D Preparation of 3-chloro-4-(3-(2-phenylethyl)-7-propyl-6-
benz[4,5]isoxazoloxy}propylthio)phenylacetic acid
Using the procedure in Example 2, methyl 3-chloro-
4-(3-(2-phenylethyl}-7-propyl-6-bent[4,5]isoxazoloxy)propylthio)-
' phenylacetate was saponified with LiOH to form 3-chloro-4-(3-(2-
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phenylethyl)-7-propyl-6-bent[4,5]isoxazoloxy)propylthio)phenylacetic '
acid. -
NMR (CDC13 ): d 7.21 - 7.35 (m, SH); 7.13 (dd, 1 H); 6.87 (d, 1 H); 4.19
(t, 2H); 3.60 (s, 2H); 3.12 - 3.26 (m, 6H); 2.88 (t, 2H), 2.20 (m, 2H);
1.69 {m, 2H); 0.95 (t, 3H)
Example 51
~t ~ ci
0
3-Chloro-4-(3-(3-{4-fluorophenyl}-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid
t 1
Commercially available 2-propylresorcinoI ( 3.0 g, 1.0 Eq,
0.019 mol ) and p-fluorobenzoic acid ( 3.2 g, 1.15 Eq, 0.023 moI ) were
dissolved in trifluoromethanesulfonic acid { IO mi ) at RT. The mixture
was heated to 85 C under N2. At 2 1/2 hrs, the reaction was cooled to
RT and poured into H20. The mixture was extracted with EtOAc. The
extracts were washed with NaHC03 sat'd. aq., washed with NaCI aq
sat'd, and dried over MgS04. The EtOAc solution was reduced i. vac
The product was purified by elution from a silica gel column {20 g E.
Merck 40-63 a ) with toluene : EtOAc 98 : 2.
Characteristic NMR Resonances; IH NMR 400MHz (CDCl3); 7.64 (m,
2H), 7.30 (d, 1 H, J = 8.8 Hz), 7. I S (m, 2H), 6.31 {d, 2H, J = 8.8 Hz),
5.47 (s, 1 H), 2.66 {dd, 2H, J = 9.3, 7.6 Hz), I .60 (m, 2H), 0.99 (t, 3H).
MS ESx M+I = 275.1. MW = 274.1
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Step 2
The ketone of Example 52 step 1 (2.5 g, I.0 Eq, 9.1 mmol ) was
converted to the oxime with NH~OH-HCl ( 2.54 g, 4.0 Eq, 37 mmol ) as
for the procedure of Example 7 Step A.The product was purified by
recrystallization from toluene to provide one isomer.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.27 (m,
2H), 7.17 (m, 2H), 6.50 (d, 1 H, J = 8.7 Hz), 6.21 (d, 1 H, 3 = 8.7 Hz),
2.66 (dd, 2H, J = 9.3, 7.6 Hz), I.61 {seat, 2H, J = 7.7 Hz), 0.99 (t, 3H, J
= 7.4 Hz).
MS ESI M+I = 290. MW = 289.
to
The oxime of Example 51 step 2 ( i .45 g, 5 mmol ) was
converted to the 3-(p-fluorophenyl)-6-hydroxy-7-propylbenzisoxazole
as for Example 7 Step A. The product was purified by recrystallization
from toluene.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCI3); 7.90 {m,
2H), 7.52 (d, 2H, J = 8.5 Hz}, 7.2 (m, 2H}, 6.86 (d, i H, J = 8.6 Hz),
5.14 (s, 1 H), 2.90 (dd, 2H, J unresolved), I .75 (sext, 2H, J = 7.5 Hz),
1.01 (t, 3H, J = 7.3 Hz).
MS ESI M+1 = 272Ø MW = 271.1
to 4
The 3-(p-fluorophenyl}-6-hydroxy-7-propylbenzisoxazole of Example
51 Step 3 ( 285 mg, 1.0 Eq, 1 mmol ) was coupled with the bromide of
Example 16 Step 1A ( 390 mg, 1.I Eq, 1.1 mmol } as for Example 16
Step 4. The product was purified by elution from a silica gel column
{40 g E. Merck 40-63 w ) with toluene : hexanes : EtOAc 70 : 26 : 4.
Characteristic NMR Resonances; 1H NMR 400MHz (CDC13}; 7.91 (m,
2H), 7.60 (d, 1 H, J = 8.7 Hz), 7.26 (m, 4H), 7.1 I (dd, 1 H, J = 8. I , 1.8
Hz}, 6.96 {d, 1H, 8.8 Hz), 4.2I {t, 2H, J = 5.8 Hz), 3.68 (s, 2H), 3.54 (s,
' 2H), 3.17 (t, 2H, J =7.1 Hz), 2.91 (dd, 2H, J unresolved}, 2.19 (pent,
w
- 2H, J = 5.9 Hz), 1.7I (sext, 2H, J = 7.5 Hz}, 0.96 (t, 3H, J = 7.4 Hz).
' . MS ESI M+I = 528.3. MW = 527.1
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_ -- I 24 -
Ste~S
The ester of Example 51 Step 4 ( 344 mg, 1.0 Eq, 0.65
mmoI) was hydrolyzed with LiOH ( 869 ~.L, 1.5 N, 2.0 Eq, I.3 mmol )
as described in Example 16 Step S.The product is puri~led by
recrystallization from MeOH.
Characteristic NMR Resonances; IH NMR 400MHz (CDCI3); 7.89-7.94
(m, 2H), 7.59 (d, 1H, J = 8.8 Hz), 7.2-7.5 (m, 4H), 7.11 (dd, 1H, J =
8.1, 1.9 Hz), 6.96 (d, 1 H, 8.8 Hz), 4.20 (t, 2H, J = 5.8 Hz), 3.58 (s, 2H),
3.17 (t, 2H, J =7.I Hz), 2.9I (t, 2H, J = 7.6 Hz), 2.20 (pent, 2H, J = 6.I
Hz), 1.70 (sext, 2H, J = 7.5 Hz), 0.96 (t, 3H, 3 = 7.4 Hz).
HPLC; 60 : 40 to 85 : 15 CH~CN : H20 0.1 % TFA 25 min linear
gradient. E. Merck 5 ~ RP-8 4 X 250 mm. RT 16.2 min. UV 210 nM.
MS ESI M+1 = 514.2. MW = 513.1
l~xatnple 52
F
N ~ Cf
i
O
O
3-Chloro-4-(3-(3-(4-fluorophenyl)-7-propyl-6-benz-[4,5)-isoxazoloxy)-
propylsulfinyl)phenylacetic acid
Step 1
The ester of Example 51 Step 4 ( 60 mg, I.0 Eq, 0.1 I4
mmol) was combined with mCPBA ( 85%, 33.4 mg, 1.5 Eq, O.i65
mmol ) in methylene chloride ( 0.5 m1 ) at 0 C. The mixture was
stirred at 0 C for 2 Hrs, followed by stirring at RT for 1 1/2 Hrs. The
mixture was diluted with EtOAc and sodium thiosulfate ~10% aq. The .
EtOAc extract was washed again with sodium thiosulfate ~IO% aq, "
followed by NaHC03 sat'd. aq. and NaCI sat'd aq. The EtOAc extracts .
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were dried over MgS04 and reduced to an oiI i. vac. Two products
were recovered by elution from a silica gel column {2.5 g E. Merck 40-
63 ~. ) with toluene : EtOAc 91 : 9
Sulfox~~Ie:
Characteristic NMR Resonances; 1 H NMR 400MHz (CDC13); 7.8-7.9
(m, 2H), 7.85 (d, 1 H, J = 8.1 Hz), 7.59 (d, 1 H, J = 8.8 Hz}, 7.42 (dd,
I H, J = 8.1, 1.8 Hz), 7.34 (d, 1 H, J = 1.7 Hz), 7.2 (m, 2H), 6.93 (d, 1 H,
J = 8.8 Hz), 4.15-4.26 ( complex m, 2H), 3.70 (s, 3H), 3.65 (s, 2H),
3.33-3.64 (complex m, 1H), 2.97-3.04 (complex m, 1H), 2.86 (dd, 2H, J
= 8.8, 7.5 Hz), 2.40-2.47 (complex m, 1 H), 2.12-2.22 (complex m,
1H), 1.68 (sext, 2H, J = 7.5 Hz), 0.933 (t, 3H, J = 7.4 Hz).
MS ESI M+1 = 544. MW = 543.5
,~ ' ne:
Characteristic NMR Resonances; 1 H NMR 400MHz (CDC13); 8.09 (d,
1 H, J = 8. I Hz), 7.9 (m, 2H), 7.58 (d, 1 H, J = 8.7 Hz), 7.49 (d, 1 H, J =
1.7 Hz), 7.38 {dd, 1 H, J = 8.1, 1.7 Hz), 7. I 4-7.24 (m, 2H), 6.90 (d, 1 H,
J = 8.8 Hz), 4.18 (t, 2H, J = 5.8 Hz), 3.71 (s, 3H), 3.67 (s, 2H}, 3.66 ( t,
2H, J obscured}, 2.87 (dd, 2H, J = 8.6, 7.4 Hz), 2.30 (m, 2H), I.67
(sext, 2H, J = 7.4 Hz), 0.94 (t, 3H, J = 7.4 Hz).
MS ESI M+1 = 560.4. MW = 559.5
to 2
The sulfoxide of Example 52 step 1 ( 45 mg, 1.0 Eq, 0.083
mmoI } was hydrolyzed with LiOH ( 1 IO ~.L, 1.5 N, 2.0 Eq, 0.166
mmol ) as described in Example I6 Step 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.88-7.92
(m, 2H), 7.85 (d, 1 H, J = 8.1 Hz), 7.58 (d, 1 H, J = 8.7 Hz), 7.42 (d, I H,
J = 8. I Hz), 7.35 (s, 1 H), 7.2I {m, 2H), 6.91 (d, 1 H, J = 8.7 Hz), 4.1-
4.25 (complex m, 2H), 3.67 (s, 2H), 3.35-3.42 (complex m, 1H}, 2.99-
3.06 (complex m, 1H), 2.85 {t, 2H, J = 7.4 Hz), 2.38-2.45 (complex m,
1H), 2.1-2.2 (complex m, 1H), i.65 (sext, 2H, J = 7.4 Hz}, 0.916 (t, 3H,
- J = 7.3 Hz}. .
" HPLC; 65 : 35 CH3CN : Hz0 0.1 % TFA isocratic. E. Merck 5 ~. RP-8
4 X 250 mm. RT 7.4 min. UV 2I0 nM.
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MS ESI M+1 = 530.3. MW = 529.1
Example 53
H ~ CI
1
O
O~ ~
3-Chloro-4-(3-(3-(4-fluorophenyl}-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylsulfonyl)) phenylacetic acid
Step
The sulfone of Example 52 step 1 ( 13 mg, 1.0 Eq, 0.023
mmol ) was hydrolyzed with LiOH ( 31 uL, 1.5 N, 2.0 Eq, 0.046 mmol
as described in Example 16 Step 5.
Characteristic NMR Resonances; 1 H NMR 400MHz (CDCl3); 8.08 {d,
1H, J = 8.1 Hz), 7.89 (m, 2H), 7.58 (d, 1H, J = $.7 Hz), 7.49 (d, IH, 3 =
1.5 Hz), 7.37 (dd, 1 H, J = 8. I , 1.5 Hz), 7.20 {m, 2H), 6.89 (d, 1 H, J =
8.8 Hz), 4.17 {t, ZH, J = 5.8 Hz), 3.69 (s, 2H), 3.66 (dd, 2H, J
obscured), 2.86 (dd, 2H, J unresolved), 2.25-2.31 {m, 2H), 1.66 {sext,
2H, J = 7.5 Hz), 0.924 (t, 3H, J = 7.4 Hz).
HPLC; 65 : 35 CH3CN : H20 0.1 °1o TFA isocratic. E. Merck 5 w RP-8
4 X 250 mm. RT 8.1 min. UV 210 nM.
MS ESy M+1 = 546.3. MW = 545.1
Example 54
C!
HO ~ CI
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-I27-
2,3-Dichloro-4.-(3-(3-neo-pental-7-propyl-6-benz-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid
Step A: Preparation of methyl 2,3-dichloro-4-dimethylcarbamoyl-
thiophenylacetate
A solution of methyl 2,3-dichloro-4-dimethylthio-
carbamoyloxyphenylacetate (5.0 g) andin tetramethylene sulfone (65
mL) was heated to reflux for 20 minutes. After 20 minutes, the
reaction was cooled as rapidly as possible with a stream of air. The
mixture was partitioned between water and ether. The combined
organics were washed with water and brine, dried over magnessium
sulfate, poured onto a column of silica gel and eluted with ethyl
acetate/hexane (20/80) to give the title compound.
1H NMR( 400MHz, CDCl3 ): S 7.49 (d, 1H, J = 8.3 Hz), 7.20 (d, 1H, J =
8.2 Hz), 3.81 (s, 2H), 3.69 (s, 3H), 3.12 {broad s, 3H), 3.00 (broad s,
3H).
Step. B: Preparation of methyl 2,3-dichloro-4-(3-(3-neo-pental-7-
propyl-6-benz-[4,5]-isoxazoloxy)propylthio)phenylacetate
Using the method of Example 20, step C, 1-bromo-3-(3-
neo-pental-7-propyl-6-benz-[4,5]-isoxazoloxy)phenoxypropane as the
starting material, the title compound was obtained.
1H NMR{ 300MHz, CDC13 ): S 7.36 (d, IH, J = 8.7 Hz), 7.I7 (d, IH, J =
8.3 Hz), 7.13 (d, 1 H, J = 8.2 Hz), 6.89 {d, 1 H, J = 8.7 Hz), 4.19 (t, 2H, J
= 5.8 Hz), 3.76 (s, 2H), 3.7I {s, 3H), 3.19 (t, 2H, 3 = 7.2 Hz), 2.88 {t,
2H, J = 7.5 Hz), 2.8'1 {s, 2H), 2.22 {quint, 2H, J = 7.1 Hz), 1.71 (hex,
2H, J = 7.3 Hz), 1.05 (s, 9H), 0.96 (t, 3H, J = 7.3 Hz)
Step C: Preparation of 2,3-dichloro-4-(3-(3-neo-pental-7-propyl-6-
bent-[4,5]- isoxazoloxy)propylthio)phenylacetatic acid
Using the method of Example 20, step D, methyl 2,3-
' dichloro-4-(3-{3-neo-pental-7-propyl-6-bent-[4,5]-
r _ isoxazoloxy)propylthio)-phenylacetate as the starting material, the title
compound was obtained.
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1H NMR( 300MHz, CDC13 ): 8 7.36 (d, IH, J = 8.7 Hz), 7.17 (d, IH, J =
8.3 Hz), 7.13 (d, 1 H, J = 8.2 Hz), 6.89 (d, 1 H, J = $.7 Hz), 4.19 (t, 2H, J
= 5.8 Hz), 3.76 (s, 2H), 3.19 (t, 2H, J = 7.2 Hz), 2.88 (t, 2H, J = 7.5
Hz), 2:81 (s, 2H), 2.22 (quint, 2H, J = 7.1 Hz), 1.71 (hex, 2H, J = 7.3
Hz), I.OS (s, 9H), 0.96 (t, 3H, J = 7.3 Hz)
ESI: MS m/e = 524 (M+1)
Example 55
o~cF3
HO
O i O~O
2-Trifloroethoxy-4-(3-{3-neo-pental-7-propyl-6-Benz-[4,5]-
isoxazoloxy)propyloxy)phenylacetic acid
Step A: Preparation of methyl 2-trifluoroethoxy-4-(3-(3-neo-pental-
7-propyl-6-benz-[4,5]-isoxazoloxy)propyloxy)phenylacetate
Using the method of Example 20, step C, I -bromo-3-(3-
neo-pental-7-propyl-6-benz-[4,5]-isoxazoloxy)phenoxypropane and
methyl 2-trifluoroethoxy-4-hydroxyphenylacetate as the starting
material, the title compound was obtained.
1H NMR{ 300MHz, CDCl3 ): S 7.34 {d, IH, J = 8.7 Hz), 7.08 (d, IH, J =
8.3 Hz), 6.92 (d, I H, J = 8.7 Hz), 6.52 (d, I H, J = 2.4 Hz), 6.42 (dd, 1 H,
J = 8.4, 2.5 Hz), 4.30 (2H, J = 8.2 Hz), 4.21 (t, 2H, J = 6.1 Hz), 4.16 (t,
2H, J = 5.9 Hz), 3.55 (s, 3H), 3.53 (s, 2H), 2.83 (t, 2H, J = 7.5 Hz), 2.78
(s, 2H), 2.27 (quint, 2H, J = 6.5 Hz), 1.65 (hex, 2H, J = 7.5 Hz), 1.02 (s,
9H), 0.92 (t, 3H, J = 7.3 Hz)
Step B: Preparation of 2-trifiuoroethoxy-4-(3-(3-neo-pental-7-
propyl-6-benz-[4,5]-isoxazoIoxy)propyloxy)phenylacetic acid ,
Using the method of Example 20, step D, methyl 2-
trifluoroethoxy-4-(3-(3-neo-pental-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
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propylthio)phenylacetate as the starting material, the title compound was
obtained.
1H NMR( 300MHz, CDC13 ): 8 7.34 (d, 1H, J = 8.7 Hz), 7.08 (d, IH, J =
8.3 Hz), 6.92 (d, 1 H, J = 8.7 Hz), 6.52 (d, 1 H, J = 2.4 Hz), 6.42 (dd, 1 H,
J = 8.4, 2.5 Hz), 4.30 (2H, J = 8.2 Hz), 4.2I (t, 2H, J = 6.1 Hz), 4.16 (t,
2H, J = 5.9 Hz), 3.53 (s, 2H), 2.83 (t, ZH, 3 = 7.5 Hz), 2.78 (s, 2H), 2.27
(quint, 2H, J = 6.5 Hz), 1.65 (hex, 2H, J = 7.5 Hz), 1.02 (s, 9H), 0.92 (t,
3H,J=7.3 Hz}
ESI: MS m/e = 538 (M+1)
Example 56
HO ~ CI
O ~ NCO ~ O
H
3-Chloro-4-(3-(3-cyclopropyl)-7-propyl-6-bent-14,5]-
isoxazoloxy)propyiamino)phenylacetate
Step A: Preparation of 4-cyclopropylcarbonyl-2-(n-
propyl}resorcinol
Using the method of Example 50, Step B, substituting
cyclopropylcarboxylic acid as the starting material, the title compound
was obtained as a coral-colored solid. NMR {CDCI3}; 8 I.00 (t, 3H);
1.05 (m, 2H); I.27 (m, 2H); 1.60 (m, 2H); 2.62 (m, 1H); 2.65 (t, 2H);
6.40 (d, 1 H); 7.76 (d, 1 H).
Step B: Preparation of 4-cyclopropylhydroxyimino-2-(n-
propyl)resorcinol
A solution of 4-cyclopropylcarbonyl-2-(n-
propyl)resorcinol (I.0 g, 4.54 mmole) in methanol (10 mL) was treated
' with hydroxylamine~HCl (1.58g, 22.7 mmole) and sodium acetate
{1.86g, 22.7 mmole) and the mixture refluxed for 7 hours. The cooled
mixture was poured into water and extracted 3x with ethyl acetate. The
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- - r
combined extracts were washed with water {2x), 10% sodium
bicarbonate, brine, dried over magnesium sulfate and concentrated in
vacuo to give a solid. The crude product was chromatographed on silica
gel eluting with methylene chloride followed by methanol:methylene
chloride (5:95) to afford the title compound. NMR (CDCl3); 8 0.89 (m,
2H); 0.94 (t, 3H); 1.10 (m, 2H); 1.76 (m, 1H); 2.61 (t, 2H); 6.35 (d,
1 H); 7.41 (d, 1 H).
Step C: Preparation of 3-cyclopropyl-6-hydroxy-7-propylbenz-
[4,5]-isoxazole
A solution of 4-cyclopropylhydroxyimino-2-(n-
propyl)resorcinol (537 mg, 2.28 mmole) in acetic anhydride (6 mL)
was stirred at room temperature for 2 days. The mixture was
concentrated in vacuo and the residue partitioned with ethyl acetate and
10% sodium carbonate and stirred for 1 hour. The organic phase was
washed with brine, dried over magnesium sulfate and concentrated in
vacuo to give a solid. Flash chromatography on silica gel in ethyl
acetate:hexane (15:85) afforded the title compound (150 mg) as a solid.
NMR (CDCl3); S 1.00 (t, 3H); 1.17 {m, 2H); 1.26 (m, 2H); 1.74 (m,
2H); 2.25 (m, 1H); 2.82 (t, 2H); 6.77 (d, 1H); 7.27 (d, 1H).
Step D: Preparation of methyl 3-chloro-4-(3-(3-cyclopropyl)-7-
propyl-6-benz-[4,5]-isoxazoloxy)propylamino)phenylacetate
To a solution of 3-cyclopropyl-6-hydroxy-7-propylbenz-
[4,5]-isoxazole (34 mg, 0.156 mmole) and methyl 3-chloro-4-(3-
bromopropyIamino)phenylacetate (Example 21, Step C, 50 mg, 0.156
mmole) m DMF (0.70 mL) was added cesium carbonate (54 mg , 0.164
mmole), and the mixture stirred at 80oC in a nitrogen atmosphere for 2
hours. The cooled mixture was dissolved in ethyl acetate and washed
with water, brine, dried over magnesium sulfate and concentrated in
vacuo to give an oil. Thin layer chromatography on silica gel eluting
with hexane:ethyl acetate {2:1) afforded the title compound (44 mg). ,
NMR (CDC13); 8 0.95 (t, 3H); 1.15 (m, 2H); I.24 (m, ZH); 1.67 (m,
2H); 2.15 (t, 2H); 2.18 (m, 1 H); 2.81 (t, 2H); 3.43 (t, 2H); 3.47 (s, 2H);
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3.67 (s, 3H); 4.10 (t, 2H); 6.65 (d, 1 H); 6.83 (d, 1 H); 7.04 (d, 1 H); 7. I
8
- (d, 1H); 7.32 (d, IH).
Step E: Preparation of 3-chloro-4-{3-(3-cyclopropyl)-7-propyl-6-
benz-[4,5]-isoxazoloxy)propylamino}phenylacetate
Using the method of Example 22, substituting methyl
3-chloro-4-(3-(3-cyclopropyl)-7-propyl-6-bent-[4,5]-isoxazoloxy}-
propylamino)phenylacetate as starting material, the title compound was
obtained. NMR (CD30D); 8 0.95 (t, 3H); I .3 (m, 4H);1.69 (m, 2H);
2.13 {m, 2H); 2.2 (m, 1H); 2.85 (t, 2H); 3.42 (t, 2H); 3.43 (s, 2H); 4.13
(m, 2H); 6.72 (d, 1H); 6.98 (d, 1H); 7.03 (dd, 1H); 7.I7 (d, IH); 7.29
(d, 1 H).
Examp la a 57
CN3
H I ~ CI
'' N
O
O
2-(3-chloro-4-(3-(3-ethyl-7-propyl-6-benz-[4,5]-
isoxazoloxy)propylthio)) phenylpropionic acid
1. 3-ethyl-6-(3-bromoprop I~loxy-7-propvlbenzf4.51isoxazole
A solution of 3-ethyl-6-hydroxy-7-propylbenz[4,5]isoxazole
(2.00 grams; 9.74 mmol) in dry DMF was treated with
dibromopropane (7.I7 mL; 38.97 mmoi) and cesium carbonate (3.49
grams; 10.71 mmol}. The solution was stirred at room temperature for
IO hours, then partioned between isopropyl acetate and pH 4.0 buffer.
The organic layer was washed twice with water, dried over magnesium
sulfate, filtered and concentrated in vacuo. Silica gel chromatography
afforded the title compound (1.74 g}.
', NMR (CDC13): 7.39 (d, 1H, 3 = 8.8 Hz); 6.91 (d, 1H, J = 8.8 H); 4.18
(t, 2H, J = 5.7 Hz); 3.63 (t, 2H, J = 6.4 Hz); 2.94 (quart, 2H, J = 7.6
Hz); 2.35 {quint, 2H, J = 6.0 Hz}; 1.40 (t, 3H, J = 7.5 Hz); 0.94 (t, 3H,
7.4 Hz).
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2. 2-(3-chloro-4-(3-(3-ethyl-7-propel-6-benzf4,51isoxazoleloxvl
prop l~thioO,_phenvl nro~ionic acid methyl ester
A solution of 2-(3-chloro-4-dimethylcarbamoylthio)phenyl
propionic acid methyl ester (0.106 g; 0.352 mmol) in dry methanol
(1.42 mL) was treated with a solution of sodium methoxide in methanol
(4.37 M; 0.113 mL; 0.493 mmol). The solution was refluxed for 4
hours and then cooled to room temperature. 3-ethyl-6-{3-
bromopropyl)oxy-7-propyl-bent[4,SJisox-azole (0.096 grams; 0.293
mmol) was added and the reaction stirred for 1 hour. The reaction
mixture was partitioned between isopropyl acetate and pH 4.0 buffer.
The organic layer was dried over magnesium sulfate, filtered and
evaporated. Silica gel chromatography afforded the title compound.
NMR (CDCl3): 7.38 {d, 1H, J = 8.4Hz); 7.25 (d, 1H, J = 5.4 Hz); 7.15
(d, I H, J = 8. I Hz); 6.87 (d, i H, J = 8.7); 4.17 (t, 2H, J = 5.6 Hz);
3.66 (quart, I H, J = 7.0 Hz); 3.60 (s, 3H}; 3.15 (t, 2H, J = 7.0 Hz);
2.94 (quart, 2H, J = 7.6 Hz); 2.85 (t, 2H, J = 7.5); 1.66 (quart, ZH, J =
7.1 Hz); 1.40 (t, 2H, J = 7.5 Hz).
3. 2-(3-chloro-4-(3-(3-ethyl-7-propel-6-benzf4 Slisoxazole~oxv) prop,
lhiol phenyl propionic acid
A solution of 2-{3-chloro-4-(3-(3-ethyl-7-propyl-6-
benz[4,5)isoxazole) oxy)propylthio)phenyl propionic acid methyl ester
(0.037 g; 0.076 mmol) in ethanol (1.0 mL) was treated with a solution
of potassium hydroxide in water (I.OM; 0.153 mL; 0.153 mmol). The
solution was refluxed for 1 hour. The reaction mixture was partitioned
between isopropyl acetate and 0.1 N HCI. The organic was dried over
magnesium sulfate, filtered and concentrated to afford the title
compound.
NMR (CDCl3): 7.38 (d, 1H, J = 8.4Hz); 7.25 (d, 1H, J = 5.4 Hz); 7.15
(d, I H, J = 8. I Hz); 6.87 (d, I H, J = 8.7); 4. I 7 (t, 2H, J = 5.6 Hz);
3.66 (quart, 1 H, J = 7.0 Hz); 3.1 S (t, 2H, J = 7.0 Hz); 2.94 (quart, 2H,
J = 7.6 Hz); 2.85 (t, 2H, J = 7.5); 1.66 (quart, 2H, J = 7.I Hz); 1.40 (t,
2H, J = 7.5 Hz).
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Example 58
..-
Ho ~ w i
o~ o ~
3-(4-{3-{3-phenyl-7-propyl-6-Benz-[4,5)-isoxazoloxy)propyloxy))
phenylpropionic acid
to 1
The methyl 3-(4-{3-bromoprop-1-oxy)phenyl)propionate
can be obtained from commercially available methyl 3-(4-
hydroxyphenyl)propionate and I,3-dibromopropane as described in
Example 16 Step 4. The product was purified by elution from a silica
gel column (E. Merck 40-63 w ) with hexanes : methylene chloride 50
50.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 6.95
(ABq, 4H), 4.06 (t, 2H, J = 5.8 Hz), 3.65 (s, 3H), 3.58 (t, 2H, J = 6.4
Hz), 2.87 (t, 2H, J = 8.0 Hz), 2.58 (t, 2H, J = 6.5 Hz), 2.28 (pent, 2H, J
= 5.9 Hz).
The 3-phenyl-6-hydroxy-7-propylbenzisoxazole of
Example 16 Step 3 { 37 mg, 1.0 Eq, 0.145 mmol ) was coupled with the
bromide of Example 59 Step 1 ( 49 mg, 1.I Eq, 0.16 mmol ) as
described in the procedure of Example 16 Step 4.The product was
purified by elution from a silica gel column (2.5 g E. Merck 40-63 a )
with toluene : hexanes : EtOAc 60 : 35 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CI?Cl3); 7.92 (m,
2H), 7.64 (d, 1 H, J = 8.7 Hz), 7.5-7.3 {m, 2H), 7.09 {d, 1 H, J = 8.8 Hz),
' . 6.99 (d, 1H, J = 8.8 Hz), 6.83 ( m, 2H), 4.26 {t, 2H, J = 6.1 Hz), 4.17
{t,
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2H, J = 6.1 Hz), 2.90 (m, 4H), 2.57 (t, 2H, J = 8.1 Hz}, 2.30 (pent, 2H, J
= 6.1 Hz), 1.69 (next, 2H, J = 7.5 Hz), 0.946 (t, 3H, J = 7.3 Hz).
MS ESI M+1 = 474.3. MW = 473.2
The ester of Example 58 Step 2 ( 46 mg, 1.0 Eq, 0.096
mmol ) was hydrolyzed with LiOH ( 150 uL, 1.5 N, 2.3 Eq, 0.255
mmol ) as described in Example 16 Step 5.
Characteristic NMR Resonances; I H NMR 400MHz (CDC13); 7.9-7.93
{m, 2H), 7.64 (d, 1 H, J = 8.7 Hz), 7.5-7.55 (m, 3H), 7.10 (d, 1 H, J = 8.7
Hz), 6.99 (d, 1 H, J = 8.7 Hz), 6.83 {d, 1 H, 3 = 8.7 Hz), 4.26 ( t, 2H, J =
5.98 Hz), 4.17 (t, 2H, J = 6.03 Hz), 2.88 (t, 2H, J = 8.4 Hz), 2.90 (t, 2H,
J = 7.7 Hz), 2.62 (t, 2H, J = 8.1 Hz), 2.30 (pent, 2H, J = 6.1 Hz), 1.69
(sext, 2H, J = 7.5 Hz), 0.945 (t, 3H, J = 7.4 Hz).
Analytical HPLC 75 : 25 CH3CN : H20 0.1 % TFA, E. Merck RP-8 5w
4 X 250 mm, 1 ml/min. UV 210, RT 6.47 min.
MS ESI M+1 = 460.3. MW = 459.2
Example 59
H ~ CI
I l '~
O ~S~
3-Chloro-4-(3-(3-{3-fluorophenyl)-7-propyl-6-bent-[4,5]-isoxazoloxy)-
propylthio)phenylacetic acid
to 1
Commercially available 2-propylresorcinol ( 3.0 g, 1.0 Eq,
0.02 mol ) and meta-fluorobenzoic acid ( 3.2 g, 1.15 Eq, 0.023 mol ) ;
were condensed as described in Example 51 Step 1.
The product was purified by elution from a silica gel column {20 g E.
Merck 40-63 a ) with toluene : hexanes : EtOAc 60 : 35 : 5.
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r
Characteristic NMR Resonances; 1H NMR 400MHz (CDCI3); 7.42-7.47
(m, 1 H), 7.36-7.4 (m, 1 H), 7.29-7.3 3 (m, 1 H), 7.2-7.26 (m, 1 H), 6.31
(d, 1H, J = 8.8 Hz), 2.66 (dd, 2H, J = 9.3, 7.6 Hz), 1.61 (sext, 2H, J =
7.7 Hz), 0.994 (t, 3H, J = 7.4 Hz).
MS ESI M+1 = 275.1. MW = 274.1
Step 2
The ketone of Example 59 Step 1 (2.6 g, 1.0 Eq, 9.4 mmol
was converted to the oxime with NH20H-HCl ( 0.7 g, 1.05 Eq, 9.8
mmoI ) as describedin the procedure of Example 7 Step A. Heating was
continued for 72 Hrs. The product was purified by elution from a silica
gel column (I 12 g E. Merck 40-63 a ) with toluene : EtOAc 97 : 3.
Characteristic NMR Resonances; IH NMR 400MHz {CDCl3); 7.0 - 7.5
( four 1 H multiplets), 6.49 (d, 1 H, J = 8.7 Hz), 6.21 (d, 1 H, J = 8.8 Hz),
2.66 (dd, 2H, J = 9.3, 7.6 Hz), 1.61 (sext, 2H, J = 7.7 Hz), 0.996 {t, 3H,
J=7.4Hz).
to 3
The oxime of Example 59 step 2 ( 846 mg, 2.9 mmoi ) was
converted to the 3-(meta-fluorophenyl)-6-hydroxy-7-
propylbenzisoxazole as described in Example 7 Step A. The product
was purified by recrystallization from toluene.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.69 (m,
1H), 7.61 (m, 1H), 7.55 (d, IH, J = 8.5 Hz), 7.50 (m, 1H), 7.20 (m, 1H),
6.88 (d, IH, J = 8.5 Hz), 5.23 {s, 1H), 2.9I (t, 2H, J = 7.5 Hz), 1.75
{sext, 2H, J = 7.5 Hz), 1.41 (t, 3H, J = 7.3 Hz).
MS ESI M+1 = 272.1. MW = 271.1
Ste$ 4
The 3-{meta-fluorophenyl)-6-hydroxy-7-
propylbenzisoxazole of Example 59 Step 3 { 34 mg, 1.0 Eq, O.I23 mmol
was coupled with the bromide of Example 16 Step 1 A ( 43 mg, I .OS
Eq, 0.128 mmol ) as described in Example 16 Step 4. The product was
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purified by elution from a silica gel column (3 g E. Merck 40-63 ~ )
with toluene : hexanes : EtOAc 60 : 35 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCI3); 7.72 (m,
1 H), 7.6 {m, 1 H), 7.63 (d, 1 H, J = 8.8 Hz), 7.51 (dt, 1 H), 7.31 (d, 1 H, J
- ~ 1.5 Hz), 7.27 (d, 1 H, J = 8.1 Hz), 7.21 (dt, I H), 7.12 (dd, I H), 6.97
(d, 1 H, J = 8.8 Hz), 4.Z I (t, 2H, J = 5.8 Hz), 3.68 (s, 3H), 3.55 (s, 2H),
3.I7 (t, 2H, J = 7 Hz), 2.92 (dd, 2H, J unresolved), 2.I9 (pent, 2H), I.71
(sext, 2H, J = 7.5 Hz), 0.964 (t, 3H, J = 7.4 Hz).
MS ESI M+1 = 528.2. MW = 527.1
Step 5
The ester of Example 59 Step 4 ( 51 mg, 1.0 Eq, 0.097 mmol ) was
hydrolyzed with LiOH ( 150 wL, 1.5 N, 2.3 Eq, 0.225 mmol ) as
described in Example 16 Step 5. The product was purified by elution
from a reversed phase RP-8 col (10 g E. Merck 40-63 a ) with 75 : 25
CH3CN : H2O 0.1 % TFA.
Characteristic NMR Resonances; I H NMR 400MHz {CDCl3); 7.70 (dd,
1 H), 7.62 (d, 1 H, J = 8.7 Hz). 7.62 (m, I H), 7.50 (dt, I H}, 7.3 I (d, 1 H,
J
= 1.9 Hz), 7.28 (d, 1 H J = 8.1 Hz), 7.20 (dt, 1 H), 7.12 (dd, 1 H), 6.97 (d,
1H, J = 8.8 Hz), 4.21 (t, 2H, J = 5.8 Hz), 3.69 (s, 2H}, 3.18 (t, 2H, J =
7.1 Hz), 2.91 (dd, 2H, J = 8.8, 7.5 Hz), 2.19 (pent, 2H}, I.71 (seat, 2H, J
= 7.7 Hz), 0.96 {t, 3H, J = 7.4 Hz).
Analytical HPLC 75 : 25 CH3CN : H20 0.1 % TFA, E. Merck RP-8 5u
4 X 250 mm, 1 ml/min. UV 210, RT 7.55 min.
MS ESI M+1 = 514.3. MW = 513.1
Example 60
O
v
HO~O I w
i O~O w O
CI
3-Chloro-4-(3-(3-neo-pental-7-propyl-6-Benz-[4,5]-isoxazoloxy)-
propyloxy)phenoxylacetic acid
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-I37-
Step A: Preparation of methyl 3-chloro-4-hydroxyphenoxylacetate
A sulotion of chlorohydroxyquinone (5.0 g), ethyl
bromoacetate (3.84 mL) and potassium carbonate (4.78 g) was refluxed
for five hours. The mixture of reaction was partitioned between water
and ether. The combined organics were washed with water and brine,
dried over magnessium sulfate, poured onto a column of silica gel and
eluted with ethyl acetate/hexane (20/80) to give the title compound.
1H NMR( 400MHz, CDC13 ): S 6.92 (m, 2H), 6.77 (dd, 1H, J = 8.8, 3.0
Hz), 5.21 (s, 2H), 4.52 (s, 3H), 4.24 (quart, 2H, J = 7.2 Hz), 1.27 (t, 3H,
J = 7.2 Hz).
Step B: Preparation of methyl 2-trifluoroethoxy-4-(3-(3-neo-pental-
7-propyl-6-benz-[4,5]-isoxazoloxy)propyloxy)phenylacetate
Using the method of Example 20, step C, 1-bromo-3-(3-
neo-pental-7-propyl-6-benz-[4,5]-isoxazoloxy)phenoxypropane and
methyl 2-trifluoroethoxy-4-hydroxyphenylacetate as the starting
material, the title compound was obtained.
IH NMR( 400MHz, CDCl3 ): 8 7.34 (d, 1H, J = 8.7 Hz), 6.97 (d, 1H, J =
3.0 Hz), 6.93 (d, 1 H, J = 8.7 Hz), 6.87 (d, I H, J = 9.0 Hz), 6.77 (dd, 1 H,
J = 9.0, 3.0 Hz), 4.52 {s, 2H), 4.27 (s, 4H), 4.16 {t, 2H, J = 5.9 Hz), 2.82
(t, 2H, J = 7.4 Hz), 2.78 (s, 2H), 2.31 {quint, 2H, J = 6.0 Hz), 1.65 (hex,
2H, J = 7.3 Hz), 1.26 (t, 2H, J = 7.I Hz), 1.02 (s, 9H), 0.90 (t, 3H, J =
7.3 Hz)
Step C: Preparation of 2-trifluoroethoxy-4-(3-(3-neo-pental-7-
propyl-6-benz-[4,5]-isoxazoloxy)propyloxy)phenylacetic acid
Using the method of Example 20, step D, methyl 2-
trifluoroethoxy-4-(3-(3-neo-pental-7-propyl-6-Benz-[4,5]-
isoxazoloxy)propylthio)phenylacetate as the starting material, the title
compound was obtained.
1H NMR( 400MHz, CDC13 ): 8 7.34 (d, 1H, J = 8.7 Hz), 6.97 (d, 1H, J =
3.0 Hz), 6.93 (d, 1H, J = 8.7 Hz), 6.87 (d, 1H, J = 9.0 Hz), 6.77 (dd, 1H,
- J = 9.0, 3.0 Hz), 4.60 (s, 2H), 4.27 (t, 2H, J = 5.9 Hz), 4. i 8 (t, 2H, J =
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5.9 Hz), 2.82 (t, 2H, J = 7.4 Hz}, 2.78 (s, 2H), 2.31 (quint, 2H, J = 6.0
Hz), 1.65 (hex, 2H, J = 7.3 Hz), 1.02 {s, 9H), 0.90 (t, 3H, J = 7.3 Hz)
ESI: MS m/e = 490 (M+1 }
Example 61
/ \
o _.
Ho~ ~ w i , ~ ~
o ~o
4-(3-(3-phenyl-7-propyI-6-benz[4,5]isoxazole)oxy)propyloxy phenoxy
acetic acid
t 1
The 6-(3-bromoprop-1-oxy)-3-phenyl-7-
propylbenzisoxazoIe can be prepared as in Example 1 Step A from 6-
hydroxy-3-phenyl-7-propylbenzisoxazole ( 1.5 g, 1.0 Eq, 6 mmol ),
prepared as described in Example I6 Step 3, and 1,3-dibromopropane
3.0 ml, S Eq, 30 mmol ).
The product was purified by elution from a silica gel column (100 g E.
Merck 40=63 ~ ) with toluene : hexanes : EtOAc 30 : 65 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDC13); 7.91 (m,
2H), 7.65 (d, I H, 3 = 8.7 Hz}, 7.5-7.55 {m, 3H), 7.24 {m, 1 H), 7.16 (m,
1H), 7.69 (d, 1H, J = 8.7 Hz), 4.22 (t, 2H, J = 5.7 Hz), 3.65 (t, 2H, J =
6.4 Hz), 2.9 (t, 2H, J = 7.4 Hz), 2.38 (pent, 2H, J = 5.9 Hz), 1.71 {sext,
2H, J = 7.4 Hz), 0.977 (t, 3H, J = 7.4 Hz).
MS ESI M+1 = 360.0 / 362. MW = 359.1 / 361.1 (Bromine isotopes).
Commercially available 4-hydroxyphenoxyacetic acid ( 2 g
was esterified as described in Example 23 Step 1. The ester was used
without purification further.
I
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_ - -I39-
Characteristic NMR Resonances; 1H NMR 400MHz (CDCI3); 6.76
(Aromatic ABq, 4H), 4.56 (s, 2H), 3.78 (s, 3H}.
MS CI NH3 M+NH4+ = 200. MW = I82.I
to 3
The 6-(3-bromoprop-1-oxy)-3-phenyl-7-
propylbenzisoxazole of Example 62 Step 1 ( 56.4 mg, 1.0 Eq, 0.I5
mmol ) was coupled with the methyl 4-hydroxyphenoxyacetate of
Example 6I Step 2 ( 32 mg, 1.I5 Eq, 0.176 mmol ) as described in the
procedure of Example 16 Step 4.
The product was purified by elution from a silica gel column (4 g E.
Merck 40-63 ~ ) with toluene : hexanes : EtOAc 60 : 35 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCI3}; 7.91 (m,
2H), 7.64 {d, 1H, J = 8.8 Hz), 7.52 (m, 3H), 6.99 ( d, iH, J = 8.8 Hz),
6.84 (s, 4H), 4.57 (s, ZH), 4.26 (t, 2H, J = 5.9 Hz), 4.I4 (t, 2H, J = 6.1
Hz), 3.78 (s, 3H}, 2.90 (dd, 2H, J unresolved), 2.29 (pent, 2H, 3 = 6.1
Hz); -1.70 (sext, 2H), 0.946 (t, 3H, J = 7.4 Hz}.
MS ESI M+1 = 476.2. MW = 475.2.
to 4
The ester of Example 61 Step 3 ( 44 mg, 1.0 Eq, 0.092
mmol ) was hydrolyzed with LiOH ( 130 wL, 1.5 N, 2 Eq, 0.195 mmol )
as described in Example I6 Step 5.
Characteristic NMR Resonances; 1H NMR 400MHz {CDC13); 7.92 (m,
2H}, 7.66 {d, 1 H, J = 8.7 Hz), 7.52 (m, 3H}, 6.99 (d, 1 H, J = 8.8 Hz),
6.87 (s, 4H), 4.62 (s, 2H), 4.28 (t, 2H, J = 5.9 Hz), 4.I7 (t, 2H, J = 6.0
Hz), 2.92 (dd, 2H, J unresolved), 2.31 (pent, 2H, J = 6.1 Hz}, 1.71
(next, 2H, J = 7.5 Hz), 0.964 (t, 3H, J = 7.3 Hz).
Analytical HPLC 75 : 25 CH3CN : H20 0.1 % TFA, E. Merck RP-8 Su
4 X 250 mm, 1 ml/min. UV 2I0, RT 5.47 min.
MS ESI M+I = 462.3. MW = 46I .2
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Example 62
H
i
O
(3-{4-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)butyloxy))
phenylacetic acid
to 1
The 6-(4-bromobut-1-oxy)-3-phenyl-7-propylbenzisoxazole
can be prepared as in Example 1 Step A from 6-hydroxy-3-phenyl-7-
propylbenzisoxazole ( 2 g, 1.0 Eq, 7.9 mmoI ), prepared as described in
Example 16 Step 3, and 1,4-dibromobutane ( 4.8 ml, 5 Eq, 39.5 mmol
).
The product was purified by elution from a silica gel column { 100 g E.
Merck 40-63 ~. ) with toluene : hexanes : EtOAc 30 : 65 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.92 (m,
2H), 7.64 (d, 1 H, J = 8.8 Hz), 7.53 (m, 3H), 6.95 (d, 1 H, J = 8.8 Hz),
4.11 (t, 2H, J = 5.9 Hz), 3.51 {t, 2H, J = 6.4 Hz), 2.91 (t, 2H, J = 7.5
Hz), 2.12 (complex m, 2H), 2.03 (complex m, 2H), 1.71 (sext, 2H, J =
7.5 Hz), 0.977 (t, 3H, J = 7.4 Hz).
MS ESI M+1 = 388.2 / 390.2. MW = 387.1 / 389.1 (Bromine
Isotopes).
to 2
The methyl 3-hydroxyphenylacetic acid from Example 23
Step 1 ( 26 mg, 1.05 Eq, 0.15 mmol ) and the 6-(4-bromobut-i-oxy)-3-
phenyl-7-propylbenzisoxazole from Example 62 Step 1 ( 42 mg, 1.0 Eq,
0.108 mmol ) were condensed as described in Example 16 Step 4.
The product was purified by elution from a silica gel column (3 g E.
Merck 40-63 ~. ) with toluene : hexanes : EtOAc 60 : 35 : 5.
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P
' Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.92 (m,
2H), 7.64 (d, I H, J = 8.8 Hz), 7.53 (m, 3H), 7.22 (t, 1 H), 6.97 {d, I H, J
= 8.8 Hz), 6.83 {m, 3H), 4.14 (t, 2H), 4.04 (t, 2H), 3.67 (s, 3H), 3.58 (s,
2H), 2.92 ( dd, 2H, J unresolved), 2.02 (m, 4H), 1.71 {sext, 2H, J = 7.5
Hz} 0.968 (t, 3H, J = 7.4 Hz}.
MS ESl M+I = 474.4. MW = 473
Step 3
The ester of Example 62 Step 2 ( 46 mg, 1.0 Eq, 0.098
mmol ) was hydrolyzed with LiOH ( 150 wL, 1.5 N, 2.3 Eq, 0.225
mmol } as described in Example I6 Step 5.
Characteristic NMR Resonances; IH NMR 400MHz (CDCl3); 7.92 (m,
2H), 7.63 (d, 1 H, J = 8.8 Hz), 7.52 (m, 3H), 7.22 {t, I H), 6.96 (d, I H, J
= 8.8 Hz}, 6.83 (m, 3H), 4.14 (t, 2H), 4.04 {t, 2H), 3.59 (s, 2H), 2.91
(dd, 2H, J unresolved), 2.02 (m, 4H), 1.7I (sext, 2H, J = 7.5 Hz}, 0.963
(t, 3H, J = 7.4 Hz).
Analytical HPLC 75 : 25 CH3CN : H24 0.1 % TFA, E. Merck RP-8 5~.
4 X 250 mm, 1 mI/min. UV 2I0, RT 6.61 min.
MS ESI M+1 = 460.4. MW = 459.2.
Examvle 63
H
O
3-(4-{4-(3-phenyl-7-propyl-6-bent-[4,5]-isoxazoloxy)butyloxy))
phenylpropionic acid
. Step 1
The 6-(4-bromobut-I-oxy)-3-phenyl-7-propylbenzisoxazole
prepared in Example 62 Step 1 ( 4$ mg, 1.0 Eq0.124 mmol ) and
commercially available methyl 3-(4-hydroxyphenyl)propionate ( 26.3
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mg, 1.15 Eq , O.I46 mmoI ) were condensed as described Example 16
Step 4.
The product was purified by elution from a silica gel column {2.5 g E.
Merck 40-63 a ) with toluene : hexanes : EtOAc 60 : 35 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.92 (m,
2H), 7.64 (d, I H, J = 8.8 Hz), 7.52 (m, 3H), 7.09 (m, 2H), 6.97 (d, 1 H, J
= 8.8 Hz), 6.81 (rn, 2H), 4.14 (t, 2H), 4.02 (t, 2H), 3.65 {s, 3H), 2.91 (t,
2H, J = 7.5 Hz), 2.89 {t, 2H, J = 8.5 Hz), 2.58 {t, 2H, J = 7.5 Hz), 2.01
(m, 4H), 1.71 (sext, 2H, J = 7.5 Hz), 0.964 (t, 3H, J = 7.3 Hz).
MS ESI M+1 = 488.4. MW = 487.2
Std
The ester of Example 63 Step 1 ( 49.3 mg, 1.0 Eq, O.lOI
mmol ) 'was hydrolyzed with LiOH ( 160 N.L, 1.5 N, 2.3 Eq, 0.240
mmol ) as described in Example 16 Step 5.
Characteristic NMR Resonances; 1 H NMR 400MHz (CDCl3); 7.9I (m,
2H), 7.64 (d, 1 H, J = 8.8 Hz), 7.52 (m, 3H), 7.10 (d, 2H, J = 8.8 Hz),
6.96 (d, 1 H, J = 8.8 Hz), 6.81 (m, 2H), 4.14 (t, 2H), 4.02 (t, 2H), 2.89
2 overlapping t, 4H), 2.65 (t, 2H, 8.I Hz), 2.01 (m, 4H), I.7I (sext, 2H),
0.964 (t, 3H, J = 7.4 Hz).
Analytical HPLC 75 : 25 CH3CN : H20 0.1 % TFA, E. Merck RP-8 5~
4 X 250 mm, I ml/min. UV 210, RT 7.22 min.
MS ESI M+I = 474.4. MW = 473.2
Ho2
E i
3-chloro-4-{3-(2-methyl-2-phenylpropyl)-7-(n-propyl)-6-bent[4,5]isox-
azoloxy)propylthio)phenylacetic acid
EXAMPLE 64
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Step A Preparation of I,3-dihydroxy-4-(3-methyl-3-phenyl-
butyryl}-2-(n-propyl}benzene
' Using the procedure in Example S1, step 1; 3-methyl-3-
phenylbutyric acid and 2-(n-propyl)resorcinol were condensed in triflic
acid to form 1,3-dihydroxy-4-(3-methyl-3-phenylbutyryl}-2-(n-propyl)-
benzene.
NMR (CDCI3): d 7.14 - 7.41 (m, 6H); 6.24 (d, 1H); 5.30 {bs, 1H); 3.21
(s, 2H); 2.58 {t, 2H); 1.55 (m, 2H); 1.49 (s, 6H); 0.96 (t, 3H).
Step B Preparation of 3-(2-methyl-2-phenylpropyi)-6-hydroxy-7-
(n-propyl)benz[4,5]isoxazole
Using the procedures in Example 51, steps 2 and 3, 1,3-
dihydroxy-4-(3-methyl-3-phenylbutyryl)-2-(n-propyl)-benzene was
converted into 3-(2-methyl-2-phenylpropyl}-6-hydroxy-7-(n-
propyl)benz-[4,5]isoxazole.
NMR {CDC13): d 7.18 - 7.42 (m, SH); 6.56 (d, 1H); 6.43 (d, 1H); 5.30
(vbs, 1H); 3.19 (s, 2H); 2.$2 (t, 2H); 1.71 (m, 2H); 1.46 (s, 6H}; 0.98 (t,
3H}.
Step C Preparation of methyl 3-chloro-4-(3-(2-methyl-2-phenyl-
propyl)-7-(n-propyl)-6-benz[4,5]isoxazoloxy)propylthio)-phenylacetate
Using the procedure Example 16, step 4, 3-(2-methyl-2-
phenylpropyl)-6-hydroxy-7-(n-propyl)benz[4,5]isoxazole. and methyl 3-
chloro-4-(3-bromopropylthio)phenylacetate were heated in DMF with
Cs2C03 to prepare methyl 3-chloro-4-(3-(2-methyl-2-phenylpropyl}-7-
propyl-6-benz[4,5]isoxazoloxy}propylthio}phenylacetate.
NMR (CDCI3): d 7.10 - 7.43 (m, 8H); 6.65 (d, 1H); 6.51 (d, 1H); 4.13
(t, 2H); 3.71 (s, 3H); 3.56 (s, 2H); 3.20 (s, 2H); 3.1 S (t, 2H); 2.83 (t,
2H); 2.I5 (m, 2H); 1.67 (m, 2H); 1.46 (s, 6H); 0.93 {t, 3H).
Step D Preparation of 3-chloro-4-(3-(2-methyl-2-phenylpropyl)-7-
(n-propyl)-6-bent[4,5]isoxazoloxy)propylthio)phenylacetic acid
Using the -procedure in Example 2, methyl 3-chioro-4-(3-
(2-methyl-2-phenylpropyl)-7-(n-propyl)-6-
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bent[4,5]isoxazoloxy)propylthio}-phenylacetate was saponified with
LiOH to form 3-chloro-4-(3-(2-methyl-2-phenylpropyl)-7-propyl-6-
benz[4,5]isoxazoloxy}propylthio)phenylacetic acid.
NMR (CDCl3 }: d 7.12 - 7.53 (m, 8H); 6.65 (d, 1 H); 6.5 I (d, 1 H}; 4.13
(t, 2H); 3.60 (s, 2H); 3.21 (s, 2H); 3.16 {t, 2H); 2.84 {t, 2H); 2.17 (m,
2H); I.67 (m, 2H); I.47 {s, 6H); 0.94 (t, 3H).
Example 65
HO ~ OCH3
O ~O ~
3-Methoxy-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-benz-[4,5]-
isoxazoloxy)propyloxy)phenylacetate
Step A: Preparation of 3-(2,2-dimethylpropyl)-6-(3-
bromopropyloxy)-7-propyl-6-benz-[4,5]-isoxazole
To a solution of 3-(2,2-dimethylpropyl)-6-hydroxy-7-
propyl-6-Benz-[4,5]-isoxazole {1.00 g, 4.04 mmole) and 1,3-
dibromopropane (2.05 mL, 20.2 mmole) in 2-butanone (20 mL) was
added potassium carbonate (585 mg, 4.29 mmole) and the resulting
mixture refluxed for 18 hours. The cooled mixture was filtered and the
filtrate concentrated in vacuo to give an oil. Flash chromatography on
silica gel eluting with methyl t-butyl ether:hexane (3:97) afforded the
title compound (1.l 1g) as a white solid. rTMR (CDCl3); 8 0.99 (t, 3H);
1.07 (s, 9H); 1.72 (m, 2H); 2.39 (m, 2H); 2.83 {s, 2H); 2.90 (m, 2H);
3.67 (t, 2H); 4.22 (t, 2H); 6.94 (d, 1H); 7.39 (d, 1H).
Step B: Preparation of methyl 3-methoxy-4-(3-(3-(2,2-
dimethylpropyl)-7-propyl-6-bent-[4,5]-isoxazoloxy)-propyloxy)-
phenylacetate
Using the method of Example 56, Step D, and substituting -
3-(2,2-dimethylpropyl)-6-(3-bromopropyloxy)-7-propyl-6-bent-[4,5]- .
isoxazole and methyl 4-hydroxy-3-methoxyphenylacetate as starting
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materials, the title compound was obtained as a gum. NMR (CDCl3); b
0.98 (t, 3H); I.07 (s, 9H); 1.69 (m, 2H); 2.37 (m, 2H); 2.82 (s, 2H);
2.88 (t, 2H); 3.58 (s, 2H); 3.71 {s, 3H); 3.85 (s, 3H); 4.26 (m, 4H); 6.83
(m, 2H); 6.88 (d, 1 H); 6.95 (d, I H); 7.37 (d, 1 H).
Preparation of 3-methoxy-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-
benz-[4,5]-isoxazoloxy)propyloxy)phenylacetate
Using the method of Example 37, Step E and substituting
methyl 3-methoxy-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-benz-[4,5~-
isoxazoloxy)propyloxy}phenylacetate, the title compound was obtained
as a gum. NMR (CDCl3) ~ 0.959 (t, 3H); 1.07 (s, 9H}; 1.69 (m, 2H};
2.37 (m, 2H); 2.82 (s, 2H); 2.87 (t, 2H); 3.61 {s, 2H); 3.85 (s, 3H); 4.27
(m, 4H); 6.83 (m, 2H); 6.94 (d, 1H); 6.95 (d, 1H}; 7.37 (d, IH). Mass
spec, m/e = 470 (m + 1 ).
Example 66
w°
Ho
0
3-(4-(2-(3-phenyl-7-propyl-6-Benz-[4,5]-isoxazoloxy)ethyloxy))
phenylpropionic acid
to 1
The 6-(2-bromoeth-1-oxy)-3-phenyl-7-propylbenzisoxazole
can be prepared as in Example 1 Step A from 6-hydroxy-3-phenyl-7-
propylbenzisoxazole ( 1 g, 1.0 Eq, 4 mmol ), prepared as described in
Example 16 Step 3, and 1,2-dibromoethane ( 1.7 ml, 5 Eq, 20 mmol ).
The product was purified by elution from a silica gel column (44 g E.
Merck 40-63 ~ ) with toluene : hexanes : EtOAc 30 : 65 : S.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.92 (m,
* , 2H), 7.65 (d, 1H, J = 8.7 Hz), 7.53 (m, 3H}, 6.94 (d, IH, J = 8.7 Hz),
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4.39 (t, 2H, J = 6.1 Hz), 3.69 (t, 2H, J = 6.1 Hz), 2.94 (dd, 2H, J = 8.9,
7.5 Hz), I.74 (sext, ZH, J = 7.5 Hz), 0.983 {t, 3H, J = 7.3 Hz).
MS ESI M+1 = 360 / 362Ø MW = 359.1 / 361.1
to 2
The 6-(2-bromoeth-1-oxy)-3-phenyl-7-propylbenzisoxazole
of example 67 Step 1 ( 47 mg, 1.0 Eq, 0.13 mmol ) and commercially
available methyl 3-(4-hydroxyphenyl}propionate ( 30 mg, 1.3 Eq, O.I6
mmol ) were condensed as described in Example 16 Step 4. The
product was puriEed by elution from a silica gel column (44 g E. Merck
40-63 a ) with toluene : hexanes : EtOAc 60 : 35 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3); 7.92 (m,
2H), 7.66 (d, 1 H, J = 8.7 Hz), 7.52 (m, 3H), 7.12 (d, 2H, J = 8.8 Hz &
fine cplg), 7.02 (d, 1 H, J = 8.8 Hz}, 6.87 (d, 2H, J = 8.7 Hz & fine
cplg.), 4.4I (complex m, 2H), 4.34 (complex m, 2H), 3.65 {s, 3H}, 2.91
(t, 2H, J = 8.7 Hz), 2.89 {t, 2H, J = 8. I Hz), 2.59 (dd, 2H, J = 8.1, 7.0
Hz), 1.71 (sext, 2H, 8.5 Hz}, 0.939 {t, 3H, J = 7.4 Hz).
MS ESI M+1 = 460.3. MW = 459.2
Step 3
The ester of Example 66 Step 2 ( 34 mg, 1.0 Eq, 0.074 mmol ) was
hydrolyzed with LiOH ( 120 wL, 1.5 N, 2.3 Eq, 0.240 mmoI } as
described in Example 16 Step 5.
Characteristic NMR Resonances; IH NMR 400MHz (CDCI3}; 7.91 (m,
2H), 7.66 (d, I H, J = 8.8 Hz), 7.51 (m, 3H), 7. I4 (d, 2H, J = 8.8 Hz &
fine spltg.), 7.02 (d, 1H, J = 8.8 Hz), 6.88 (d, 2H, J = 8.7 Hz & fine
spltg.), 4.41 (m, 2H), 4.34 (m, 2H), 2.90 (m, 4H), 2.64 (t, 2H, J = 8.0
Hz}, I.71 {sext, 2H, J = 7.4 Hz), 0.938 (t, 3H, J = 7.4 Hz).
Analytical HPLC 75 : 25 CH3CN : H20 O.I % TFA, E. Merck RP-8 5~.
4 X 250 mm, 1 ml/min. UV 210, RT 5.42 min.
MS ESI M+1 = 446.3. MW = 445.2.
Example 67
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0
t~o~° I w °
{3-(4-(3-phenyl-7-propyl-6-Benz-[4,Sj-isoxazoloxy)butyloxy))
phenoxyacetic acid
Step 1
Resorcinol ( 11 g, 4.0 Eq, 0.1 mol } and methyl a-
bromoacetate ( 2.37 mI, 1.0 Eq, 0.025 mol ) were combined in DMF
50 ml ) with CsC03 ( 8.96 g, 1.1 Eq, 0.0275 mol ). The mixture was
stirred at RT 16 Hrs. The mixture was poured into 2 N HCl and
EtOAc. The aqueous phase was extracted with EtOAc and the extracts
washed with NaHC03 sat'd. aq. The extracts were dried over Na2S04
and reduced i. vac. The product was purified by elution from a silica
gel column (220 g E. Merck 40-63 w ) with toluene : EtOAc 82 : 18.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCl3}; 7.12 (t,
IH), 6.4-6.46 (m, 2H), 4.60 (s, 2H}, 3.79 (s, 3H).
to 2
The 6-(4-bromobut-1-oxy)-3-phenyl-7-propylbenzisoxazole of Example
62 Step 1 ( 123 mg, I.OS Eq, 0.316 mmol } and methyl 3-
hydroxyphenoxyacetate of Example 67 Step I ( 50 mg, I.0 Eq , 0.301
mmol ) were condensed as described in Example 16 Step 4. The
product was purified by elution from a silica gel column (10 g E. Merck
40-63 ~ ) with toluene : hexanes : EtOAc 50 : 45 : 5.
Characteristic NMR Resonances; IH NMR 400MHz (CDC13}; 7.92 (m,
2H), 7.64 (d, 1H, J = 8.7Hz}, 7.52 (m, 3H), 7.16 (t, IH, J = 8.2 Hz),
6.97 (d, 1H, J = 8.8 Hz}, 6.54 ( dd, 1H, J = 8.3, 2.3 Hz), 6.46 {m, 2H),
4.60 (s, 2H), 4.14 {t, 2H, J = 5.8 Hz), 4.03 {t, 2H, J = 5.8 Hz}, 3.78 (s,
3H), 2.9I (dd, 2H, J = 8.7, 7.5 Hz), 2.01 (m, 4H), 1.71 (sext, 2H, J = 7.5
Hz), 0.968 (t, 3H, J = 7.4 Hz).
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MS ESI M+I = 490.3. MW = 489.22.
to 3
The ester of Example 67 Step 2 ( 110 mg, I.0 Eq, 0.225
mmol ) was hydrolyzed with LiOH ( 299 ~.L,, I.5 N, 2.0 Eq, 0.45 mmol
as described in Example 16 Step 5.
Characteristic NMR Resonances; 1H NMR 400MHz {CDCl3); 7.91 (m,
2H), 7.63 (d, 1 H, J = 8.8 Hz), 7.51 (m, 3H), 7.18 {t, 2H, J = 8.1 Hz),
6.96 (d, I H, J = 8.8 Hz), 6.57 (dd, I H, J = 7.5, 2.0 Hz), 6.48 (m, 2H),
4.64 (s, 2H), 4.14 (t, 2H, J = 5.6 Hz), 4.02 (t, 2H, J = 5.6 Hz}, 2.91 (dd,
2H, J unresolved), 2.02 (m, 4H), 1.71 (sext, 2H, 3 = 7.5 Hz), 0.964 (t,
3H, J = 7.4 Hz).
MS ESI M+1 = 476.3. MW = 475.2
Example 68
HO v/ ~ ~ ~ ~ N
p~/~ ~ ~ O
E-(4-{3-(3-phenyl-7-propyl-6-bent[4,5]isoxazole)oxy)propyloxy)
cinnamic acid
St-ep,1
Commercially available 4-hydroxycinnamic acid ( 2 g } was
esterified as described in Example 23 Step 1. The ester was used
without purification further.
Characteristic NMR Resonances; I H NMR 400MHz (CDCl3); 7.62 (d,
1H, J = 16 Hz), 7.41 (d, ZH, J = $.6 Hz with fine splitting), 6.82 (d, 2H,
J = 8.6 I-iz with fine splitting), 6.28 (d, 1H, J = 16 Hz), 5.32 (s, 1H),
3.78 (s, 3H).
MS ESI M+1 = l 79. l . MW = 178.2
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Step 2
The 6-{3-bromoprop-1-oxy}-3-phenyl-7-
propylbenzisoxazole of Example 6I Step 1 ( 35.3 mg, 1.05 Eq, 0.85
mmol ) and methyl 4-hydroxycinnamate of Example 68 Step 1 ( 16.3
mg, 1.6 Eq , 0.092 mmol ) were condensed as described in Example 16
Step 4. The product was purified by elution from a silica gel column (2
g E. Merck 40-63 a ) with toluene : hexanes : EtOAc 60 : 35 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDC13}; 7.92 (m,
2H), 7.63 7.66 ( ovelapping d's, 2H}, 7.53 (m, 3H), 7.47 (d, 1H, J = 8.8
Hz), 7.2 (m, 1 H), 7.0 (d, 1 H, 3 = 8.8 Hz), 6.92 (d, 1 H, J = 8.8 Hz), 6.30
(d, 1H, J = 16 Hz), 4.29 (t, 2H, J = 6.0 Hz), 4.25 (t, ZH, J = 6.I Hz),
3.79 (s, 3H), 2.92 (dd, 2H, J unresolved), 2.35 {m, 2H), 1.71 sext, 2H, J
= 7.5 Hz), 0.96 (t, 3H, 3 = 7.5 Hz).
MS ESI M+I = 472.3. MW = 471.2
Step 3
The ester of Example 68 Step 2 ( 25.9 mg, 1.0 Eq, 0.055
mmol ) was hydrolyzed with LiOH ( 60 uL,, 1.5 N, 2.2 Eq, 0.120 mmol
as described in Example I6 Step 5.
Characteristic NMR Resonances; 1H NMR 400MHz {CDCl3); 7.91 (m,
2H), 7.71 (d, 1H J = 16 Hz), 7.64 (d, 1H, J = 8.7 Hz), 7.51 {m, 3H), 7.0
(d, IH, 3 = 8.8 Hz), 6.92 (d, 1H, J = 8.9 Hz plus fine coupling), 6.92 (d,
1 H, J = I 6 Hz), 4.28 (t, 2H, J = 5.9 Hz), 4.24 (t, 2H, 3 = 6.2 Hz), 2.91 (t,
2H, J = 7.4 Hz}, 2.34 (m, 2H), 1.69 (sext, 2H, J = 7.5 Hz), 0.95 (t, 3H, J
= 7.4 Hz).
Analytical HPLC 75 : 25 CH3CN : H20 0.1 % TFA, E. Merck RP-8 5w
4 X 250 mm, I ml/min. UV 210, RT 6.63 min.
MS ESI M+I = 458.4. MW = 457.2
a
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Example 69
i
I ~ I ~ rv
w ~ ~ ~ o
0
E-(3-(3-(3-phenyl-7-propyl-6-bent[4,5]isoxazole)oxy)propyloxy)
cinnamic acid
to I
Commercially available 3-hydroxycinnamic acid ( 2 g ) was esterified as
described in Example 23 Step 1. The ester was used without
purification further.
Characteristic NMR Resonances; 1H NMR 400MHz {CDC13); 7.62 (d,
1 H, J = 16 Hz), 7.24 {m, 1 H), 7.70 (d, 1 H, J = 7.7 Hz), 6.99 (m, I H),
6.85 {dd, 1 H, J = 8.1, 2.1 Hz), 6.39 {d, 1 H, J = 16 Hz}, 5.40 (s, 1 H),
3.79 (s, 3H).
MS ESI M+I =179.1. MW = 178.1
to 2
The 6-{3-bromoprop-I-oxy)-3-phenyl-7-
propylbenzisoxazole of Example 61 Step I { 31.4 mg, I.0 Eq, 0.084
mmol ) and methyl 3-hydroxycinnamate of Example 69Step 1 ( 30 mg,
2.0 Eq , 0.169 mmol ) were condensed as described in Example 16 Step
4.The product was purified by elution from a silica gel column (2 g E.
Merck 40-63 a ) with toluene : hexanes : EtOAc 60 : 35 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDC13); 7.92 (m,
2H), 7.66 (d, 1 H J = 16 Hz), 7.67 (d, 1 H, J = 8.0 Hz), 7.52 {m, 3H),
7.30 {t, 1 H, J = 7.8 Hz), 7.11 {m, 1 H), 7.05 (brd s, 1 H), 7.01 (d, 1 H, J =
8.7 Hz}, 6.95 (dd, 1H), 6.42 (d, 1H, J = 16 Hz), 4.29 (t, 2H, J = 6.0 Hz),
4.24 (t, 2H, 3 = 6.0 Hz), 3.80 (s, 3H), 2.93 (t, 2H, J = 7.2 Hz), 2.35
{pent, 2H, J = 5.8 Hz), 1.71 (sext, 2H, J = 7.4 Hz), 0.96 (t, 3H, J = 7.4
Hz}.
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MS ESI M+I = 472.3. MW = 471.2
Step 3
The ester of Example 69 Step 2 ( 27.7 mg, 1.0 Eq, 0.055
mmol ) was hydrolyzed with LiOH ( 65 wL, 1.5 N, 2.2 Eq, 0.131 mmol
as described in Example 16 Step 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDC13); 7.92 (m,
2H), 7.72 (d, 1H, J = I6 Hz), 7.64 (d, 1H, J = 8.7 Hz), 7.52 (m, 3H},
7.30 (t, 1 H, J = 8.0 Hz), 7. I 3 (m, i H}, 7.08 (brd s, 1 H), 7.00 (d, 1 H, J
=
8.8 Hz), 6.96 (dd, 1 H), 6.41 (d, 1 H, J = 16 Hz), 4.29 (t, 2H, J = 6.0 Hz),
4.23 (t, 2H, J = 6.0 Hz), 2.91 (t, ZH, J = 7.5 Hz), 2.34 (pent, 2H), 1.69
(sext, 2H, J = 7.5 Hz), 0.95 (t, 3H, J = 7.3 Hz).
Analytical HPLC 75 : 25 CH~CN : H20 0.1 % TFA, E. Merck RP-8 5~
4 X 250 mm, 1 ml/min. UV 210, RT 6.89 min.
MS ESI M+1 = 458.3. MW = 457.2
Example 70
~I
HO
O
3-(3-(3-(3-phenyl-7-propyl-6-benz[4,5]isoxazole)oxy)propyloxy)
phenylpropionic acid
to 1
Methyl 3-hydroxycinnamate of Example 69 Step 1 ( 1.1 g, 1.0 Eq , 6.2
mmol ) was hydrogenated at atmospheric pressure in EtOAc ( 45 ml )
with 10 % Pd on carbon ( 98 mg ) as catalyst. After complete
consumption of the starting cinnamate, the hydrogenation mixture was
' filtered through celite and reduced i. vac. The ester was used without
purification.
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Characteristic NMR Resonances; 1 H NMR 400MHz (CDCI3); 7.14 (dd,
1H, J unresolved), 6.75 (d, 1H, J = 7.8 Jz), 6.65 (m, 1H), 4.73 (s, 1H),
2.89 (t, 2H, J = 7.5 Hz), 2.60 (t, 2H, J = 7.5 Hz). "
MS EI M+ = 180.1. MW = 180.1
Step 2
The 6-(3-bromoprop-I-oxy)-3-phenyl-7-
propylbenzisoxazole of Example 61 Step 1 ( 38.4 mg, I.0 Eq, 0.103
mmol ) and methyl 3-(3-hydroxyphenyl)propionate of Example 70 Step
I { 20 mg, 2.0 Eq , 0.1 I 1 mmol ) were condensed as described in
Example 16 Step 4. The product was purified by elution from a silica
gel column (2 g E. Merck 40-63 w ) with toluene : hexanes : EtOAc 60
35 : 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCI3); 7.92 (m,
2H), 7.66 (d, 1 H, J = 8.7 Hz), 7.53 (m, 3H), 7.20 {m, I H), 7.01 (d, 1 H, J
= 8.7 Hz), 6.78 (m, 3H), 4.29 (t, 2H, J = 6.0 Hz), 4.20 (t, 2H, J = 6.0
Hz), 3.66 (s, 3H), 2.92 (overlapping m's, 4H), 2.62 (t, 2H, J = 7.5 Hz),
2.33 (pent, 2H, J = 6.3 Hz), 1.71 (sext, 2H, J = 7.5 Hz), 0.97 (t, 3H, J =
7.5 Hz).
MS ESI M+1 = 474.4. MW = 473.2
Step 3
The ester of Example 70 Step 2 ( 32.7 mg, 1.0 Eq, 0.069
mmol ) was hydrolyzed with LiOH ( 100 ~.L, 2.0 N, 2.9 Eq, 0.200
mmol ) as described in Example 16 Step 5.
Characteristic NMR Resonances; 1H NMR 400MHz (CDCI3); 7.92 (m,
2H), 7.63 (d, 1H, J = 8.7 Hz), 7.52 (m, 3H), 7.19 (m, 1H), 6.99 {d, 1H, J
= 8.7 Hz), 6.78 {m, 3H), 4.27 (t, 2H, J = 6.0 Hz), 4.18 (t, 2H, J = 6.0
Hz), 2.9I (overlapping t's, 4H), 2.65 (t, 2H, J = 8.1 Hz), 2.31' (pent, 2H,
J = 6.1 Hz), 1.7I (sext, 2H, J = 7.3 Hz), 0.95 {t, 3H, J = 7.4 Hz).
Analytical HPLC 75 : 25 CH3CN : H20 0.1 %v TFA, E. Merck RP-8 5w
4 X 250 mm, 1 ml/min. UV 210, RT 6.55 min.
MS EST M+1 = 460.3. MW = 459.2 -
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example 7I
O
N~
H02C ~ / H
N-((4-carbomethoxymethyl)benzoyl)-3(3-phenyl-7-propyl-6-Benz-[4,7]-
isooxazolyloxy) propylamine
Step A: Preparation of 3-phenyl-6-(3-aminopropyl)oxy-7-propyI benz-
[4,7]-isoxazole hydrochloride: 506 mg (2.0 mmole, 1.0 eq.) of 3-
phenyl-6-hydroxy-7-propyl benz-[4,7]-isoxazole {example 16, step 3)
was dissolved in 20 ml of freshly distilled tetrahydrofuran, after which
525 mg (2.0 mmole, 1.0 eq.) triphenylphosphine and 0.34 ml (2.0
mmole, 1.0 eq.) of tert-butyl N-(3-hydroxypropyl}carbamate were
added with srirring. The reaction vessel was cooled to 0°C and 0.31 ml
(2.0 mmole, 1.0 eq.) of diisopropyl azodicarboxylate was added
dropwise. Once addition was complete the cooling bath was removed
and the reaction was allowed to stir at room temperature for 24 hours.
Saturated sodium bicarbonate solurion was added to the stirring reaction
mixture, which was then extracted with ethyl acetate. The ethyl acetate
layer was washed with dilute HCI, dried over sodium sulfate, filtered
and the filtrate evaporated. The residue was then treated with 10 ml of
4N HCl in dioxane (40 mmole, 20 eq.). After 20 minutes TLC shows
Boc removal complete, so dioxane was evaporated and ether was added,
upon which a precipitate formed. The suspension was stirred for 20
minutes, then filtered. The recovered solid was pumped on high
vacuum to give 550 mg (79°lo yield) of the dtie compound.
r
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1H NMR (500 MHz, CD30D): 8 7.93 {m, 2H), 7.80 {d, 1H), 7.57 (m,
3H), 7.I 9 (d, I H), 4.27 (t, 2H), 3.21 (t, 2H), 2.93 (t, 2H), 2.23 (m, 2H),
I.73 (m, 2H), 0.99 (t, 3H).
Step B: Preparation of N-((4-carbomethoxymethyl)benzoyI)-3(3-phenyl-
7-propyl-6-bent-[4,7J-isooxazolyloxy) propylamine: 19.4 mg (0.10
mmole, 1.0 eq.) of the known compound methyl 4-carboxyphenyl
acetate was dissolved in 1 ml dichloromethane, then treated with 2i.I
mg (0.I1 mmole, I.1 eq.) of I-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride and 14.9 mg (0.11 mmole, 1.0 eq.) 1-
hydroxybenzotriazole. After stirring together for 20 minutes, 34.7 mg
(0.10 mmole, 1.0 eq) of 3-phenyl-6-(3-aminopropyl)oxy-7-propyl benz-
[4,7J-isoxazole hydrochloride from Example 72 step A and 26 ~.l (0.I5
mmole, 1.5 eq.) of diisopropylethylamine were added and the reaction
stirred for 16 hours. The reaction mixture was then diluted with
dichloromethane, washed twice each with 5% citric acid and 5% sodium
bicarbonate solutions. The dichloromethane was then dried over sodium
sulfate, filtered, evaporated and purified by silica gel chromatography
to give 37 rng (76% yield) of the title compound.
1H NMR (500 MHz, CDCl3): b 7.95 (dd, 2H), 7.74 (d, 2H), 7.6$ (d,
1 H), 7.55 (m, 3H), 7.35 (d, 2H), 7.01 (d, 1 H), 6.45 (br t, 1 H), 4.23 (t,
2H), 3.74 (q, 2H), 3.71 (s, 3H), 3.68 (s, 2H), 2.93 (t, 2H), 2.22 (m, 2H),
1.74 (m, 2H), 0.98 (t, 3H).
Step C: Preparation of N-((4-carboxymethyl)benzoyl)-3(3-phenyl-7-
propyl-6-bent-[4,7]-isooxazolyloxy) propylamine: IO mg {20.6 .mole,
1.0 eq.) of N-((4-carbomethoxymethyl)benzoyl)-3(3-phenyl-7-propyl-6-
benz-[4,7J-isooxazolyloxy) propylamine from Example 72 step B was
dissolved in 0.45 ml tetrahydrofuran and 0.25 ml of methanol. Then
0.15 mI of water and O.IO mI of 0.25 N (25 ~tmole, 1.2 eq.) lithium
hydroxide were added. The reacrion was heated to 40°C and after two
hours diluted with water, acidified and extracted twice with
dichloromethane. The dichioromethane was dried over sodium sulfate,
filtered and the filtrate evaporated to give the title compound.
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1H NMR (500 MHz, CDC13): ~ 7.94 (dd, 2H), 7.73 (d, ZH), 7.65 (d,
1H), 7.55 {m, 3H), 7.34 (d, 2H), 6.99 (d, 1 H), 6.56 (br t, 1 H), 4.20 (t,
2H), 3.72 (q, 2H), 3.69 {s, 2H), 2.91 (t, 2H), 2.20 (m, 2H), 1.74 (m,
ZH), 0.95 (t, 3H).
MS(ESI, TFA/HCOONH4): m/e 473.3 [M+1].
Example 72
/ \
HO ' ~ \ ~ ~ H
O
2-(4-(3-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propyloxy))
phenoxypropionic acid
to 1
The commercially avaiiabie 2-(4-hydroxyphenoxy)propionic acid ( 2 g )
was esterified as for Example 23 Step 1. The ester was used without
purification.
Characteristic NMR Resonances; IH NMR 400MHz (CDCl3); 6.75
(collapsed ABq, 4H), 4.66 (q, 1H, J = 6.9 Hz), 3.75 (s, 3H), 1.58 (d, 3H,
J = 6.9 Hz).
MS CI NH3 M+NH4+ = 214.1. MW = 196
Step 2
The 6-(3-bromoprop-1-oxy)-3-phenyl-7-
propylbenzisoxazole of Example 61 Step I ( 31.7 mg, I.0 Eq, 0.85
mmol ) and methyl 2-(4-hydroxyphenoxy)propionate of Example 72
Step 1 ( 27 mg, 1.6 Eq , 0.138 mmol ) were condensed as described in
Example 16 Step 4.
The product was purified by elution from a silica gel column (2 g E.
Merck 40-63 ~. ) with toluene : hexanes : EtOAc 60 : 35 : 5.
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Characteristic NMR Resonances; 1H NMR 400MHz (CDCI3); 7.92 (m,
2H), 7.66 (d, 1 H, J = 8.7 Hz), 7.53 (m, 3H), 7.00 (d, I H, J = $.9 Hz), -
6.83 (s, 4H), 4.67 (q, 1 H, J = 6.8 Hz), 4.28 (t, 2H, J = 6.0 Hz), 4.I 6 (t,
2H, J = 6.0 Hz), 3.75 (s, 3H), 2.92 (dd, 2H, J = 8.7, 7.4 Hz), 2.30 {pent,
2H, J = 6.1 Hz), I.7I (sext, 2H, J = 7.6 Hz), 1.59 (d, 3H, J = 6.8 Hz),
0.97 (t, 3H, J = 7.4 Hz).
MS ESI M+1 = 490.4. MW = 489.2
to 3
Tie ester of Example 72 Step 2 { 29 mg, 1.0 Eq, 0.059
mmol ) was hydrolyzed with LiOH ( 80 ~.L,, 2.0 N, 2.7 Eq, 0.16 mmoI
as described in Example I6 Step 5.
Characteristic NMR Resonances; IH NMR 400MHz (CDC13); 7.92 (m,
2H), 7.63 (d, 1 H, J = 8.8 Hz), 7.51 (m, 3H), 6.98 (d, 1 H, J = 8.7 Hz),
6.84 (s, 4H), 4.68 (q, I H, J = 6.9 Hz), 4.26 (t, 2H, J = 5.9 Hz), 4. I 4 (t,
ZH, J = 6.0 Hz), 2.89 (dd, 2H, J unresolved), 2.29 (pent, 2H, J = 6.0
Hz), 1.69 {sext, 2H, J = 7.5 Hz), 1.60 (d, 3H, J = 6.8 Hz), 0.94 {t, 3H, J
= 7.4 Hz).
Analytical HPLC 75 : 25 CH3CN : HaO O.I % TFA, E. Merck RP-8 Sw
4 X 250 mm, I mljmin. UV 2I0, RT 6.09 min.
MS ESI M+I = 476.3. MW = 475.2
Example 73
H
O
O
2-(4-(4-(3-phenyl-7-propyl-6-bent-[4,5)-isoxazoloxy)butyloxy))
phenoxypropionic acid
to 1
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WO 97/28137 PCT/US97/OI749
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The 6-(3-bromobut-1-oxy)-3-phenyl-7-propylbenzisoxazole
of Example 62 Step 1 ( 37 mg, I.2 Eq, 0.095 mmol ) and methyl 2-(4-
hydroxyphenoxy)propionate of Example 72 Step 1 ( 16 mg, 1.0 Eq ,
0.082 mmol ) were condensed as described in Example 16 Step 4. The
product was purified by elution from a silica gel column (2 g E. Merck
40-63 ~ ) with toluene : hexanes : EtOAc 60 : 35 : 5.
Characteristic NMR Resonances; IH NMR 400MHz (CDC13); 7.92 {m,
2H), 7.65 (d, I H, J = 8.7 Hz), 7.53 (m, 3H), 6.98 (d, 1 H, J = 8.7 Hz},
6.83 (s, 4H), 4.67 (q, I H, J = 6.8 Hz), 4.10 (t, 2H}, 4.01 (t, 2H), 3.75 (s,
3H), 2.93 (dd, 2H, J = 8.6, 7.4 Hz}, 2.02 (m, 4H}, 1.73 (sext, 2H, J = 7.5
Hz), 1.59 (d, 3H, J = 6.8 Hz), 0.99 (t, 3H, J = 7.4 Hz).
MS ES I M+ 1 = 504.5. MW =503.2
Step 2
The ester of Example 73 Step 1 ( 35 mg, 1.0 Eq, 0.069 mmol ) was
hydrolyzed with LiOH { 90 wL, 2.0 N, 2.6 Eq, 0.18 mmol ) as described
in Example 16 Step 5.
Characteristic NMR Resonances; 1H NMR 400MHz {CDCl3); 7.92 (m,
ZH), 7.63 (d, IH, J = 8.7 Hz), 7.53 (m, 3H), 6.96 (d, 1H, J = 8.7 Hz),
6.83 (collapsed ABq, 4H), 4.69 (q, 1H, J = 6.9 Hz), 4.14 (t, 2H, J = 6.0
Hz}, 4.00 (t, 2H, J = 6.0 Hz), 2.90 (dd, 2H, J = 8.7, 7.5 Hz), 2.00 (m,
4H}, 1.71 (sext, 2H, 3 = 7.4 Hz), 1.6i (d, 3H, J = 6.8 Hz}, 0.96 {t, 3H, J
= 7.4 Hz).
Analytical HPLC 75 : 25 CH3CN : H20 0.1 °lo TFA, E. Merck RP-8 5u
4 X 250 mrn, 1 mi/min. UV 210, RT 6.84 min.
MS ESI M+1 = 490.5. MW = 489.2
Example 74
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3-chloro-4-(3-(7-cyclopropylmethyl-3-phenyl-6-bent-[4, 5]-
isoxazoloxy)propyl-thio)phenylacetic acid
STEP A: Preparation of 7-cyclopropylmethyl-3-phenyl-6-
hydroxybenz-[4, 5]-isoxazole
Using the method and materials in example 24 the titled
compound was obtained.
STEP B: Preparation of Methyl 3-chloro-4-(3-(7-cyclopropylmethyl-3-
phenyI-6-bent-[4, 5]-isoxazoloxy}propyl-thio)phenylacetate
Using the method in example 20 step C (19632PV2},
substituting 7-cyclopropylmethyl-3-phenyl-6-hydroxybenz-[4, 5]-
isoxazole, the titled compound was obtained.
NMR (CDCI3 } 8 7.92 (m, 2H}; 7.66 (d, 1 H); 7.51 (m, 3H}; 7.29 (m,
2H); 7.13 (d, 1H); 6.98 (d, 1H, J = 8.75 Hz); 4.22 (t, 2H, J = 5.78 Hz};
3.67 (s, 3H}; 3.54 (s, 2H); 3.17 (t, 2H, J = 7.12 Hz); 2.86 (d, 2H, J =
6.87 Hz); 2.15 (m, 2H); 0.43 (m, 1 H}; 0.34 (m, 1 H).
STEP C: Preparation of 3-chloro-4-(3-(7-cyclopropylmethyl-3-phenyI-
6-benz-[4, 5]-isoxazoloxy)propyl-thio)phenylacetic acid
Using the method in example 2 step A THERE IS NO STEP
A IN 19630PV2 OR 19632PV2, substituting Methyl 3-chloro-4-(3-(7-
cyclopropylmethyl-3-phenyl-6-bent-[4, 5]-isoxazoIoxy)propyl-
thio)phenylacetate, the titled compound was obtained.
NMR (CDCI3) S 7.91 {m, 2H}; 7.66 (d, 1H, 3 = 8.70 Hz}; 7.52 (m, 3H};
7.29 (m, 2H); 7.i4 (d, 1H, J = 1.89 Hz); 6.98 (d, 1H, J = 8.77 Hz}; 4.22
(t, 2H, J = 5.78 Hz}; 3.57 (s, 2H}; 3.18 (t, 2H, J = 7.16 Hz); 2.86 (d, 2H,
J = 6.75 Hz}; 2.20 (m, 2H}; 0.42 (m, iH); 0.31 {m, 1H}.
ESI: Mass spec: m/e = 508 (M+l }.
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~xamp i~ a 75
H ~ Cl
O
S
1-(3-chloro-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-6-
benz[4,5Jisoxazole)oxy)propylthio) phenyl cyclopropane carboxylic acid
1. 3-C2,2-dimeth~propyl)-6-(3-bromopropylox~propylbenzf4,51
isoxazole
A solution of 3-(2,2-dimethylpropyl)-6-hydroxy-7-
propylbenz[4,5] isoxazole (2.000 grams; 8.090 mmol) in dry DMF (20
mL) was treated with I ,3-dibromopropane (4.29 mL; 42.263 mmol).
Cesium carbonate (2.900 grams; 8.901 mmol) was added and the
mixture stirred at 20° for 8 hours. The reaction mixture was
partitioned between isopropyl acetate and pH 4 buffer. The organic was
washed with water, then dried over magnesium sulfate. Filtration and
evaporation afforded an oil which was chromatographed over silica gel,
giving the title compound.
NMR (CDC13): 7.37 (d, 1H, J = 8.8 Hz); 6.91 (d, 1H, J = 8.7 Hz); 4.19
(t, 2H, J = 5.6 Hz); 3.63 {t, 2H, J = 7.0 Hz); 2.86 {bt, 2H, J = 7.4 Hz);
2.80 {s, 2H); 1.03 (s, 9H).
2. 1-f 3-chloro-4-t3-(3-(2,2-dimethylpropyl)-7-propel-6-benz~4.51
i_soxazole)oxv)prop lt~phenyl-1-c cy lopropane carboxylic acid meth
ester
A solution of I -(3-chloro-4-dimethylcarbamoylthio)phenyl-
1-cyclopropane carboxylic acid methyl ester (0.059 grams; 0.188
mmol) in dry methanol (1 mL) was treated with a solution of sodium
methoxide in methanol (4.37 M; 0.060 mL; 0.263 mmol). The
solution was stirred at 60° C for 4 hours. The reaction was allowed to
cool to 50° C and treated with 3-(2,2-dimethylpropyl)-6-(3-
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bromopropyloxy)-7-propylbenz[4,5]-isoxazoie (0.083 grams; 0.226
mmol). The reaction was stirred for 2 hours more, then partitioned
between isopropyl acetate and pH 4 buffer. The organic was dried over
magnesium sulfate, filtered and evaporated to a residue which was
chromatographed to afford the title compound.
NMR (CDCl3): 7.34 (d, IH, J = 8.4 Hz); 7.33 (d, IH, J = 1.8 Hz); 7.24
(d, I H, J = 8.1 Hz); 7. I 6 (dd, 1 H, J = 8.1, I .9 Hz); 6.88 (d, 1 H, J =
8.6
Hz); 4.17 (t, 2H, J = 5.8 Hz); 3.61 (s, 3H); 3.16 (t, 2H, J = 7.1 Hz);
2.86 (bt, 2H, J = 7.6 Hz); 2.79 (s, 2H); I.59 (apparent quart, 2H, 3 =
3.7 Hz); 1.13 (apparent quart, 2H, J = 3.7 Hz); 1.03 (s, 9H).
3. 1-!3-chloro-4-!3-!3-l2.2-dimethvlpropvl)-7-prowl-6-benzf4 51
isoxazoleloxvlpropvlthio)phenyl-1-cvcIopropane carboxylic acid
A solution of 1-(3-chloro-4-(3-(3-(2,2-dimethylpropyl)-7-
propyl-6-benz[4,5]isoxazole)oxy)propylthio)phenyl-I-cyclopropane
carboxylic acid methyl ester (0.051 grams; 0.096 mmol) in isopropanol
(2 mL} was refluxed. The solution was treated with a solution of KOH
in water (1.00 M; 0.192 mL; 0.192 mmol). Refluxing was continued
for 1 hour. The reaction was partitioned between isopropyl acetate and
0.1 N HCI. The organic was dried over magnesium sulfate, filtered and
concentrated to the title compound as a solid.
NMR {CDCl3): 7.34 (d, IH, J = 8.4 Hz); 7.33 (d, 1H, J = 1.8 Hz); 7.24
(d, 1 H, J = 8.1 Hz}; 7. I 6 (dd, 1 H, J = 8. I , 1.9 Hz); 6.8 8 (d, I H, J =
8.6
Hz); 4.17 (t, 2H, J = 5.8 Hz); 3.61 (s, 3H); 3.16 (t, 2H, J = 7.I Hz);
2.86 (bt, 2H, J = 7.6 Hz); 2.79 (s, 2H); 1.65 (apparent quart, 2H, J =
3.1 Hz}; 1.20 (apparent quart, 2H, J = 3.3 Hz); 1.03 (s, 9H).
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- Example 76
H02C I ~ CI
O~
4-(3-(3-(Ethyl)-7-(phenyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)-3-
chloro-a, a-dimethyl-phenyl propionic acid
Step A: Preparation of 3-chloro-(4-hydroxyphenyl)propionate:
In a 0°C ice bath, 3-chloro-(4-hydroxyphenyl)acetic acid
(2.06 g; I 1.0 mmol), was dissolved in 3 ml of ether. Added to this
solution was about 35 mL of diazomethane dissolved in ether (0.32
mmoL/ mL). Allowed to stir for 5 minutes, vented the excess
diazomethane to a cololess solution and concentrated in vacuo to afford
a light yellow oil. Isolated 2.34 g of the title compound and used
without further purification. NMR: 8 7.27 (m, l H); 7.10 (m, l H);_ 6.97
(d, l H) 3.7 I (s,3H}; 3.56 (s,2H)
Step B: Preparation of 3-phenyl-7-propyl-6-(3-bromopropyl)oxy-
benz-[4,5]-isoxazole
To a mixture of 3-phenyl-7-propyl-6-hydroxy-bent-[4,5]-
isoxazole (1.0 g; 3.95 mmol, Prepared in Example 16 Step C), I,3-
dibromopropane (3.98g, 19.5 mmol) and potassium carbonate (0.573g,
4.i5 mmol) in 4.0 mL of methyl ethyl ketone was warmed to reflux for
i6 hours. Filtered, concentrated and chromatographed (silica gel, 30%
ethyl acetate in hexane) to yeild 1.025 g of the title compound as a white
solid. NMR (CDCl3): 8 7.95 {d,2H); 7.69 {d,lH); 7.55 (m,3H); 7.03
~ (d, l H}; 4.25 {t,2H}; 3.68 (t,2H); 2.95 {t,2H); 2.41 (m,2H); 1.76
(m,2H); I.OI (t,3H)
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Step C: Preparation of 4-(3-(3-(Ethyl)-7-{phenyl)-6-benz-[4,5]-
isoxazoloxy)propyloxy)-3-chloro-phenyl propionate
A mixture of 3-chloro-(4-hydroxyphenyl)propionate (301.9
mg; 1.51 mmol), 3-(3-(Ethyl)-7-(phenyl)-6-Benz-[4,5]-isoxazoloxy)-
propyloxy bromide (540.2 mg; 1.66 mmol), cesium carbonate (514.0
mg; 1.58 mmol) in about 10.0 ml dry dimethyl-formamide was stirred
and heated for I.5 hours. Concentrated, diluted with water and
extracted with ethyl acetate, dried (Na2S04), concentrated in vacuo and
chromatographed (silica gel, 30% ethyl acetate in hexane) to yield 633.4
mg of the title compound as a light yellow oil. NMR (CDCl3): 8 7.95
(d,2H); 7.67 (d, l H); 7.54 (m,3H); 7.31 (s, l H); 7. I4 (q, I H); 7.05
(d, IH); 6.93 (d, l H); 4.35 {t,2H); 4.27 (t,2H); 4.13 (t,2H); 3.70
(s,3H); 3.55 (s,2H); 2.93 (t,2H); 2.38 (m,2H)
Step D: Preparation of 4-(3-(3-(Ethyl)-7-(phenyl)-6-benz-[4,5]-
isoxazoloxy)propyloxy)-3-chloro-oc-methyl-phenyl propionate
To a solution of 4-(3-(3-{Ethyl)-7-(phenyl)-6-bent-[4,5]-
isoxazoloxy)propyloxy)-3-chloro-phenyl propionate {148.0 mg; 0.332
mmol) in ca. 2.0 ml of dry tetrahydrofuran in a -78°C ice bath under
nitrogen was added hexamethyl-disilylazid (0.5 M solution in toluene,
730 ~.L; 0.365 mmol) and stirred for 30 minutes. To this solution was
added iodoethane (53.1 IaL,; 0.664 mmol) and was allowed to warm to
room temperature and stir for 1 hour. The solution was quenched with
1 M(aq) NH2Cl and washed with water and extracted with ethyl acetate,
dried (Na2S04) and concentrated in vacuo and chromato-graphed
(silica gel 30% ethyl acetate) to yeild 32.1 mg of the title compound as a
colorless oil. NMR (CDC13): S 7.95 (d,2H); 7.68 (d,iH); 7.55 (m,3H);
7.33 (s, I H); 7. I 6 (d,1 H); 7.07 (d, l H); 6.93 (d, l H); 4.35 {t,2H); 4.28
(t,2H);
Step E: Preparation of 4-(3-(3-(Ethyl)-7-(phenyl)-6-Benz-[4;5]
isoxazoloxy)propyloxy)-3-chloro-oc, oc -dimethyl-phenyl propionate
The title compound was prepared by following the
procedures in Example l, step G affording 30.0 mg of viscous oil. ,
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NMR (CDCI3): 8 7.95 (d,2H); 7.67 (d,iH); 7.56 {m,4H); 7.41 (d,lH);
7.05 (d,IH); 6.94 (d,IH); 4.36 {t,2H); 4.30 (t,2H);. 3.79 (s,3H);
Step F: Preparation of 4-(3-(3-{Ethyl)-7-{phenyl)-6-benz-[4,5}-
isoxazoloxy)propyloxy}-3-chloro-a, a-dimethyl-phenyl propionic acid
A solution of 29.0 mg (0.0526 mmol) 4-(3-(3-{Ethyl)-7-
(phenyl)-6-benz-[4,5]-isoxazoloxy)propyloxy)-3-chloro-a, a -dimethyl-
phenyl propionate ca. 2.0 ml of isopropyl alcohol and 1 M aqueous
potassium hydroxide (210 ~t.L; 4 eq) was heated at 60°C for 36 hours.
The mixture was diluted with ethyl acetate and acidified to pH 5-6 with
1 M HCI, washed with water (2 times}, brine (1 time) and dried over
sodium sulfate, concentrated concentrated in vacuo and preparatory
plate chromatography (silica 30% ethyl acetate in hex) to afford 20.0
mg of the title compound. (Mass Spec= 536.3, calc= 535.2}; NMR
{CDC13): 8 7.92 (d,2H); 7.63 (d,1H); 7.51 (m,4H); 6.99 (d, l H); 6.80
{d,iH); 4.29 {t,2H); 4.29 (t,2H); 3.46 (s,lH); 2.90 (t,2H); 2.32
(t,2H)
Example 72
HO ~
l
O ~ ~ O~O ~ l O
'O
3-Ethoxy-4-(3-{3-(2,2-dimethylpropyl)-7-propyl-6-bent-[4,5]-
isoxazoioxy)propyloxy)phenylacetate
Step A: Preparation of methyl 3-ethoxy-4-(3-(3-(2,2-dimethylpropyl)-
7-propyl-6-benz-[4,5]-isoxazoloxy)propyloxy)benzoate
Using the method of Example 56, Step D, and substituting
3-(2,2-dimethylpropyl)-6-(3-bromopropyloxy)-7-propyl-6-bent-[4,5]-
isoxazole {Example 65, Step A) and methyl 4-hydroxy-3-
ethoxybenzoate as starting materials, the title compound was obtained as
an oil. NMR (CDCI3); 8 0.95 {t, 3H); 1.07 (s, 9H); 1.45 (t, 3H); 1.70
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(m, 2H); 2.40 {m, ZH); 2.82 (s, 2H); 2.88 (t, 2H); 3.90 (s, 3H); 4.13 (q, '
2H); 4. I 2 (t, 2H); 4.13 (t, 2H); 6.93 (d, 1 H); 6.94 (d, 1 H);7.37 (d, 1 H);
7.56 (s, 1 H); 7.66 (d 1 H). -
Step B: Preparation of 3-ethoxy-4-(3-(3-(2,2-dimethylpropyl)-7-
propyl-6-benz-[4,5]-isoxazoloxy)propyloxy)benzoate
Using the method of Example 37, Step E and substituting
methyl 3-ethoxy-4-(3-(3-{2,2-dimethylpropyl)-7-propyl-6-bent-[4,5]-
isoxazoloxy)propyloxy)benzoate, the title compound was obtained as an
oil. NMR (CDCI3); 8 0.96 (t, 3H); I.07 (s, 9H); 1.46 (t, 3H);1.69 (m,
2H); 2.40 (m, 2H); 2.83 (s, 2H); 2.88 (t, 2H); 4.I4 (q, 2H); 4.31 (t, 2H);
4.34 {t, 2H); 6.96 (d, 2H); 7.38 (d, IH); 7.6 (s, IH); 7.75 (d, IH).
Step C: Preparation of methyl 3-ethoxy-.4-(3-(3-(2,2-dimethylpropyl)-
7-propyl-6-benz-[4,5]-isoxazoloxy)propyloxy)phenylacetate
To a solution of 3-ethoxy-4-(3-(3-{2,2-dimethylpropyl)-7-
propyl-6-benz-[4,5]-isoxazoloxy)propyloxy)benzoate (184 mg, 0.392
mmole) in methylene chloride (2 mL) and DMF (2 drops) at OoC was
added oxalyl chloride (36 ~,L, 0.411 mmole). The mixtue was stirred at
room temperature for 30 minutes and then concentrated in vacuo. The
residue was concentrated in vacuo 3x from methylene chloride The
final residue was dissolved in ether (5. 1nL) and treated with excess
dia.zomethane in ether until the yellow color persisted. The yellow
solution was stirred at room temperature for 3 hours. Nitrogen was
bubbled through the solution for 5 minutes before concentrating in
vacuo. The residue was dissolved in ethyl acetate and washed with IN
sodium bicarbonate; water, brine, dried over magnesium sulfate and
concentrated in vacuo to give a yellow oil. The oil was dissolved in
methanol (4 mL) and triethylamine (850 ~.L) and stirred with silver
benzoate (37 mg, 0.16 mmole) at room temperature for 18 hours.
Celite and brine were added and the mixture was filtered, washing with
methanol. The filtrate was concentrated in vacuo and the residue
partitioned with ethyl acetate and 1 N HCI. The organic phase was
washed with water, brine, dried over magnesium sulfate and
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concentrated in vacuo to give an oil. Thin layer chromatography on
silica gel eluting with hexane:2-propanol (9:1 ) provided the crude title
compound (I04 mg). A second thin layer chromatography on silica gel
eluting with ethyl acetate:hexane (15:85) afforded the title compound
{30 mg) as an oil. NMR (CDCl3); 8 0.96 (t, 3H); 1.07 (s, 9H}; 1.4i {t,
3H); 1.69 (m, 2H); 2.35 (m, 2H}; 2.82 (s, 2H); 2.87 (t, 2H); 3.56 {s,
2H); 3.70 (s, 3H); 4.06 {q, 2H); 4.25 {t, 2H); 4.29 (t, 2H); 6.80 (d, 1H);
6.83 (d, 1H); 6.88 (d, 1H); 6.95 (d, 1H); 7.37 {d, 1H).
Step D: Preparation of 3-ethoxy-4-(3-(3-(2,2-dimethylpropyl)-7-
propyl-6-benz-[4,5]-isoxazoloxy)propyloxy)phenylacetate
Using the method of Example 37, Step E and substituting
methyl 3-ethoxy-4-(3-(3-(2,2-dimethylpropyl}-7-propyl-6-bent-[4,5]-
isoxazoloxy)propyloxy)phenylacetate, the title compound was obtained
as a gum. NMR (CDCl3) 8 0.95 (t, 3H); I .07 (s, 9H}; 1.41 (t, 3H);1.69
(m, 2H); 2.35 (m, 2H); 2.82 (s, 2H}; 2.87 (t, 2H); 3.59 (s, 2H); 4.07 (q,
2H); 4.25 (t, 2H); 4.29 (t, 2H); 6.82 {d, 1H); 6.87 (d, 1H}; 6.95 (d, IH);
7.37 (d, 1 H). Mass spec, m/e = 484 (m + 1 ).
Example 78
s
_N
O
H02C
(/
S O
3-chloro-4-(3-(3-phenyl-6-propyl-5-bent-[4,7]-isoxazolyloxy}-
r propylthio) phenyiacetic acid
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Step A: Preparation of 3-phenyl-5-hydroxy-6-propyI bent-[4,7]-
isoxazole: 245 mg (0.90 mmole, 1.0 eq.} of 2,5-dihydroxy-4-propyI
benzoxime from example 25, step G was dissolved in 5 ml acetic
anhydride and allowed to stir 8 hours. The acetic anhydride was
removed by high vacuum rotary evaporation and pumped on high
vacuum for 16 hours. The crude material was then taken up in 3 ml
pyridine and refluxed for 8 hours. Water and 2N HCi were added and
the aqueous was extracted with ethyl acetate. The organic was dried
over sodium sulfate, filtered and the filtrate evaporated. The residue
was purified by silica gel chromatography to give 74.1 mg (32% yield)
of the title compound, which was assigned after 1H NMR, NOE
difference spectroscopy, and mass spectrometry.
1H NMR {500 MHz, CDCl3): S 7.93 (m, 2H), 7.54 (m, 3H), 7.42 (s,
I H), 7.26 (s, 1 H}, 2.77 (t, 2H), 1.75 (m, 2H}, 1.05 (t, 3H).
MS (ESI, TFA/HCOONH4}: mJe 254.1 [M+1].
Step B: Preparation of methyl 4-(i-oxo-2-amino-5-(3-phenyl-7-propyl-
6-bent-[4,7]-isoxazolyloxy}pentyl) phenyl acetate: 20 mg (79 ~t.mole,
1.0 eq.) of 3-phenyl-5-hydroxy-6-propyl bent-[4,7]-isoxazole from
Example 78 step A was dissolved in 0.75 ml of N,N-
dimethylformamide. 27 mg (83 .mole, 1.05 eq.} of cesium carbonate
and 26.7 mg (79 ,mole, I.0 eq.) of methyl 3-chloro-4-{3-
bromopropylthio) phenyl acetate (example 25, step I) were then added
and the reaction stirred at 60°C for 200 minutes. The reaction was
cooled to room temperature, diluted with water and ethyl acetate, then
acidified with dilute aqueous HCI. The organic layer was dried over
sodium sulfate, filtered and the filtrate evaporated. The crude material
was purified by preparative TLC to give the title compound.
1H NMR (400 MHz, CDCl3): 8 7.89 (m, 2H), 7.53 (m, 3H}, 7.40 (s,
1H), 7.29 (d, IH), 7.27 (d, IH), 7.13 (s, 1H), 7.10 (dd, IH), 4.14 (t,
2H), 3.68 (s, 3H), 3.52 (s, ZH), 3.18 (t, ZH}, 2.74 (t, 2H), 2.21 (m, 2H),
1.66 (m, 2H), 0.98 (t, 3H).
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Step C: Preparation of 4-(1-oxo-2-amino-5-(3-phenyl-7-propyl-6-benz-
P
[4,7]-isoxazolyloxy)pentyl) phenylacetic acid: 14.2 mg (28 ~tmole, 1.0
eq.) of methyl 4-(1-oxo-2-amino-5-(3-phenyl-7-propyl-6-Benz-[4,7]-
isoxazol-yloxy)pentyl) phenyl acetate from step B was dissolved in 0.4
ml of 1:1 tetrahydrofuran:methanol and 0.14 ml of 0.25 N (35 ~tmole,
1.25 eq.) of lithium hydroxide and allowed to stir for 16 hours. The
reaction mixture was then diluted with water, acidified with dilute
aqueous HCI, and extracted with ethyl acetate. The organic layer was
dried over sodium sulfate, filtered and the filtrate evaporated. The
residue was purified by silica gel chromatography to give IO mg (73%
yield) of the title compound.
1H NMR (500 MHz, CDCl3): 8 7.93 (rn, 2H), 7.57 (m, 3H), 7.43 (s,
1H), 7.33 {d, 1 H), 7.29 (d, IH), 7.I5 {s, 1 H), 7.13 (dd, 1 H), 4.17 (t,
2H), 3.60 (s, 2H), 3.21 (t, 2H), 2.77 (t, 2H), 2.24 (m, 2H), I.70 (m,
2H), 1.00 (t, 3H).
MS (ESI, TFA/HCOONH4): m/e 496.3 [M+1].
BIt)L~(.~GIC.~I-, ASSAYS
I. White Adipose Tissue in vitro Assay
The ability of compounds of the present invention to
enhance the insulin activation of 14C-glucose incorporation into
glycogen in white adipose tissue (WAT) was determined by the
following assay.
This assay measures the efficacy of the instant compounds
to enhance the insulin activation of 14C-glucose incorporation into
glycogen in white adipose tissue (WAT) in a 5 hour completely in vitro
system. All procedures are performed in medium 199 containing I %
bovine serum albumen, 5 mM HEPES, and antibiotic (I00 units/ml
penicillin, 100 ~,g/ml streptomycin sulfate, 0.25 pg/ml amphotericin B ),
hereafter called culture medium. Epididymol fat pads are minced with
scissors into small fragments , approximately 1 mm in diameter.
Minced WAT fragments (100 mg) are incubated in a total volume of 0.9
ml culture medium containing 1 mU/ml insulin and test compound in
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tissue culture incubator at 37oC with 5% C02 with orbital shaking for 3
hours. 14C-labeled glucose is added and incubation continued for 2
hours. Tubes are centrifuged at Iow speed, infranatant is removed and 1
M NaOH is added. Incubation of alkali-txeated VAT for 10 minutes at
60oC solubilizes tissue. Resulting tissue hydrolyzate is applied to
Whatrnazi filter paper strips which are then rinsed in 66% ethanol
followed by 100% acetone which removes unincorporated 14C-glucose
from bound 14C-glycogen. The dried paper is then incubated fn
solution of amyloglucosidase to cleave glycogen into glucose.
Scintillation fluid is added and samples are counted for 14C activity.
Test compounds that resulted in 14C activity substantially above
incubations with insulin alone are considered active insulin-enhancing
agents. Active compounds were titrated to determine the compound
concentration which resulted in 50% of maximum enhancement of
insulin activation and were termed ECgp values. EC50 values for the
instant compounds were found to be 50 pM or less, preferably 5.0 to
.0001 pM or less.
II. PPAR Receptor Binding and/or Transactivation Assa,
Compounds of the instant invention which are useful for the
above discussed treatments can be identified and/or characterized by
employing the PPAR S; and y binding assays and/or PPAR ~, PPAR oc
and PPAR~y transactivation assays. The assays are useful in predicting
or quantitating in vivo effects having to do with the control or
modulation of glucose, free fatty acid, triglyceride, insulin or
cholesterol. To evaluate ICSO or EC50, values the compounds were
titrated in the appropriate assay using different concentrations of the
compound to be tested. To obtain the appropriate values (%Inhibition-
IC$0, or %Activation-ECgO), the data resulting from the assays were
then analyzed by determining the best fit of a 4 parameter function to
the data using the Levenberg-Marquardt non-linear fitting algorithm in
Kaleidagraph~'(Synergy Software, Reading, PA). The human nuclear
receptor cDNA for PPARb (hPPARB) has been cloned from a human
osteosarcoma cell cDNA library and is fully described in A. Schmidt et
* Trade-mark
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al., Molecular Endocrinology, 6:1634-1641 {1992).
See A. Elbrecht et al., Biochem. and
Biophy. Res. Comm. 224:431-437 (1996) and T. Sher et aL, Biochem.
32:5598-5604 (i993) for a description of the human nuclear receptor
gene PPARY and a.
The hPPARb binding assay comprises the steps of:
(a) preparing multiple test samples by incubating separate aliquots of the
receptor hPPARB with a test compound in TEGM containing 5-10%
COS-1 cell cytoplasmic lysate and 2.5 nM labeled {[3H2]Compound
D, I7 Ci/mn~ole) for a minimum of 12 hours, and preferably for
about 16 hours, at 4 °C, wherein the concentration of the test
compound in each test sample is different, and preparing a control
sample by incubating a further separate aliquot of the receptor
hPPARB under the same conditions but without the test compound;
then
(b) removing unbound ligand by adding dextran/gelatin-coated charcoal
to each sample while maintaining the samples at 4 °C and allowing at
least 10 minutes to pass, then
(c) subjecting each of the test samples and the control sample from step
(b) to centrifugation at 4 °C until the charcoal is pelleted; then
(d) counting a portion of the supernatant fraction of each of the test
samples and the control sample from step (c) in a liquid scintillation
counter and analyzing the results to determine the ICSp of the test
compound.
In the hPPAR~ binding assay, preferably at least four test
samples of varying concentrations of a single test compound are
prepared in order to determine the IC50.
The hPPARS transactivation assay comprises the steps of:
(a) seeding an hPPARB/GR stable CHO-K 1 cell line into alpha MEM
containing 10% FCS,10 mM HEPES, and S00 mg/ml 6418 at 37°C
in an atmosphere of 10% CO2 in air,
(b) incubating the cells from step (a) for 16 to 48 hours, preferably
about 20 hours, at 37°C in an atmosphere of 10% C02 in air,
(c) washing the cells from step {b) with alpha MEM;
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(d) preparing multiple test cell groups by incubating separate groups of
the cells from step (c) with the test compound in alpha MEM
containing S% charcoal stripped FCS, 10 mM HEPES, and 500
mg/ml 6418, for 24 to 48 hours, preferably about 24 hours, at 37°C
in an atmosphere of 10% C02 in air, wherein the concentration of
the test compound in each test cell group is different, and preparing a
control cell group by incubating a further separate group of the cells
from step {c) under the same conditions but without the test
compound; then
(e) preparing cell lysates from each of the test cell groups and the
control cell group of step (d) using an aqueous detergent lysis buffer,
and
(fj measuring the luciferase activity of the test cell groups and the
control cell group of step (e) and analyzing the results to determine
the ECSp of the test compound.
In the hPPARB transacrivation assay, preferably at least
four test cell groups of varying concentrations of a single test compound
are prepared in order to determine the EC50.
Particular teens and abbreviations used herein are defined
as follows: gst is glutathione-S-transferase; EDTA is ethylenediamine-
tetraacetic acid; HEPES is N-[2-hydroxyethyl] piperazine-N'-[2-
ethanesuifonic acid; FCS is fetal calf serum; Lipofectamine is a 3:1
(w/w) liposome formulation of the polycationic lipid 2,3-dioleyloxy-N-
[2(spermine-carboxamido)ethyl]-N,N-dimethyl-1-propanaminium-
trifluoroacetate and the neutral lipid dioleoyl phosphatidylethanolamine
in water; Ci418 is genencin; MEM is Minimum Essential Medium; Opti
MEM~1 Reduced-Serum Medium is an aqueous composition containing
HEPES buffer, 2400 mg/L sodium bicarbonate, hypoxanthine,
thymidine, sodium pyruvate, L-glutamire.. trace elements, growth
factors, and phenol red reduced to 1.1 mg/L; Luciferase Assay Reagent
{in re-constituted form) is an aqueous composition containing 20 mM
tricine, 1.07 mM {MgC03)4Mg(OH)2~5H20, 2.67 mM MgS04, 0.1 mM
EDTA, 33.3 mM DTT, 270 ~,M coenzyme A, 470 ~,M luciferin, 530
~,M ATP, having a final pH of 7.8.
* Trade-mark
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_ - 171 -
y
AD-5075 has the following stnlcture:
O
~ 1 [ ~ NH
N o i Sue(
off o
AD-5075 {Takeda}
Opti MEM 1 Reduced-Serum Medium, alpha MEM, 6418,
and Lipofectamine are commercially available from GibcoBRL Life
Technologies, Gaithersburg, Maryland. Alpha MEM is an aqueous
composition having the following components:
Component: Inorganic Salts mg/L
CaCl2 (anhyd.) 200.00
CaCl22H20 --
KCl 400.00
MgSO~ (anhyd.) 97.67
MgSOq.7H20 --
NaCl 6800.00
NaHC03 2200.00
NaH2P04H2O 140.00
NaH2P042H20 _ _
Other Components: mg/L
D-Glucose 1000.00
Lipoic Acid 0.20
' - Phenol Red 10.00
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r
Sodium Pyruvate 110.00 '
Amino Acids: mg/L -
L-Alanine 25.00
L-ArginineHCl 126.00
L-AsparagineH20 50.00
L-Aspartic Acid 30.00
L-Cystine --
L-Cystine2HC1 31.00
L-Cysteine HCI --
L-Cysteine HClH20 100.00
L-Glutamic Acid 75.00
L-Glutamine 292.00
L-Alanyl-L-Glutamine --
Glycine 50.00
L-Histidine HClH20 42.00
L-Isoieucine 52.00
L-Leucine 52.00
L-LysineHCl 73.00
L-Methionine 15.00
L-Phenylalanine 32.00
L-.Pro line 40.00
L-Serine 25.00
L-Threonine 48.00
L-Tryptophan 10.00
L-Tyrosine --
L-Tyrosine (disodium salt) 52.00
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r L-V cline 46.00
Vitamins: mg/L
L-Ascorbic acid 50.00
Biotin 0.10
D-Ca Pantothenate 1.00
Choline Chloride 1.00
Folic acid 1.00
i-Inositol 2.00
Niacinamide I .00
Pyridoxal HCl 1.00
Riboflavin 0.10
Thiamine HCl 1.00
Vitamin B 12 1.40
Ribonucleosides mg/L
Adenosine 10.00
Cytidine 10.00
Guanosine 10.00
Uridine 10.00
Deoxyribonucleosides mg/L
2' Deoxyadenosine 10.00
2' Deoxycytidine HCl I 1.00
2' Deoxyguanosine 10.00
Thymidine 10.00
f
The instant compounds, which are useful for treating the
above discussed disease states, will preferably have IC50 values at one,
two or all of the PPAR (PPAR~y, PPARB or PPARa) receptor cites of
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Y
equal to or less than 10 p.M binding assay, and an EC~p equal to or less
than 10 ~,M in the transactivation assay. Preferably, an ICSp of 100 nM
in the binding assay, and an ECSp equal to or less than 100 nM in the
transactivation assay. More preferably, the instant compounds have an
ICSp equal to or less than 50 nM in the binding assay, and an EC50
equal to or less than 50 nM in the transactivation assay. Most
preferably, the instant compounds have an ICSp equal to or less than 10
nM in the binding assay, and an ECSp equal to or less than 10 nM in the
transactivation assay..
PPAR Receptor Bindin Assax
A. Preparation of Human PPAR~2 and 8
Human PPAR~2 and PPARS, independently, were prepared
as gst-fusion proteins in E. toll. The full length human cDNA for
PPAR~2 and PPARB were subcloned into the PGEX-2T and PGEX-KT,
respectively, expression vector (Pharmacia). E. toll containing the
plasmid were grown, induced, and then harvested by centrifugation. The
resuspended pellet was broken in a French press and debris was
removed by centrifugation at 12,OOOXg. Receptors were purified from
the supernatant by affinity chromatography on glutathione sepharose.
After application to the column, and 1 wash, receptor was eluted with
glutathione. Glycerol was added to stabilize the receptor and aliquots
were frozen at -80 °C for later use.
B. j~HIAD-5075 and Example 11 Displacement Assav
for PPAR~CZ and PPARB resne~elv
For each assay, an aliquot of receptor (1:1000-1:3000
dilution) was incubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA,
10% glycerol, 7 p!/100 ml 13-mercaptoethanol, 10 mM Na molybdate, 1
mM dithiothreitol, 5 ug/ml aprotinin, 2 ug/mI Ieupeptin, 2 ug/ml
benzamide and 0.5 mM PMSF) containing 5-10% COS-1 cell
cytoplasmic iysate and ~10 nM labeled thiazolidinedione ([3H2~AD-5075,
21 Ci/mmole), f test compound compound, [3H2]Example 1 I, I7
Ci/mmoie), t test compound, respectively. Assays were incubated for
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~16 h at 4 °C in a final volume of 300 p1. Unbound ligand was removed
by addition of 200 111 dextran/gelatin-coated charcoal, on ice, for ~10
minutes. After centrifugation at 3000 rpm for 10 min at 4 °C, 200 u1 of
the supernatant fraction was counted in a liquid scintillation counter. In
this assay the KD for AD-5075 and Example I I is I nM, respectively.
SPAR Receptor Transactivation Assay
A. Activation of hPPAR7 and hPPARSMethods
1. Plasmids
The chimeric receptor expression constructs, pSGS-
hPPAR~2/GR and pSGS-hPPARS/GR, were prepared by inserting the
DNA binding domain of the murine glucocorticoid receptor adjacent to
the ligand binding domain of hPPAR~2 or hPPARB. These vectors were
kindly provided by Dr. Azriel Schmidt (MRL). The glucocorticoid
receptor -responsive reporter vector, pMMTV/luc/neo, contains the
murine mammary tumour virus (MMTV) promoter adjacent to the
luciferase gene (iuc) and the neomycin resistance gene (neo). It was
constructed from pMMTV/luc which was provided by Dr. Azriel
Schmidt {Merck Research Laboratories). Prior to transfection into
CHO-K1 cells, pSGS-hPPAR~2/GR and pSGS-hPPARB/GR were
linearized with Xba I. pMMTV/luc/neo DNA was cut with Pvu I. Wild
type receptor constructs, pSGS-hPPAR~2, pSGS-hPPARS and pSGS-
hPPARa were prepared by inserting the full-length hPPAR~2, hPPARB
and PPARoc cDNAs adjacent to the SV40 promoter in pSGS. The
PPAR-responsive reporter construct, pPPRE-luc, contained 3 copies of
a generic PPRE placed adjacent to the thymidine kinase minimal
promoter and the luciferase reporter gene. The transfection control
vector, pCMV-lacZ, contains the galactosidase Z gene under the
regulation of the cytomegalovirus promoter.
2. Production of stable cell lines
CHO-K1 cells were seeded overnight at 6xI05 cells /60 mm
' dish in alpha Minimum Essential Medium (MEM) containing 10% fetal
calf serum (FCS), 10 mM HEPES, I00 units/ml PenicillinG and 100
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pug/ml streptomycin sulfate at 37°C in an atmosphere of 10% C02 in
air. The cells were washed once with OptiMEM 1 Reduced-Serum
Medium and then cotransfected with 4.5 ~.g of pSGS-hPPAR~2 /GR or
pSGS-hPPARB/GR expression vector and 0.5 llg of p14~1~IT'V/luc/neo in
the presence of 100 pg Lipofectamine (GIBCO BRL) according to the
instructions of the manufacturer. Transfecrion medium was removed 2 h
later and replaced with growth medium. After being incubated for 3
days, cells were subcultured by diluting the cell suspension 1/1250 and
1/6250 and placing the cells in a 100 mm culture dish. Selection of the
stable cell lines was initiated the next day by adding 500 pg/ml 6418 to
the medium. Cells were routinely fed with the selection media for 1
month at which time 120 colonies were picked and transferred to 24
well culture plates. Ten days later, confluent colonies were transferred
to 6 well plates to maintain stocks and to 9f well plates to assay for
Iuciferase activity. Positive clones were characterized and validated by
titrating 4 known agonists on each clone. Two clones, g2B2P2D9 and
d2A5P2G3, were selected for screening purposes.
B. hPPAR/GR transactivation screens in stably
transfected CHO-K 1 cells
The hPPAR~Z/GR and hPPARS/GR stable CHO-K 1 cell
lines were seeded at 1xI04 cells/well in 96 well cell culture plates in
alpha MEM containing 10% FCS,10 mM HEPES, and 500 mg/ml 6418
at 37°C in an atmosphere of 10% CQ2 in air. After a 20 hour
incubation, cells were washed once with alpha MEM and then incubated
in an atmosphere of 10% C~2 in air in alpha MEM containing 5%
charcoal stripped FCS, 10 mM HEPES, and 500 mg/ml 6418. The cells
were incubated for 24 hours in the absence of test compound or in the
presence of a range of concentrations of test compound. Cell Iysates
were prepared from washed cells using Reporter Lysis Buffer
(Promega) according to the manufacturer's directions. Luciferase
activity in cell extracts was determined using Luciferase Assay Reagent
buffer (Promega) in a ML3000 Iuminometer (Dynatech Laboratories}.
* Trade-mark
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Transactivation Wild-Tvne Assav
A. Characterization of ligand activity on wild-type
hPPARy, hPPARB and hPPARa.
COS-1 cells were seeded at 0.5 X 105 cells/dish into 24 well
plates in Dulbecco's modified Eagle medium (high glucose) containing
10% charcoal stripped fetal calf serum, nonessential amino acids, 100
units/m1 Penicillin G and 100 pg/ml Streptomycin sulfate at 37°C in a
humidified atmosphere of 10% C02. After 24 hours, transfections
were performed with Lipofectamine (Gibco-BRL, Gaithersburg, MD)
according to the instructions of the manufacturer. In general, for
transactivation experiments, transfection mixes contained 0.15 mg of
hPPARy2 hPPARoc or hPPARB expression vector, 0.15 mg of reporter
vector pPPRE-luc and 0.001 mg of pCMV-lacZ as an internal control of
transfection efficiency. Compounds demonstrating significant agonist
activity in the above primary screen were further characterized by
incubation with transfected cells for 48h across a range of
concentrations. Luciferase activity was determined as described above.
In a similar manner, hPPARyl cDNA can be used in place
of hPPAR~Z cDNA in the methods described in Example 5 to make the
wild type receptor construct, pSGS-hPPAR~yl.
IILIn Vivo Studies
Methods
db/db Mice are obese, highly insulin resistant animals. The
db locus has been shown to code for the leptin receptor. These animals
are substantially hypertriglyceridemic and hyperglycemic.
Male db/db mice (10-11 week old C57BI/KFJ, Jackson
Labs, Bar Harbor, ME) were housed 5/cage and allowed ad lib. access to
ground Purina rodent chow and water. The animals, and their food,
were weighed every 2 days and were dosed daily by gavage with vehicle
(0.5% carboxymethylcellulose) t test compound at the indicated dose.
Drug suspensions were prepared daily. Plasma glucose, Cholesterol and
triglyceride concentrations were determined from blood obtained by tail
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i7$
bleeds art 3-5 day intervals during the study period. Glucose, cholesterol
and triglyceride, determinations were performed on a Boehringer
Mannheim Hitachi~91 i automatic analyzer (Boehringer Mannheim,
Indianapolis, IN) using heparinized plasma diluted 1:5, or 1:6 (v/v) with
normal saline: Lean animals were age-matched heterozygous mice
maintained in the same manner. The instant compounds were found to
lower triglyceride and glucose levels at a dose of about iOUmg/kg,
preferably a dose of about 10-50 mg/kg, when administered by oral
gavage daily for a period of at least 5 days.
Lipoprotein analysis was performed on either serum, or
EDTA treated plasma obtained by heart puncture from anesthetized
animals at the end of the study. Apolipoprotein concentrations were
determined by ELISA, and cholesterol particles were analyzed by
FPLC, precipitation, or ultracentrifugation. Total liver RNA was
prepared from tissue that had been frozen on liquid nitrogen at the time
of euthanasia. Apolipoprotein mRNA was analyzed on Northern Blots
using specific probes for mouse or rat proteins.
* Trade-mark
