CONTRAST AGENTS FOR MYOCARDIAL PERFUSION IMAGING
The present disclosure relates to novel compounds comprising imaging
moieties, and their use for diagnosing certain disorders in a patient.
Mitochondria are membrane-enclosed organelles distributed through the
cytosol of most eukaryotic cells. Mitochondria are especially concentrated in
myocardium tissue.
Complex 1 ("MC-1") is a membrane-bound protein complex of 46 dissimilar
subunits. This enzyme complex is one of three energy-transducing complexes that -
constitute the respiratory chain in mammalian mitochondria. This NADHubiquinone
oxidoreductase is the point of entry for the majority of electrons that
traverse the respiratory chain, eventually resulting in the reduction of oxygen to water
(Q. Rev. Biophys. 1992, 25, 253-324).
Known inhibitors of MC-1 include deguelin, piericidin A, ubicidin-3,
rolliniastatin-1, rolliniastatin-2 (bullatacin), capsaicin, pyridaben, fenpyroximate,
amytal, MPP+, quinolines, and quinolones (BBA 1998,1364, 222-235).
The present disclosure is based, in part, on the recognition that interrupting
the normal function of mitochondria could advantageously concentrate certain
compounds in the mitochondria, and hence in the mitochondria-rich myocardium
tissue. If these compounds were labeled with an imaging moiety, such a build up
could be detected, thereby providing valuable diagnostic markers for myocardial
perfusion imaging. For purposes of this specification, a compound is referred to as
"labeled" when an imaging moiety is attached to the compound.
In one embodiment the present disclosure provides a method of imaging
myocardial perfusion comprising administering to a patient a contrast agent which
comprises an imaging moiety and a compound selected from deguelin, pyridaben,
pyridimifen, tebufenpyrad, fenazaquin, a deguelin analog, a pyridaben analog, a
pyridimifen analog, a tebufenpyrad analog, and an fenazaquin analog; and scanning
the patient using diagnostic imaging. In another embodment the imaging moiety is a
radioisotope for nuclear medicine imaging, a paramagnetic species for use in MRI
imaging, an echogenic entity for use in ultrasound imaging, a fluorescent entity for
use in fluorescence imaging, or a light-active entity for use in optical imaging.
In another embodiment the present disclosure provides a contrast agent
comprising an imaging moiety and a compound selected from deguelin, pyridaben,
- 2 -
pyridimifen, tebufenpyrad, fenazaquin a deguelin analog, a pyridaben analog, a
pyridimifen analog, a tebufenpyrad analog, and an fenazaquin analog. In another
embodiment the imaging moiety is a radioisotope for nuclear medicine imaging, a
paramagnetic species for use in MRI imaging, an echogenic entity for use in
ultrasound imaging, a fluorescent entity for use in fluorescence imaging, or a lightactive
entity for use in optical imaging.
In another embodiment the paramagnetic species for use in MRI imaging is
Gd3+,Fe3+,In3+,orMn2+.
In another embodiment the echogenic entity for use in ultrasound imaging is a
fluorocarbon encapsulated surfactant microsphere.
In another embodiment the radioisotope for nuclear medicine imaging is UC,
,3N> ,8Fi 123^ 125^ 99mTc! 95^ 1,1^ 62^ 64^ 67^ Qf 68^ ^ ^^
1 S embodiment the imaging moiety is F. In another embodiment the imaging moiety
is 99mTc.
In another embodiment the present diclosure provides a contrast agent
comprising an imaging moiety and a compound selected from deguelin, pyridaben,
pyridimifen, tebufenpyrad, fenazaquin a deguelin analog, a pyridaben analog, a
pyridimifen analog, a tebufenpyrad analog, and an fenazaquin analog wherein the
contrast agent is of formula (I)
10
(I),
wherein
each A is independently selected from O, CHR1, S, and NR1;
- 3 -
B is selected from hydrogen, Ci-C6 alkyl optionally substituted with an
imaging moiety, and an imaging moiety;
C is selected from hydrogen, Cj-Ce alkyl optionally substituted with an
imaging moiety, an imaging moiety, and a bond to B;
D is selected from hydrogen, C\-C(, alkyl optionally substituted with an
imaging moiety, and an imaging moiety;
E is selected from hydrogen, Cj-Ce alkyl optionally substituted with an
imaging moiety, and an imaging moiety; or
E and D, together with the carbon atom to which they are attached, form a
double bond; or
E and D, together with the carbon atom to which they are attached, form a
cyclopropyl ring;
a is a single or a double bond;
R1, R2, R3, R4, R9, R10, R13, and R14, are each independently selected from
hydrogen, Ci-C6 alkyl optionally substituted with an imaging moiety, and an imaging
moiety;
R5 and R6 are each independently selected from hydrogen, C\-C(, alkyl
optionally substituted with an imaging moiety, halo, hydroxy, and an imaging
moiety;
"7 8 when present, R and R are independently selected from hydrogen, Q-C6
alkyl optionally substituted with an imaging moiety, halo, hydroxy, and an imaging
moiety; or
R5 and R7 together form an oxo group; or
R6 and R8 together form an oxo group; or
R7 is O and R8 is a bond to R7;
provided that when a is a double bond, R7 and R8 are absent;
R is hydrogen or hydroxy;
R12 is selected from hydrogen, Ci-Ce alkyl optionally substituted with an
imaging moiety, and an imaging moiety; or
R1' and R12 together form an oxo group or =CHR';
with the proviso that at least one imaging moiety is present in formula (I).
- 4 -
In another embodiment
AisO;
B and C are each independently
D and E are each independently
R5, R6, R9, and R10 are each independently hydrogen or 18F; and
R11 and'R12 together form an oxo group.
In another embodiment the contrast agent is selected from
or CH2
18F;
or CH2
18F;
In another embodiment the present diclosure provides a contrast agent
comprising an imaging moiety and a compound selected from deguelin, pyridaben,
pyridimifen, tebufenpyrad, fenazaquin a deguelin analog, a pyridaben analog, a
pyridimifen analog, a tebufenpyrad analog, and an fenazaquin analog wherein the
contrast agent is of formula (II),
- 5 -
R23
R24
(II),
wherein
R P
S29
R30
mis 0 or 1;
a' b
nzz and ^^ each independently represent a single or a double
bond;
R27, R30, R31, R32, R33, and R34 are independently selected from
hydrogen, C\-C(, alkyl optionally substituted with an imaging moiety, and an imaging
moiety;
when present, R,2 8 is selected from hydrogen and C)-C6 alkyl
b
optionally substituted with an imaging moiety, provided that when ^^^ is a double
bond, R,2 8 is absent;
when present, R,2 9 is Ci-Cf, alkyl optionally substituted with an
imaging moiety, provided that when ^^ is a double bond, R,2 9 is absent;
R36 R37
Pis , wherein R,3-5" , rR»3J6O , rR,3J7/ , RJ8, and R3j9y are
independently selected from hydrogen, Cj-Ce alkyl optionally substituted with an
-6-
imaging moiety, and an imaging moiety;
when present, P' is hydrogen; or
P and P' together form an oxo group;
a'
provided that when ^^ is a double bond, P' is absent;
Q is halo or haloalkyl;
J is selected from N(R27), S, O, C(=O), C(=O)O, NHCH2CH2O, a bond, and
C(=O)N(R27), with each group being drawn with its left end attached to G and its
right end attached to the carbon substituted with R21 and R22;
when present, K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, Ci-C6
alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging
moiety;
when present, L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C\-Cf,
alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging
moiety;
M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C\-C(, alkyl
optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety; or
L and M, together with the atom to which they are attached, form a three- or
four-membered carbocyclic ring;
n isO, 1, 2, or 3;
R21, R22, R23, R24, R25, and R26 are independently selected from hydrogen, d-
C6 alkyl optionally substituted with an imaging moiety, and an imaging moiety; and
Y is selected from a bond, carbon, and oxygen; provided that when Y is a
bond, K and L are absent and M is selected from aryl and heteroaryl; and provided
that when Y is oxygen, K and L are absent and M is selected from hydrogen,
alkoxyalkyl, aryl, C\-C(, alkyl optionally substituted with an imaging moiety, and
heteroaryl;
provided that at least one imaging moiety is present in formula (II).
In another embodiment R29 is C\-C(, alkyl wherein the C\-C(, alkyl is tertbutyl.
In another embodiment R28 is C\-C(, alkyl wherein the C\-C(, alkyl is methyl.
In another embodiment the present diclosure provides a contrast agent
comprising an imaging moiety and a compound selected from deguelin, pyridaben,
- 7 -
pyridimifen, tebufenpyrad, fenazaquin a deguelin analog, a pyridaben analog, a
pyridimifen analog, a tebufenpyrad analog, and an fenazaquin analog wherein the
contrast agent is of formula (III)
23
R24
R2 K
(Ill),
wherein:
J is selected from N(R27), S, O, C(=O), C(=O)O, NHCH2CH2O, a bond, or
C(=O)N(R27), with each group being drawn with its left end attached to G and its
right end attached to the carbon substituted with R21 and R22;
when present, K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C\-C(,
alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging
moiety;
when present, L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C\-C(,
alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging
moiety;
M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C1-C& alkyl
optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety; or
L and M, together with the atom to which they are attached, form a three- or
four-membered carbocyclic ring;
Q is halo or haloalkyl;
n isO, 1, 2, or 3;
R21, R22, R23, R24, R25, R26, and R27 are independently selected from hydrogen,
Ci-Ce alkyl optionally substituted with an imaging moiety, and an imaging moiety;
R29 is Ci-C6 alkyl optionally substituted with an imaging moiety; and
Y is selected from a bond, carbon, and oxygen; provided that when Y is a
bond, K and L are absent and M is selected from aryl and heteroaryl; and provided
- 8 -
that when Y is oxygen, K and L are absent and M is selected from hydrogen,
alkoxyalkyl, aryl, C\-C(, alkyl optionally substituted with an imaging moiety, and
heteroaryl;
provided that at least one imaging moiety is present in formula (III).
In another embodiment J is O and R29 is Ci-C6 alkyl wherein the Ci-C6 alkyl
is tert-buty\.
In another embodiment the contrast agent is selected from
In another embodiment the present diclosure provides a contrast agent
comprising an imaging moiety and a compound selected from deguelin, pyridaben,
pyridimifen, tebufenpyrad, fenazaquin a deguelin analog, a pyridaben analog, a
pyridimifen analog, a tebufenpyrad analog, and an fenazaquin analog wherein the
contrast agent is of formula (IV):
,23
,24
K
(IV),
wherein:
J is selected from N(R27), S, O, C(=O), C(=O)O, NHCH2CH2O, a bond, and
C(=O)N(R27), with each group being drawn with its left end attached to G and its
right end attached to the carbon substituted with R21 and R22;
when present, K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C]-C(,
alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging
moiety;
L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, Ci-C6 alkyl
-9-
optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety;
M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C\-C(, alkyl
optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety; or
L and M, together with the atom to which they are attached, form a three- or
four-membered carbocyclic ring;
Q is halo or haloalkyl;
n isO, 1, 2, or 3;
R21, R22, R23, R24, R25, R26, R27, R28, R35, R36, R37, R38, and R39 are
independently selected from hydrogen, C\-C(, alkyl optionally substituted with an
imaging moiety, and an imaging moiety; and
Y is selected from a bond, carbon, and oxygen, provided that when Y is a
bond, K and L are absent and M is selected from aryl and heteroaryl; and provided
that when Y is oxygen, K and L are absent and M is selected from hydrogen,
alkoxyalkyl, aryl, Ci-Ce alkyl optionally substituted with an imaging moiety, and
heteroaryl;
provided that at least one imaging moiety is present in formula (IV).
In another embodiment J is C(=O)N(H), and R28 is C\-C(, alkyl wherein the
Q-Ce alkyl is methyl.
In another embodiment the contrast agent is selected from
18F
In another embodiment the present diclosure provides a contrast agent
comprising an imaging moiety and a compound selected from deguelin, pyridaben,
pyridimifen, tebufenpyrad, fenazaquin a deguelin analog, a pyridaben analog, a
pyridimifen analog, a tebufenpyrad analog, and an fenazaquin analog wherein the
-10-
contrast agent is of formula (V)
R34
R23
24
(V),
wherein
J is selected from N(R>2"7)x, S, O, C(=O), C(=O)O, NHCH2CH2O, a bond, and
C(=0)N(R27);
K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, Ci-Ce alkyl
optionally substituted with an imaging moiety, heteroaryl, and an imaging moiety;
when present, L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C\-C(,
alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging
moiety;
when present, M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, Ci-
Cf, alkyl optionally substituted with an imaging moiety, heteroaryl, and an imaging
moiety; or
L and M, together with the atom to which they are attached, form a three- or
four-membered carbocyclic ring;
T and U are independently selected from hydrogen, alkoxy, alkoxyalkyl, QCf,
alkyl optionally substituted with an imaging moiety, halo, and an imaging moiety;
or
T and U, together with the carbon atoms to which they are attached, form a
five- to six-membered aromatic or non-aromatic ring containing zero to two
heterotoms selected from oxygen, nitrogen, and sulfur; wherein said ring is optionally
substituted with one, two, or three substituents independently selected from Ci-C&
alkyl optionally substituted with an imaging moiety and an imaging moiety;
n isO, 1, 2, or 3; and
R,2 1 , tR.2 2, R , R , R , R/0, R,27 , and R34J4 are independently selected from
-11 -
hydrogen, Ci-C6 alkyl optionally substituted with an imaging moiety, and an imaging
moiety;
Y is selected from a bond, carbon, and oxygen, provided that when V i s a
bond, K and L are absent and M is selected from aryl and heteroaryl; and provided
that when Y is oxygen, K and L are absent and M is selected from hydrogen,
alkoxyalkyl, aryl, C\-C(, alkyl optionally substituted with an imaging moiety, and
heteroaryl;
provided at least one imaging moiety is present in formula (V).
In another embodiment J is O.
In another embodiment the present diclosure provides a contrast agent
comprising an imaging moiety and a compound selected from deguelin, pyridaben,
pyridimifen, tebufenpyrad, fenazaquin a deguelin analog, a pyridaben analog, a
pyridimifen analog, a tebufenpyrad analog, and an fenazaquin analog wherein the
contrast agent is of formula (VI)
(VI),
wherein
>23 -r.24 R", R^, RZ3, R26, and R34 are independently selected from hydrogen, d-C6
alkyl optionally substituted with an imaging moiety, and an imaging moiety;
provided that at least one imaging moiety is present in formula (VI).
In another embodiment the contrast agent is selected from
- 12-
, and
Imaging moieties
Nuclear medicine contrast agents of the present disclosure include UC, 13N,
18F, 1231,125I,99mTc,95Tc, mIn,62Cu,64Cu,67Ga,and68Ga. UC-Palmitate has been
used to probe fatty acid oxidation and uC-acetate has been used to assess oxidative
metabolism in the myocardium (Circulation 1987, 76, 687-696). 13N-Ammonia has
been used widely to image myocardial perfusion (Circulation 1989, 80, 1328-37).
1 8 Agents based on F have been used as imaging agents for hypoxia and cancer
(Drugs of the Future 2002, 27, 655-667). 15-(p-(123I)-iodophenyl)-pentadecanoic
acid and 15-(p-(123I)-iodophenyl)-3(R,S)-methylpentadecanoic acid are two iodinated
agents that have been used for imaging myocardial metabolism. In one embodiment,
1 R the imaging moiety employed in the present contrast agents is F. Further imaging
moieties of the present disclosure may be comprised of one or more X-ray absorbing
or "heavy" atoms of atomic number 20 or greater, further comprising an optional
linking moiety, L, between the parent molecular moiety and the X-ray absorbing
atoms. A frequently used heavy atom in X-ray contrast agents is iodine. Recently,
X-ray contrast agents comprised of metal chelates (U.S. Pat. No. 5,417,959) and
polychelates comprised of a plurality of metal ions (U.S. Pat. No. 5,679,810) have
been disclosed. More recently, multinuclear cluster complexes have been disclosed
as X-ray contrast agents (U.S. Pat. No. 5,804,161, WO 91/14460, and WO
- 13-
92/17215). In certain embodiments of the present disclosure the specific metals used
in the X-ray contrast agents include Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au,
Yb, Dy, Cu, Rh, Ag, and Ir.
MRI contrast agents of the present disclosure may be comprised of one or
more analog moieties attached to one or more paramagnetic metal ions, further
comprising an optional linking moiety, L, between the analog moieties and the
paramagnetic metal ions. The paramagnetic metal ions may be present in the form of
metal chelates or complexes or metal oxide particles. U.S. Pat. Nos. 5,412,148, and
5,760,191, describe examples of chelators for paramagnetic metal ions for use in
MRI contrast agents. U.S. Pat. No. 5,801,228, U.S. Pat. No. 5,567,411, and U.S. Pat.
No. 5,281,704, describe examples of polychelants useful for complexing more than
one paramagnetic metal ion for use in MRI contrast agents. U.S. Pat. No. 5,520,904,
describes particulate compositions comprised of paramagnetic metal ions for use as
MRI contrast agents. Examples of specific metals include Gd3+, Fe3+, In3+, and Mn2+.
The ultrasound contrast agents of the present disclosure may comprise a
plurality of analog moieties attached to or incorporated into a microbubble of a
biocompatible gas, a liquid carrier, and a surfactant microsphere, further comprising
an optional linking moiety, L, between the analog moieties and the microbubble. In
this context, the term "liquid carrier" means aqueous solution and the term
"surfactant" means any amphiphilic material which may produce a reduction in
interfacial tension in a solution. A list of suitable surfactants for forming surfactant
microspheres is disclosed, for example, in EP0727225A2. The term "surfactant
microsphere" includes microspheres, nanospheres, liposomes, vesicles and the like.
The biocompatible gas can be any physiologically accepted gas, including, for
example, air, or a fluorocarbon, such as a C3-C5 perfluoroalkane, which provides the
difference in echogenicity and thus the contrast in ultrasound imaging. The gas may
be encapsulated, contained, or otherwise constrained in or by the microsphere to
which is attached the analog moiety, optionally via a linking group. The attachment
can be covalent, ionic or by van der Waals forces. Specific examples of such contrast
agents include, for example, lipid encapsulated perfluorocarbons with a plurality of
tumor neovasculature receptor binding peptides, polypeptides or peptidomimetics.
Examples of gas filled imaging moieties include those found in U.S. Patent
Application Serial No. 09/931,317, filed August 16, 2001, and U.S. Patent Nos.
- 14-
5,088,499, 5,547,656, 5,228,446, 5,585,112, and 5,846,517.
Chelators
Many approaches to labeling compounds with 99mTc are known, including
direct labeling of the compound or inclusion of a chelating moiety ("chelator"). In
one embodiment, the chelator is DADT, MAG3, MAMA, PAMA, or DOTA.
The compounds of the disclosure may optionally contain a chelator ("C"). In
certain embodiments of the compounds of the disclosure, the chelator is a surfactant
capable of forming an echogenic substance-filled lipid sphere or microbubble. In
certain other embodiments, the chelator is a bonding unit having a formula selected
from
A1
1/E
A1
E,
A1
\ E /
A1
-15-
3 TT E A
, and
wherein
each A1 is independently selected from -NR46R47, -NHR53, -SH, -S(Pg), -OH,
-PR46R47, -P(O)R48R49, and a bond to the compound that binds MC-1;
each A2 is independently selected from N(R53), N(R46), S, O, P(R46), and
-OP(O)(R48)O-;
A3 is N;
A4 is selected from OH and OC(=O)CrC2o alkyl;
A5isOC(=O)C,-C2oalkyl;
each E is independently selected from Ci-Ci6 alkylene substituted with 0-3
R50, C6-Cio arylene substituted with 0-3 R50, Cs-Cio cycloalkylene substituted with 0-
3 R50, heterocyclyl-C,-Cio alkylene substituted with 0-3 R50, C6-Cio aryl-Ci-Cjo
alkylene substituted with 0-3 R50, and heterocyclylene substituted with 0-3 R50;
E1 is selected from a bond and E;
each E2 is independently selected from Ci-C16 alkyl substituted with 0-3 R50,
C6-C10 aryl substituted with 0-3 R50, C3-Ci0 cycloalkyl substituted with 0-3 R50,
heterocyclyl-Ci-Cio alkyl substituted with 0-3 R50, C6-Ci0 aryl-Ci-Cio alkyl
substituted with 0-3 R50, Ci-C10 alkyl-C6-Cio aryl substituted with 0-3 R50, and
heterocyclyl substituted with 0-3 R50;
E3 is Ci-Cio alkylene substituted with 1-3 R59;
- 16-
Pg is a thiol protecting group;
R46 and R47 are each independently selected from a bond to the compound
that binds MC-1, hydrogen, Ci-Cio alkyl substituted with 0-3 R50, aryl substituted
with 0-3 R50, C3-Cio cycloalkyl substituted with 0-3 R50, heterocyclyl-Ci-Cio alkyl
substituted with 0-3 R50, C6-Ci0 aryl-Ci-Cio alkyl substituted with 0-3 R50, and
heterocyclyl substituted with 0-3 R50;
R48 and R49 are each independently selected from a bond to the compound
that binds MC-1, -OH, Ci-Cio alkyl substituted with 0-3 R50, aryl substituted with 0-3
R50, C3-Cio cycloalkyl substituted with 0-3 R50, heterocyclyl-Ci-Cm alkyl substituted
with 0-3 R50, C6-C,0 aryl-Ci-Cio alkyl substituted with 0-3 R50, and heterocyclyl
substituted with 0-3 R50;
each R50 is independently selected from a bond to the compound that binds
MC-1, =O, halo, trifluoromethyl, cyano, -CO2R51, -C(=O)R51, -C(=O)N(R51)2, -CHO,
-CH2OR51,
-OC(=O)R51, -OC(=O)OR51, -OR51, -OC(=O)N(R5I)2, -NR51C(=O)R51, -
NR5IC(=O)OR51,
-NR51C(=O)N(R51)2, -NR51SO2N(R51)2, -NR51SO2R51, -SO3H, -SO2R51,
-SR51, -S(=O)R51, -SO2N(R5I)2, -N(R51)2, -NHC(=S)NHR51, =NOR51, NO2, -
C(=O)NHOR51, -C(=O)NHN(R51)2, -OCH2CO2H, 2-(l-morpholino)ethoxy, d-C5
alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C^-C(, cycloalkylmethyl, C2-C6 alkoxyalkyl,
aryl substituted with 0-2 R51, and heterocyclyl;
each R51 is independently selected from a bond to the compound that binds
MC-1, hydrogen, C\-C(, alkyl, phenyl, benzyl, and C]_6 alkoxy;
R53 is a co-ordinate bond to a metal;
each R59 selected from R61, =O, -CO2R60, -C(=O)R60, -C(=O)N(R60)2, -
CH2OR60,
-OR60, -N(R60)2, and C2-C4 alkenyl;
each R60 is independently selected from R61, hydrogen, C\-C(, alkyl, phenyl,
benzyl, and trifluoromethyl; and
R61 is a bond to the compound that binds MC-1;
wherein at least one of A1, R46, R47, R48, R49, R50, R51, and R61 is a bond to the
compound that binds MC-1.
-17-
Methods of Making
Typically 18F labeled compounds are synthesized by Sn2 displacement of an
appropriate leaving group. These leaving groups are preferrably sulfonic acid esters
such as toluenesulfonate (tosylate, TsO), methanesulfonate (mesylate, MsO), or
trifluoromethanesulfonate (Inflate, TfO). The leaving group may also be a halide, a
phosphineoxide (via Mitsunobu reaction), or an internal leaving group (such as an
epoxide or cyclic sulfate). These compounds are made from highly activated, dry
K18F, that is made "hotter" by the addition of cryptands such as krytofix[2.2.2].
Purification is generally via salt removal by reverse-phase chromatography (Sep-
Pak).
Representative methods of making the contrast agents are described in the
following examples. The foregoing chemical transformations may be conducted
using techniques which would be readily apparent to one of ordinary skill in the art,
once armed with the teachings in the present applications. Representative reaction
solvents include, for example, DMF, NMP, DMSO, THF, ethyl acetate,
dichloromethane, and chloroform. The reaction solution may be kept neutral or basic
by the addition of an amine such as triethylamine or DIEA. Reactions may be carried
out at ambient temperatures and protected from oxygen and water with a nitrogen
atmosphere.
Temporary protecting groups may be used to prevent other reactive
functionality, such as amines, thiols, alcohols, phenols, and carboxylic acids, from
participating in the reaction. Representative amine protecting groups include, for
example, tert-butoxycarbonyl and trityl (removed under mild acidic conditions),
Fmoc (removed by the use of secondary amines such as piperidine), and
benzyloxycarbonyl (removed by strong acid or by catalytic hydrogenolysis). The
trityl group may also used for the protection of thiols, phenols, and alcohols. In
certain embodiments the carboxylic acid protecting groups include, for example, tertbutyl
ester (removed by mild acid), benzyl ester (usually removed by catalytic
hydrogenolysis), and alkyl esters such as methyl or ethyl (usually removed by mild
base). All protecting groups may be removed at the conclusion of synthesis using the
conditions described above for the individual protecting groups, and the final product
may be purified by techniques which would be readily apparent to one of ordinary
skill in the art, once armed with the present disclosure.
- 18-
Use
The contrast agents of the present disclosure may be used in a method of
imaging, including methods of imaging in a patient comprising administering the
contrast agent to the patient by injection, infusion, or any other known method, and
imaging the area of the patient wherein the event of interest is located.
The useful dosage to be administered and the particular mode of
administration will vary depending upon such factors as age, weight, and particular
region to be treated, as well as the particular contrast agent used, the diagnostic use
contemplated, and the form of the formulation, for example, suspension, emulsion,
microsphere, liposome, or the like, as will be readily apparent to those skilled in the
art.
Typically, dosage is administered at lower levels and increased until the
desirable diagnostic effect is achieved. In one embodiment, the above-described
contrast agents may be administered by intravenous injection, usually in saline
solution, at a dose of about 0.1 to about 100 mCi per 70 kg body weight (and all
combinations and subcombinations of dosage ranges and specific dosages therein), or
preferably at a dose of about 0.5 to about 50 mCi. Imaging is performed using
techniques well known to the ordinarily skilled artisan.
For use as nuclear medicine contrast agents, the compositions of the present
disclosure, dosages, administered by intravenous injection, will typically range from
about 0.5 umol/kg to about 1.5 mmol/kg (and all combinations and subcombinations
of dosage ranges and specific dosages therein), preferably about 0.8 (amol/kg to about
1.2 mmol/kg.
For use as MRI contrast agents, the compositions of the present disclosure
may be used in a similar manner as other MRI agents as described in U.S. Patent No.
5,155,215; U.S. Patent No. 5,087,440; Magn. Reson. Med. 1986, 3, 808; Radiology
1988,166, 835; and Radiology 1988,166, 693. Generally, sterile aqueous solutions
of the contrast agents may be administered to a patient intravenously in dosages
ranging from about 0.01 to about 1.0 mmoles per kg body weight (and all
combinations and subcombinations of dosage ranges and specific dosages therein).
The ultrasound contrast agents of the present disclosure may be administered
by intravenous injection in an amount from about 10 to about 30 fJiL (and all
combinations and subcombinations of dosage ranges and specific dosages therein) of
-19-
the echogenic gas per kg body weight or by infusion at a rate of approximately 3
/xL/kg/min.
Another aspect of the present disclosure is diagnostic kits for the preparation
of diagnostic agents for detecting, imaging, and/or monitoring myocardial perfusion.
Diagnostic kits of the present disclosure comprise one or more vials containing the
sterile, non-pyrogenic, formulation comprising a predetermined amount of a reagent
of the present disclosure, and optionally other components such as one or two
ancillary ligands such as tricine and 3-[bis(3-sulfophenyl)phosphine]benzenesulfonic
acid (TPPTS), reducing agents, transfer ligands, buffers, lyophilization aids,
stabilization aids, solubilization aids and bacteriostats. The kits may also comprise a
reducing agent, such as, for example, tin(II).
Buffers useful in the preparation of contrast agents and kits include, for
example, phosphate, citrate, sulfosalicylate, and acetate buffers. A more complete
list can be found in the United States Pharmacopoeia.
Lyophilization aids useful in the preparation of contrast agents and kits
include, for example, mannitol, lactose, sorbitol, dextran, FICOLL® polymer, and
polyvinylpyrrolidine (PVP).
Stabilization aids useful in the preparation of contrast agents and kits include,
for example, ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodium
metabisulfite, gentisic acid, and inositol.
Solubilization aids useful in the preparation of contrast agents and kits
include, for example, ethanol, glycerin, polyethylene glycol, propylene glycol,
polyoxyethylene sorbitan monooleate, sorbitan monoloeate, polysorbates,
poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block copolymers
("Pluronics") and lecithin. In certain embodiments the solubilizing aids are
polyethylene glycol and Pluronics.
Bacteriostats useful in the preparation of contrast agents and kits include, for
example, benzyl alcohol, benzalkonium chloride, chlorbutanol, and methyl, propyl,
or butyl paraben.
A component in a diagnostic kit can also serve more than one function. For
example, a reducing agent for a radionuclide can also serve as a stabilization aid, or a
buffer can also serve as a transfer ligand, or a lyophilization aid can also serve as a
transfer, ancillary, or co-ligand.
-20-
The compounds herein described may have asymmetric centers. Unless
otherwise indicated, all chiral, diastereomeric and racemic forms are included in the
present disclosure. Many geometric isomers of olefins, C=N double bonds, and the
like can also be present in the compounds described herein, and all such stable
isomers are contemplated in the present disclosure. It will be appreciated that
compounds of the present disclosure may contain asymmetrically substituted carbon
atoms, and may be isolated in optically active or racemic forms. It is well known in
the art how to prepare optically active forms, such as by resolution of racemic forms
or by synthesis from optically active starting materials. Two distinct isomers (cis and
trans) of the peptide bond are known to occur; both can also be present in the
compounds described herein, and all such stable isomers are contemplated in the
present disclosure. The D- and L-isomers of a particular amino acid are designated
herein using the conventional 3-letter abbreviation of the amino acid, as indicated by
the following examples: D-Leu, or L-Leu.
For the sake of simplicity, connection points ("-") are not depicted. When an
atom or compound is described to define a variable, it is understood that it is intended
to replace the variable in a manner to satisfy the valency of the atom or compound.
en sn For example, if a variable A" was identified as C(R )=C(R ), both carbon atoms
would form a part of the chain in order to satisfy their respective valences.
When any variable occurs more than one time in any substituent or in any
formula, its definition in each occurrence is independent of its definition at every
other occurrence. Thus, for example, if a group, or plurality of groups, is shown to
be substituted with 0-2 R80, then said group(s) may optionally be substituted with up
o(\ or» to two R , and R at each occurrence in each group is selected independently from
the defined list of possible R80. Also, by way of example, for the group -N(R81)2,
each of the two R81 substituents on N is independently selected from the defined list
of possible R81. Combinations of substituents and/or variables are permissible only if
such combinations result in stable compounds. When a bond to a substituent is
shown to cross the bond connecting two atoms in a ring, then such substituent may be
bonded to any atom on the ring.
Definitions
The number of carbon atoms in any particular group is denoted before the
recitation of the group. For example, the term "Ce-Cioaryl" denotes an aryl group
-21 -
containing from six to ten carbon atoms, and the term "C6-Ci0aryl-Ci-Ci0alkyl,"
refers to an aryl group of six to ten carbon atoms attached to the parent molecular
moiety through an alkyl group of one to ten carbon atoms.
The term "alkenyl," as used herein, refers to a straight or branched chain
hydrocarbon containing at least one carbon-carbon double bond.
The term "alkoxy," as used herein, refers to a Ci-C6 alkyl group attached to
the parent molecular moiety through an oxygen atom.
The term "alkoxyalkyl," as used herein, refers to a C\-C(, alkyl group
substituted with one, two, or three alkoxy groups.
The term "alkyl," as used herein, refers to a group derived from a straight or
branched chain saturated hydrocarbon.
The term "alkylaryl," as used herein, refers to an alkyl group attached to the
parent molecular moiety through an aryl group.
The term "alkylene," as used herein, refers to a divalent group derived from a
straight or branched chain saturated hydrocarbon.
The term "alkyloxy," as used herein, refers to a C\-C(, alkyl group attached to
the parent molecular moiety through an oxygen atom.
The term "analog moiety," as used herein, refers to the compounds of the
present disclosure excluding the imaging moiety or moieties.
The term "aryl," as used herein, refers to a phenyl group, or a bicyclic fused
ring system wherein one or more of the rings is a phenyl group. Bicyclic fused ring
systems consist of a phenyl group fused to a monocyclic cycloalkenyl group, a
monocyclic cycloalkyl group, or another phenyl group. The aryl groups of the
present invention can be attached to the parent molecular moiety through any
substitutable carbon atom in the group. Representative examples of aryl groups
include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl,
naphthyl, phenyl, andtetrahydronaphthyl.
The term "arylalkyl," as used herein, refers to an alkyl group substituted with
one, two, or three aryl groups.
The term "arylalkylene," as used herein, refers to a divalent arylalkyl group,
where one point of attachment to the parent molecular moiety is on the aryl portion
and the other is on the alkyl portion.
The term "arylene," as used herein, refers to a divalent aryl group.
-22-
As used herein, the terms "ancillary" or "co-ligands" refers to ligands that
serve to complete the coordination sphere of the radionuclide together with the
chelator or radionuclide bonding unit of the reagent. For radiopharmaceuticals
comprising a binary ligand system, the radionuclide coordination sphere comprises
one or more chelators or bonding units from one or more reagents and one or more
ancillary or co-ligands, provided that there are a total of two types of ligands,
chelators or bonding units. For example, a radiopharmaceutical comprised of one
chelator or bonding unit from one reagent and two of the same ancillary or co-ligands
and a radiopharmaceutical comprising two chelators or bonding units from one or
two reagents and one ancillary or co-ligand are both considered to comprise binary
ligand systems. For radiopharmaceuticals comprising a ternary ligand system, the
radionuclide coordination sphere comprises one or more chelators or bonding units
from one or more reagents and one or more of two different types of ancillary or
co-ligands, provided that there are a total of three types of ligands, chelators or
bonding units. For example, a radiopharmaceutical comprised of one chelator or
bonding unit from one reagent and two different ancillary or co-ligands is considered
to comprise a ternary ligand system.
Ancillary or co-ligands useful in the preparation of radiopharmaceuticals and
in diagnostic kits useful for the preparation of said radiopharmaceuticals comprise
one or more oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, selenium, and
tellurium donor atoms. A ligand can be a transfer ligand in the synthesis of a
radiopharmaceutical and also serve as an ancillary or co-ligand in another
radiopharmaceutical. Whether a ligand is termed a transfer or ancillary or co-ligand
depends on whether the ligand remains in the radionuclide coordination sphere in the
radiopharmaceutical, which is determined by the coordination chemistry of the
radionuclide and the chelator or bonding unit of the reagent or reagents.
A "bacteriostat" is a component that inhibits the growth of bacteria in a
formulation either during its storage before use of after a diagnostic kit is used to
synthesize a radiopharmaceutical.
The term "bubbles" or "microbubbles," as used herein, refers to vesicles
which are generally characterized by the presence of one or more membranes or
walls surrounding an internal void that is filled with a gas or precursor thereto.
Exemplary bubbles or microbubbles include, for example, liposomes, micelles, and
-23-
the like.
The terms "chelator" and "bonding unit," as used herein, refer to the moiety
or group on a reagent that binds to a metal ion through one or more donor atoms.
The term "contrast agent," as used herein, refers to an agent used to highlight
specific areas so that organs, blood vessels, and/or tissues are more visible. By
increasing the visibility of the surfaces being studied, the presence and extent of
disease and/or injury can be determined.
The term "cycloalkenyl," as used herein, refers to a non-aromatic, partially
unsaturated monocyclic, bicyclic, or tricyclic ring system having three to fourteen
carbon atoms and zero heteroatoms. Representative examples of cycloalkenyl groups
include, but are not limited to, cyclohexenyl, octahydronaphthalenyl, and
norbornylenyl.
The term "cycloalkyl," as used herein, refers to a saturated monocyclic,
bicyclic, or tricyclic hydrocarbon ring system having three to fourteen carbon atoms
and zero heteroatoms. Representative examples of cycloalkyl groups include, but are
not limited to, cyclopropyl, cyclopentyl, bicyclo[3.1.1]heptyl, and adamantyl.
The term "C^-C\o cycloalkylene," as used herein, refers to a divalent
cycloalkyl group containing from three to ten carbon atoms.
The term "diagnostic imaging," as used herein, refers to a procedure used to
detect a contrast agent.
A "diagnostic kit" or "kit" comprises a collection of components, termed the
formulation, in one or more vials which are used by the practicing end user in a
clinical or pharmacy setting to synthesize diagnostic radiopharmaceuticals. The kit
preferably provides all the requisite components to synthesize and use the diagnostic
pharmaceutical except those that are commonly available to the practicing end user,
such as water or saline for injection, a solution of the radionuclide, equipment for
heating the kit during the synthesis of the radiopharmaceutical, if required, equipment
necessary for administering the radiopharmaceutical to the patient such as syringes,
shielding, imaging equipment, and the like. Contrast agents are provided to the end
user in their final form in a formulation contained typically in one vial, as either a
lyophilized solid or an aqueous solution. The end user typically reconstitutes the
lyophilized material with water or saline and withdraws the patient dose or just
withdraws the dose from the aqueous solution formulation as provided.
-24-
The term "donor atom," as used herein, refers to the atom directly attached to
a metal by a chemical bond.
The terms "halo" and "halogen," as used herein, refer to F, Cl, Br, or I.
The term "haloalkyl," as used herein, refers to a Ci-Ce alkyl group substituted
by one, two, three, or four halogen atoms.
The term "heteroaryl," as used herein, refers to an aromatic five- or sixmembered
ring where at least one atom is selected from N, O, and S, and the
remaining atoms are carbon. The term "heteroaryl" also includes bicyclic systems
where a heteroaryl ring is fused to a four- to six-membered aromatic or non-aromatic
ring containing zero, one, or two additional heteroatoms selected from N, O, and S.
The heteroaryl groups are attached to the parent molecular moiety through any
substitutable carbon or nitrogen atom in the group. Representative examples of
heteroaryl groups include, but are not limited to, benzoxadiazolyl, benzoxazolyl,
benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl,
isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl,
thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl.
The term "heterocyclyl," as used herein, refers to a five-, six-, or sevenmembered
ring containing one, two, or three heteroatoms independently selected
from the group consisting of nitrogen, oxygen, and sulfur. The five-membered ring
has zero to two double bonds and the six- and seven-membered rings have zero to
three double bonds. The term "heterocyclyl" also includes bicyclic groups in which
the heterocyclyl ring is fused to a phenyl group, a monocyclic cycloalkenyl group, a
monocyclic cycloalkyl group, or another monocyclic heterocyclyl group. The
heterocyclyl groups of the present invention can be attached to the parent molecular
moiety through a carbon atom or a nitrogen atom in the group. Examples of
heterocyclyl groups include, but are not limited to, benzothienyl, furyl, imidazolyl,
indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl,
piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, thiazolyl,
thienyl, and thiomorpholinyl.
The term "heterocyclylalkyl," as used herein, refers to an alkyl group
substituted with one, two, or three heterocyclyl groups.
The term "heterocyclylalkylene," as used herein, refers to a divalent
-25-
heterocyclylalkyl group, where one point of attachment to the parent molecular
moiety is on the heterocyclyl portion and the other is on the alkyl portion.
The term "heterocyclylene," as used herein, refers to a divalent heterocyclyl
group.
The term "hydroxy," as used herein, refers to -OH.
The term "imaging moiety," as used herein, refer to a portion or portions of a
molecule that allow for the detection, imaging, and/or monitoring of the presence
and/or progression of a condition(s), pathological disorder(s), and/or disease(s).
The term "linking group," as used herein, refers to a portion of a molecule
that serves as a spacer between two other portions of the molecule. Linking groups
may also serve other functions as described herein. Examples of linking groups
include linear, branched, or cyclic alkyl, aryl, ether, polyhydroxy, polyether,
polyamine, heterocyclic, aromatic, hydrazide, peptide, peptoid, or other
physiologically compatible covalent linkages or combinations thereof.
As used herein, the term "lipid" refers to a synthetic or naturally-occurring
amphipathic compound which comprises a hydrophilic component and a hydrophobic
component. Lipids include, for example, fatty acids, neutral fats, phosphatides,
glycolipids, aliphatic alcohols and waxes, terpenes and steroids. Exemplary
compositions which comprise a lipid compound include suspensions, emulsions and
vesicular compositions.
"Liposome" refers to a generally spherical cluster or aggregate of amphipathic
compounds, including lipid compounds, typically in the form of one or more
concentric layers, for example, bilayers. They may also be referred to herein as lipid
vesicles.
A "lyophilization aid" is a component that has favorable physical properties
for lyophilization, such as the glass transition temperature, and is generally added to
the formulation to improve the physical properties of the combination of all the
components of the formulation for lyophilization.
The term "oxo," as used herein, refers to =O.
As used herein, the phrase "pharmaceutically acceptable" refers to those
compounds, materials, compositions, and/or dosage forms that are, within the scope
of sound medical judgment, suitable for use in contact with the tissues of human
beings and animals without excessive toxicity, irritation, allergic response, or other
-26-
problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt," as used herein, represents salts
or zwitterionic forms of the compounds of the present invention which are water or
oil-soluble or dispersible, which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of patients without excessive toxicity,
irritation, allergic response, or other problem or complication commensurate with a
reasonable benefit/risk ratio, and are effective for their intended use The salts can be
prepared during the final isolation and purification of the compounds or separately by
reacting a suitable nitrogen atom with a suitable acid. Representative acid addition
salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate; digluconate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesitylenesulfonate,
methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,
palmoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate,
succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate,
bicarbonate, para-toluenesulfonate, and undecanoate. Examples of acids which can
be employed to form pharmaceutically acceptable addition salts include inorganic
acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids
such as oxalic, maleic, succinic, and citric.
By "reagent" is meant a compound of this disclosure capable of direct
transformation into a metallopharmaceutical of this disclosure. Reagents may be
utilized directly for the preparation of the metallopharmaceuticals of this disclosure
or may be a component in a kit of this disclosure.
A "reducing agent" is a compound that reacts with a radionuclide, which is
typically obtained as a relatively unreactive, high oxidation state compound, to lower
its oxidation state by transferring electron(s) to the radionuclide, thereby making it
more reactive. Reducing agents useful in the preparation of radiopharmaceuticals
and in diagnostic kits useful for the preparation of said radiopharmaceuticals include,
for example, stannous chloride, stannous fluoride, formamidine sulfinic acid,
ascorbic acid, cysteine, phosphines, and cuprous or ferrous salts. Other reducing
agents are described, for example, in Brodack et. al., PCT Application 94/22496.
A "stabilization aid" is a component that is typically added to the
-27-
metallopharmaceutical or to the diagnostic kit either to stabilize the
metallopharmaceutical or to prolong the shelf-life of the kit before it must be used.
Stabilization aids can be antioxidants, reducing agents or radical scavengers and can
provide improved stability by reacting preferentially with species that degrade other
components or the metallopharmaceuticals.
By "stable compound" or "stable structure" is meant herein a compound that
is sufficiently robust to survive isolation to a useful degree of purity from a reaction
mixture, and formulation into an efficacious pharmaceutical agent.
A "solubilization aid" is a component that improves the solubility of one or
more other components in the medium required for the formulation.
The term "thiol protecting group," as used herein, refers to a group intended
to protect a thiol group against undesirable reactions during synthetic procedures.
Any thiol protecting group known in the art may be used. Examples of thiol
protecting groups include, but are not limited to, the following: acetamidomethyl,
benzamidomethyl, 1-ethoxyethyl, benzoyl, and triphenylmethyl.
A "transfer ligand" is a ligand that forms an intermediate complex with a
metal ion that is stable enough to prevent unwanted side-reactions but labile enough
to be converted to a contrast agent. The formation of the intermediate complex is
kinetically favored while the formation of the metallopharmaceutical is
thermodynamically favored. Transfer ligands useful in the preparation of contrast
agents and in diagnostic kits useful for the preparation of diagnostic
radiopharmaceuticals include, for example, gluconate, glucoheptonate, mannitol,
glucarate, N,N,N',N'-ethylenediaminetetraacetic acid, pyrophosphate and
methylenediphosphonate. In general, transfer ligands are comprised of oxygen or
nitrogen donor atoms.
As used herein, the term "vesicle" refers to a spherical entity which is
characterized by the presence of an internal void. In one embodiment vesicles are
formulated from lipids, including the various lipids described herein. In any given
vesicle, the lipids may be in the form of a monolayer or bilayer, and the mono- or
bilayer lipids may be used to form one of more mono- or bilayers. In the case of
more than one mono- or bilayer, the mono- or bilayers are generally concentric. The
lipid vesicles described herein include such entities commonly referred to as
liposomes, micelles, bubbles, microbubbles, microspheres and the like. Thus, the
-28-
lipids may be used to form a unilamellar vesicle (comprised of one monolayer or
bilayer), an oligolamellar vesicle (comprised of about two or about three monolayers
or bilayers) or a multilamellar vesicle (comprised of more than about three
monolayers or bilayers). The internal void of the vesicles may be filled with a liquid,
including, for example, an aqueous liquid, a gas, a gaseous precursor, and/or a solid
or solute material, including, for example, a bioactive agent, as desired.
As used herein, the term "vesicular composition" refers to a composition
which is formulate from lipids and which comprises vesicles.
The present disclosure will now be described in connection with certain
embodiments which are not intended to limit its scope. On the contrary, the present
disclosure covers all alternatives, modifications, and equivalents as can be included
within the scope of the claims. Thus, the following examples will illustrate one
practice of the present invention, it being understood that the examples are for the
purposes of illustration of certain embodiments and are presented to provide what is
believed to be the most useful and readily understood description of its procedures
and conceptual aspects.
Synthesis of Fenazaquin Analog:
Example 1A
Synthesis of 4-[4-(2-Hydroxyethyl)phenyl]-4-oxo-butyric acid methyl ester
o
CO2Me
2. Sodium
MeOH
To a dry 250 mL flask under a nitrogen atmosphere was added phenethyl
alcohol (2.50 g, 0.02 mol), anhydrous dichloromethane (150 mL), and methyl-4-
chloro-4-oxobutyrate (6.02 g, 0.04 mol). The contents of the flask were cooled to 0
°C with an ice bath. To the solution was added aluminum chloride (25 g, 0.2 mol) in
portions being careful to avoid a violent exotherm. The resulting yellowish mixture
was stirred for 3 hours. At this point the reaction was quenched with ice water. The
mixture was diluted with dichloromethane and transferred to a separatory funnel.
The organic layer was washed with a saturated solution of sodium bicarbonate, brine
-29-
and then dried over magnesium sulfate. Filtration and concentration of the filtrate
under reduced pressure provided a crude yellow oil. The oil was suspended in
anhydrous methanol (100 mL) and sodium metal was added to the mixture until a pH
of 9 was obtained. The mixture was stirred for 3 hours. The volume was reduced
and then diluted with ethyl acetate. The solution was transferred to a separatory
funnel and washed with aqueous 0.05 N hydrochloric acid, brine and dried over
magnesium sulfate. The solution was concentrated under reduced pressure to give a
crude yellow oil with a mass of 5.88 g. Column chromatography [silica gel; eluent
hexanes-ethyl acetate (3:2)] provided the desired product (2.69 g, 57 %). !H (CDC13)
5(ppm): 2.65 (t, 2H); 2.81 (t, 2H); 3.19 (t, 2H); 3.6 (s, 3H); 3.75 (t, 2H); 7.22 (d, 2H);
7.81 (d, 2H). 13C (CDC13) 5(ppm): 27.76, 33.03, 38.66, 51.52, 62.68, 127.97, 128.99,
134.47, 144.78, 173.21,197.64.
Example IB
Synthesis of 4-[4-(2-hydroxyethyl)phenyl]butyric acid methyl ester
C02Me
H2, Pd/C
MeOH
HOT ^^ ^" HO"
A mixture of Example 1A (2.50 g, 11 mmol), 10 % Pd/C (0.25 g, 0.23 mmol
of Pd metal) in anhydrous methanol (25 mL) was first degassed to remove air (two
vacuum/H2 cycles) after which it was capped and a balloon filled with Ha was applied
to it for 12 hours. After this time the reaction mixture was filtered through
diatomaceous earth (Celite®) and the filtrate was concentrated under reduced
pressure to give 2.32 g of crude material. Column chromatography [silica gel; eluent
hexanes-ethyl acetate (2:1)] provided the desired product (0.92 g, 39 %). *H (CDC13)
5(ppm): 1.91-1.96 (m, 2H); 2.32 (t, 2H); 2.62 (t, 2H); 2.83 (t, 2H); 3.66 (s, 3H); 3.85
(t, 2H);7.11-7.15(m,4H).
-30-
Example 1C
Synthesis of 4-{4-[2-(quinazolin-4-yloxy)ethyl]phenyl}butyric acid methyl ester
CO2Me
NaH
THF
'CO2Me
A dry 50 mL flask was fitted with an addition funnel. To the flask were
added 4-chloroquinazoline (592 mg, 3.6 mmol), anhydrous tetrahydrofuran (10 mL),
and 60 wt % sodium hydride (187 mg, 4.7 mmol). A solution of Example IB (800
mg, 3.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise using the
addition funnel. The reaction was stirred for 3.5 hours. The reaction was diluted
with ethyl acetate and quenched by the addition of aqueous 0.1 N hydrochloric acid.
The mixture was transferred to a separatory funnel and washed with brine. The
organic layer was dried over magnesium sulfate, filtered, and concentrated. Column
chromatography [silica gel; eluent hexanes-ethyl acetate (4:1)] provided the desired
product (538 mg, 43 %). 'H(CDC13) 8(ppm): 1.92-1.98 (m, 2H); 2.33 (t, 2H); 2.64 (t,
2H); 3.19 (t, 2H); 3.66 (s, 3H); 4.79 (t, 2H); 7.15 (d, 2H); 7.27 (d, 2H); 7.57 (t, IH);
7.83 (t, IH); 7.94 (d, IH); 8.15 (d, IH); 8.80 (s, IH). 26.68, 33.59, 34.93, 35.03,
51.67,67.89, 116.48, 123.72, 127.23, 127.82, 128.87, 129.24, 133.74, 135.76,
139.90, 151.08, 154.56, 166.89, 174.10.
Example ID
Synthesis of 4-{4-[2-(Quinazolin-4-yloxy)ethyl]phenyl}butan-l-ol
^N ^^ N
To a dry 15 mL flask was added lithium aluminum hydride (233 mg, 6.0
mmol) and anhydrous diethyl ether (3 mL). The mixture was cooled with an ice bath.
A solution of Example 1C (538 mg, 1.54 mmol) in anhydrous diethyl ether (3 mL)
was slowly added with vigorous stirring. The bath was removed and the slurry was
stirred for 15 minutes. The reaction was quenched with water (0.233 mL), aqueous
-31-
15 % sodium hydroxide (0.233 mL) and water (0.699 mL). The white solid was
filtered and the filtrate was dried over magnesium sulfate, filtered, and concentrated
under reduced pressure to give a clear oil. The oil was then dissolved in anhydrous
dichloromethane (10 mL) and manganese(IV) oxide (500 mg, 5.8 mmol) was added
to the solution. The mixture was stirred for 12 hours. Filtration through
diatomaceous earth (Celite®) followed by concentration of the filtrate under reduced
pressure afforded 395 mg of crude product. Column chromatography [silica gel;
eluent pentane-ethyl acetate (2:3)] provided the desired product (225 mg, 49 %). *H
(CDC13) 5(ppm): 1.55-1.61 (m, 2H); 1.65-1.68 (m, 2H); 2.61 (t, 2H); 3.17 (t, 2H);
3.64 (t, 2H); 4.79 (t, 2H); 7.12 (d, 2H); 7.23 (d, 2H); 7.56 (t, IH); 7.82 (t, IH); 7.93
(d, IH); 8.14 (d, IH); 8.77 (s, IH). 13C (CDC13) 5(ppm): 27.52, 32.31, 34.89, 35.21,
62.81,67.74, 116.67, 123.54, 127.08, 127.49, 128.63, 128.98, 133.61, 135.23,
140.64, 150.68, 154.29, 166.79.
Example IE
Synthesis of Toluene-4-sulfonic acid 4-{4-[2-(quinazolin-4-
yloxyethyl]phenyl}butyl ester
TsCI
DMAP
TEA
DCM
To a dry 10 mL flask was added p-toluenesulfonyl chloride (32.5 mg, 0.17
mmol), 4-(dimethylamino)pyridine (20.7 mg, 0.17 mmol), Example ID (50.0 mg,
0.16 mmol), anhydrous dichloromethane (1 mL) and triethylamine (17.2 mg, 0.17
mmol). The resulting solution was stirred for 2 hours, concentrated under reduced
pressure, and purified by column chromatography [silica gel; eluent pentane-ethyl
acetate (1.86:1)] to provide the desired product (52 mg, 70 %). ^(CDC^) 5(ppm):
1.64-1.68 (m, 4H); 2.44 (s, 3H); 2.56 (t, 2H); 3.19 (t, 2H); 4.04 (t, 2H); 4.78 (t, 2H);
7.08 (d, 2H); 7.26 (d, 2H); 7.57 (t, IH); 7.78 (d , 2H); 7.84 (t, IH), 8.14 (d, IH); 8.80
(s, IH).
-32-
Example IF
Synthesis of 4-{2-[4-(4-Fluorobutyl)phenyl]ethoxy}quinazoline
.OTs
KF
Kryptofix
ACN
N'
A dry 5 mL flask was fitted with a reflux condenser. To the flask was added
potassium fluoride (6.1 mg, 0.1 mmol), kryptofix (40 mg, 0.1 mmol) and anhydrous
acetonitrile (0.5 mL). To the resulting solution was added a solution of Example IE
(25 mg, 0.05 mmol) in anhydrous acetonitrile (1 mL). The flask was placed in a 90
°C oil bath. The solution was stirred for 1 hour. After cooling the reaction mixture
was diluted with diethyl ether, transferred to a separatory funnel, and washed with
aqueous 0.1 N hydrochloric acid, saturated aqueous solution of sodium bicarbonate,
and then brine. The organic layer was dried with magnesium sulfate, filtered, and
concentrated under reduced pressure. Column chromatography [silica gel; eluent
hexanes-ethyl acetate (3:1)] provided the desired product (10.7 mg, 63 %).
'H(CDC13) 5(ppm): 1.65-1.73 (m, 4H); 2.63 (t, 2H); 3.17 (t, 2H); 4.40 (t, 1H); 4.48 (t,
1H); 4.77 (t, 2H); 7.13 (d, 2H); 7.24 (d, 2H); 7.55 (1H); 7.82 (t, 1H); 7.92 (d, 1H);
8.13 (d, 1H); 8.78 (s, 1H). 13C (CDC13) 8(ppm): 27.19 (d, 4JCF = 4.5), 30.20 (d, 3JCF
= 19.5), 35.15 (d, 2JCF = 27.0), 67.94, 84.17 (d, 'JCF= 163.3), 116.93, 123.75, 127.26,
127.84, 128.82, 129.23, 129.42, 133.77, 135.62, 138.21, 140.54, 151.08, 154.59.
19F(CDC13,CFC13 internal standard;
Synthesis of Pyridaben Analogs:
standard) S(ppm): -218.59 (t of t, J = -27.6, -50.4).
Example 2A
Synthesis of Butyric acid 4-phenylbutyl ester
O
OH
DCM
To 4-phenyl-l-butanol (7.0 g, 0.047 mol) was added anhydrous
dichloromethane (20 mL). A solution of butyryl chloride (4.79 g, 0.045 mol) in
anhydrous dichloromethane (20 mL) was added dropwise. The solution was stirred
- 3 3 -
for 36 hours. At this point the reaction was concentrated under reduced pressure to
give a crude oil. Column chromatography [silica gel; eluent hexanes-ethyl acetate
(3:1)] provided the desired product (9.8 g, 94%) as a clear viscous liquid. 'H(CDCl3)
5(ppm): 0.94 (t, 3H); 1.61-1.71 (m, 6H); 2.27 (t, 2H); 2.64 (t, 2H); 4.08 (t, 2H); 7.16-
7.19 (m, 3H); 7.25-7.29 (m, 2H).
Example 2B
Synthesis of 4-(4-Hydroxybutyl)benzoic acid methyl ester
o
o
AlClg
DCM
° 2. MeOH
O
To aluminum chloride (6.7 g, 0.05 mol) in a dry 250 mL round bottom flask
was added anhydrous dichloromethane (100 mL). The flask was cooled in a 0 °C ice
bath. Oxalyl chloride (6.4 g, 0.05 mol) was added dropwise to the flask. The
mixture was allowed to stir for 5 minutes. A solution of Example 2A (9.8 g, 0.044
mol) in anhydrous dichloromethane (50 mL) was then added dropwise. The mixture
was allowed to stir for 4 hours at 0 °C. The reaction mixture was poured into a
separatory funnel containing ice and brine. The organic layer was washed with brine
and dried over magnesium sulfate. Filtration and concentration under reduced
pressure provided 9.1 g of yellow oil. 9.0 g of this oil was suspended in methanol
and the pH adjusted to 2 and stirred for 48 hours. The reaction mixture was
concentrated under reduced pressure. Column chromatography [silica gel; eluent
hexanes-ethyl acetate (2.57:1)] provided the desired product (2.80 g, 31%) as a clear
viscous liquid. 'H (CDC13) 5(ppm): 1.56-1.61 (m, 2H); 1.63-1.73 (m, 2H); 2.67 (t,
2H); 3.64 (t, 2H); 3.88 (s, 3H); 7.23 (d, 2H); 7.93 (d, 2H).
Example 2C
Synthesis of 4-[4-(tert-Butyldimethylsilanyloxy)butyl]benzoic acid methyl ester
TB.SCI , ^ /\ /\ .OTBS
imidazole
^CX
o o
To Example 2B (1.0 g, 4.8 mmol) was added anhydrous dimethylformamide
(10 mL), imidazole (0.5 g, 7.2 mmol) and tert-butyldimethylsilyl chloride (1.08 g, 7.3
-34-
mmol). The solution was stirred in a water bath for 2 hours. The reaction mixture
was diluted with ethyl acetate, poured into a separatory funnel, washed with water
(20 mL, 5x) then washed with a saturated sodium bicarbonate solution (20 mL, 2x).
The organic layer was dried with magnesium sulfate, filtered, and concentrated under
reduced pressure to give the desired product (1.17 g, 75 %) which was used without
further purification in the next step.
Example 2D
Synthesis of {4-[4-(tert-Butyldimethylsilanyloxy)butyl]phenyl}-methanol
OTBS LAH
ether
To Example 2C (1.17 g, 3.6 mmol) was added anhydrous diethyl ether (14
mL). The solution was cooled to 0 °C with an ice bath. Lithium aluminum hydride
(0.28 g, 7.2 mmol) was added to the solution in portions. The mixture was stirred for
1 hour. To the reaction mixture was added distilled water (0.28 mL) and the mixture
was stirred for 5 minutes. Next was added an aqueous 15% sodium hydroxide
solution and the mixture was stirred for 5 minutes. Lastly distilled water (0.84 mL)
was added and the mixture was stirred for 5 minutes. The white solid was removed
by filtration. The filtrate was dried with magnesium sulfate, filtered, and
concentrated to give 1.23 g of crude product. Column chromatography [silica gel;
eluent hexanes-ethyl acetate (4:1)] provided the desired product (1.02 g, 96%) as a
clear viscous liquid.
Example 2E
Synthesis of 2-tert-Butyl-5-{4-[4-(tert-butyldimethylsilanyloxy)butyl]benzyloxy}-
4-chloro-2H-pyridazin-3-one
"OTBS
To a dry 25 mL round bottom flask, fitted with a reflux condenser, was added
the product of Example 2D (0.41 g, 1.4 mmol), 2-tert-butyl-4,5-dichloro-2Hpyridazin-
3-one (0.93 g, 4.2 mmol), cesium carbonate (1.37 g, 4.2 mmol), and
anhydrous dimethylformamide (11 mL). The reaction flask was placed in a 68 °C oil
bath and the reaction was stirred for 12 hours. The reaction flask was removed from
-35-
the oil bath and allowed to cool. The mixture was diluted with ethyl acetate,
transferred to a separatory funnel and washed with water (25 mL, 5x). The organic
layer was dried with magnesium sulfate, filtered, and concentrated under reduced
pressure to give 1.3 g of crude product. Column chromatography [silica gel; eluent
hexanes-ethyl acetate (9:1)] provided the desired product (594 mg, 89%). 'H(CDC13)
S(ppm): 0.05 (s, 6H); 0.90 (s, 9H); 1.64 (s, 9H); 2.65 (t, 2H); 3.64 (t, 2H); 5.23 (s,
2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, 1H). 13C (CDC13) 5(ppm): 18.57, 26.19,
27.75, 28.09, 32.58, 35.61, 63.14, 66.57, 72.14, 118.46, 125.41, 127.44, 129.23,
132.38, 143.72, 154.02, 159.30.
Example 2F
Synthesis of 24ert-Butyl-4-chloro-5-[4-(4-hydroxy-butyl)-benzyloxy]-2Hpyridazin-
3-one
TBAF
THF
OTBS
To the product of Example 2E (594 mg, 1.45 mmol) was added anhydrous
tetrahydrofuran (3 mL) and a 1.0 M solution of tert-butylammonium fluoride in
tetrahydrofuran (2.9 mL, 2.9 mmol). The solution was stirred for 1 hour then
concentrated under reduced pressure. Column chromatography [silica gel; eluent
pentane-ethyl acetate (1.8:1)] provided the desired product (410 mg, 77%). 'H
(CDC13) 5(ppm): 1.61-1.64 (m, 11H); 1.67-1.74 (m, 2H); 2.68 (t, 2H); 3.68 (t, 2H);
5.23 (s, 2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, 1H). 13C (CDC13) 5(ppm): 27.43,
27.86, 32.56, 35.35, 62.74, 66.36, 71.88, 118.27, 125.18, 127.27, 128.99, 132.28,
143.17,153.78,159.07.
Example 2G
Synthesis of Toluene-4-sulfonic acid 4-[4-(l-tert-butyl-5-chloro-6-oxo-l,6-
dihydro-pyridazin-4-yloxymethyl)-phenyl]-butyl ester
TsCI
DMAP
DIEA
DCM
OTs
To a 5 mL round bottom flask was added the product of Example 2F (200 rng,
0.55 mmol), p-toluenesulfonyl chloride (125 mg, 0.66 mmol), 4-
-36-
(dimethylamino)pyridine (80 mg, 0.66 mmol), diisopropylethylamine (85 mg, 0.66
mmol) and anhydrous dichloromethane (2 mL). The resulting solution was stirred for
2 hours. The reaction mixture was diluted with ethyl acetate, transferred to a
separatory funnel and washed with a solution of aqueous 0.1 N hydrochloric acid and
then washed with brine. The organic layer was dried with magnesium sulfate,
filtered, and concentrated under reduced pressure to give 299 mg of crude product.
Column chromatography [silica gel; eluent pentane-ethyl acetate (3:1)] provided the
desired product (197 mg, 69%). ^(CDCh) S(ppm): 1.62-1.70 (m, 13H); 2.43 (s,
3H); 2.58 (t, 2H); 4.03 (t, 2H); 7.15 (d, 2H); 7.29-7.33 (m, 4H); 7.72 (s, 1H); 7.77 (d,
2H). 13C (CDC13) 8(ppm): 21.63, 26.98, 27.86, 28.34, 34.80, 66.37, 70.23, 71,81,
118.25, 125.12, 127.32, 127.87, 128.93, 129.82, 132.48, 133.15, 142.40, 144.72,
153.75, 159.05.
Example 2H
Synthesis of 2-tert-butyl-4-chloro-5-(4-(4-fluorobutyl)benzyl)oxy 3(2H)
pyridazinone
KF-K222
N ^X^n^^^ AcN, 90C
\X\^\/^F
"OTs h
The product of Example 2G (57 mg, 0.10 mmol) was dissolved in 1 mL
acetonitrile and to this was added a mixture of KF-K222 (1:1; 0.164 mmol) dissolved
in 1 mL acetonitrile. The entire mixture was then immersed in an oil bath at 90 °C
and heated at reflux for 15 minutes at which point the reaction was shown to be
complete by TLC. The volatile components were removed in vacua and the crude
oil was purified by flash silica gel chromatography (hexanes-ethyl acetate (4:1)) to
provide 28 mg of the desired product as a oil which solidified upon standing. !H
(CDC13) 6(ppm): 1.6 (s, 9H), 1.7 (m, 4H), 2.6 (t, 2H), 4.44 (d of t, 2H, J = 41.4 & 6
Hz), 5.2 (s, 2H), 7.2 (d, 2H, J = 8.4 Hz), 7.3 (d, 2H, J = 8.4 Hz), 7.71 (s, 1H). 13C
(CDC13) 5(ppm): 26.8 (3JCF = 4.65 Hz), 27.8, 29.8(2JCF= 19.8 Hz), 35.1, 66.3,71.8,
83.8 ('JCF = 163.8 Hz), 118.2, 125.1, 127.2, 128.9, 132.3, 142.8, 153, 159.
19F(CDC13, CFC13 as internal standard) 8(ppm): - 218.6 ( t of t, J = -27.6, -50.4)
-37-
Example 3 A
Synthesis of (±)-l-tert-butyldimethylsilyloxy-2-hydroxybutane
TBSCI, Imidazole
H0 OH DMF TBSO OH
A 50mL round bottom flask was charged with (±)-l,2-butanediol (Ig, 1 1.09
mmol) and to it was added dimethylformamide (8mL) followed by tertbutyldimethylsilyl
chloride (2.5g, 16.64 mmol) and imidazole (1.88g, 27.7 mmol).
The reaction mixture was stirred for 10 hours after which it was diluted with
dichloromethane and poured into a separatory funnel and washed with water (80 mL)
and brine and dried over magnesium sulfate. After filtration and concentration the
crude oil was purified by silica gel flash chromatography (hexanes:ethylacetate) to
obtain Igm of pure desired product in 45% yield. *H (CDC^) 8 (ppm): 3.6 (m, IH).
3.5 (m, IH), 3.4 (m, IH), 2.4 (s, IH), 1.44 (m, 2H), 0.99 (t, 3H), 0.9 (s, 9H), 0.06 (s,
6H).
Example 3B
Synthesis of (±)-4-(l-tertbutyldimethylsilyloxy but-2-oxy) methylbenzoate
PPh3, DIAD
TBSO OH THFi oc
\j^"
-OTBS
4-Hydroxymethylbenzoate (l.lg, 7.34 mmol), the product of Example 3A
(0.75g, 3.67 mmol) and triphenylphosphine (1.972 g, 7.34 mmol) were added to a
round bottom flask and 8 mL tetrahydrofuran was added. The flask was cooled in an
ice bath to 0 °C after which diisopropylazodicarboxylate (1.485g, 7.34mmol) was
added via syringe. The reaction mixture was stirred for 2 hours after which the
reaction was deemed complete by thin layer chromatography. All the solvent was
removed under reduced pressure and the crude oil directly subjected to purification
by silica gel flash chromatography (hexanes : diethyl ether) to obtain 1.0 gm (83%)
of the desired compound as a thick oil. 'H (CDC13) 6 (ppm): 7.9 (d, 2H), 6.9 (d, 2H),
4.3 (p, IH, J = 5.4 Hz), 3.9 (s, 3H), 3.7 (2H), 1.78 (m, IH), 1.7 (m, IH), 0.9 (t, 3H, J
= 7.8 Hz), 0.89 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H). 13C (CDC13) 5 (ppm): 166.8,
162.8, 131.5, 122.3, 115.2, 80, 64.5, 51.7, 25.8, 24.1, 18.2, 9.5, -5.3.
- 3 8 -
Example 3C
Synthesis of (±)-4-(l-tertbutyldimethylsilyloxy but-2-oxy) benzylalcohol
MeO,
LAH, Et2O
OTBS
To a solution of the product of Example 3B (Ig, 2.95 mmol) in ether (15mL)
was added lithium aluminum hydride (0.336g, 8.8 mmol) and the mixture was stirred
under nitrogen for 1.5 hours. The reaction was complete as shown by TLC by this
time and was quenched by addition of 0.336 mL water, 0.336 mL of 15% NaOH
solution and 1.00 mL water in succession. The resulting mixture was stirred for an
additional 20 minutes after which the white precipitate formed was filtered and
washed with ether. The filtrate was then dried over magnesium sulfate. Filtration
and removal of the solvent gave 0.50g (54%) of the desired product as a white solid.
'H (CDC13) 5 (ppm): 7.2 (d, 2H), 6.9 (d, 2H), 4.3 (p, IH), 3.77 (d of d, IH), 3.66 (d
of d, IH), 1.77-1.72 (m, IH), 1.68-1.61 (m, IH), 1.5 (t, IH, J = 5.4 Hz), 0.9 (t, 3H, J
= 7.8 Hz), 0.89 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H). 13C (CDC13) 8 (ppm): 158.5, 133,
128.4, 116.1, 80.1, 65, 64.5, 25.8, 24.1, 18.2, 9.5, -5.3
Example 3D
Synthesis of (±)-2-tert-butyl 4-chloro 5-(4-(l-tertbutyldimethylsilyloxy but-2-
oxy) benzyl)oxy 3(2H)-pyridazinone
OTBS
(±)-2-Tert-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone(0.48g, 2.417
mmol) was charged to a 100 mL round bottom flask and tetrahydrofuran (40mL) was
added. After the solution turned clear, Example 3C (0.5g, 1.611 mmol) and
triphenylphosphine (0.633g, 2.417 mmol) were added to the flask and the flask was
cooled to 0°C. Diisopropyl azodicarboxylate (0.488g, 2.417 mmol, 0.468 mL) was
then added via a syringe and the reaction was stirred for two hours after which time it
was shown to be complete by TLC. The contents of the flask were then concentrated
-39-
in vacua and the crude oil obtained was purified by flash chromatography using silica
gel (hexanes:ethyl acetate) to obtain 0.33 g of the desired compound as an oil. *H
(CDC13) 5 (ppm): 7.72 (s, 1H), 7.2 (d, 2H), 6.9 (d, 2H), 5.2 (s, 2H), 4.2 (p, 1H), 3.75
(d of d, 1H), 3.68 (d of d, 1H), 1.75 (m, 2H), 1.65 (m, 1H), 1.6 (s, 9H), 0.99 (t, 3H),
0.85 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H). 13C (CDC13) 6 (ppm): 159.6, 159.3, 154,129,
126.9, 125, 118.5, 116.5, 80.3, 72.1, 66.5, 64.8, 28.1, 26, 24.4, 18.4, 9.6, -5.3
Example 3£
Synthesis of (±)-2-tert-butyl-4-chloro-5-(4-(l-hydroxy-but-2-oxy)benzyl)oxy-
3(2H)-pyridazinone
OTBS TBAFinTHF
To the product of Example 3D (0.3 g, 0.6 mmol) in a 10 mL round bottom
flask was added tetrahydrofuran (2 mL). Upon solution, tetrabutylammonium
fluoride (1.8 mmol, 1.8 mL, IM solution in THF) was added and the reaction mixture
was stirred for 90 minutes. The contents were then concentrated under reduced
pressure and the crude mixture purified by flash chromatography using silica gel
(hexanes:ethyl acetate) to obtain 185 mg (80%) of pure desired product. *H (CDCb)
5 (ppm): 7.74 (s, 1H), 7.3 (d, 2H), 6.9 (d, 2H), 5.2 (s, 2H), 4.3 (m, 1H), 3.81-3.77
(two br s, 2H), 1.84 (br t, 1H), 1.77-1.69 (m, 2H), 1.64 (s, 9H), 0.98 (t, 3H); 13C
(CDC13) 5 (ppm): 159.2, 158.9, 153.9, 129.2, 127.5, 125.4, 116.6, 80.4, 71.9, 66.5,
64.2, 28, 23.5, 9.7.
Example 3F
Synthesis of (±)-2-tert-butyl 4-chloro 5-(4-(l-tosyloxy-but-2-oxy) benzyl)oxy
3(2H)-pyridazinone
o
TsCI, DMAP
DCM, DIEA
Into a 10 mL round bottom flask was added the product of Example 3E
(0.05g, 0.13 mmol) followed by dichloromethane (2 mL). Toluenesulfonyl chloride
-40-
(0.075g, 0.39 mmol), 4-N,N-dimethylaminopyridine (0.048g, 0.39 mmol) and
diisopropylethylamine (0.05g, 0.39 mmol, 68.7(^1) were then added in succession to
the reaction mixture and this was stirred for 35 minutes. Water was then added to the
mixture and the solution poured into a separatory funnel and the layers separated.
The organic layer was washed with water and brine and dried over magnesium
sulfate. The crude oil obtained after filtration and concentration was purified by
silica gel flash chromatography (hexanes:ethyl acetate) to obtain 54 mg (77%) of the
desired compound as a thick colorless oil. ]H (CDC13) 8 (ppm): 7.74 (3H, two
singlets), 7.3 (m, 4H), 6.8 (d, 2H), 5.2 (s, 2H), 4.38 (p, 1H), 4.15 (m, 2H), 2.44 (s,
3H), 1.72 (m, 2H), 1.6 (s, 9H), 0.95 (t, 3H); 13C (CDC13) 8 (ppm): 159.2, 158.5,
153.9, 145.1, 133, 130, 129, 128.1, 127.2, 125.4, 118.5, 116.5, 71.9, 70.2, 66.6, 28.1,
24.2,21.8,9.4.
Example 3G
Synthesis of (±)-2-tert-butyl-4-chloro 5-(4-(l-fluoro-but-2-oxy)benzyl)oxy-3(2H)-
pyridazinone
KF/K222
,OTs
AcN, 90C
The product of Example 3F (28mg, 52.4 |imol) was dissolved in 0.5 mL
acetonitrile in a 5 mL flask and to this was added a solution of potassium fluoride
(4.5 mg, 78.6 ^mol) and Kryptofix 222 (29.6 mg, 78.6 (imol) in 0.5 mL acetonitrile.
The above solution was then immersed in a oil bath preheated to 90 °C. The reaction
was allowed to stir for 90 minutes after which all the volatiles were removed under
reduced pressure and the crude mixture purified by preparative thin layer
chromatography to obtain 13 mg (65%) of pure desired compound. !H (CDC13) 8
(ppm): 7.72 (s, 1H), 7.3 (d, 2H), 6.9 (d, 2H), 5.23 (s, 2H), 4.57-4.59 (m, 2H), 4.4 (m,
4H), 1.74 (m, 2H), 1.6 (s, 9H), 1.0 (t, 3H). 13C (CDC13) 8 (ppm): 159, 158.7, 153.7,
129, 127.5, 125.2, 118.3, 116.4, 83.85 (d, 'jCF = 772.2), 78, 71.1, 66.3, 27.8, 23.2,
9.48. 19F (CDC13, CFC13 as internal standard) S (ppm): -228 (d of t, J =-19, -60 Hz )
-41-
Example 4A
Synthesis of 4-(3-hydroxypropoxy)-benzoic acid methyl ester
K2C03
DMF
HO' ^ O
To a 250 mL flask was added 3-bromo-l-propanol (4.17 g, 0.03 mol),
anhydrous dimethylformamide (40 mL), methyl-4-hydroxybenzoate (3.0 g, 0.02 mol)
and potassium carbonate (4.15 g, 0.03 mol). The flask was placed in a 50 °C oil bath
and stirred for 12 hours. After cooling the reaction was diluted with ethyl acetate,
transferred to separatory funnel, washed with aqueous 0.1 N hydrochloric acid, water
then brine. The organic layer was dried with magnesium sulfate, filtered, and
concentrated under reduced pressure to give 5.14 g of crude oil. Column
chromatography [silica gel; eluent hexanes-ethyl acetate (1.68:1)] provided the
desired product (1.25 g, 30 %) as a white powder. 'H (CDC13) 5(ppm): 2.04-2.08 (m,
2H); 3.86-3.88 (m, 5H); 4.17 (t, 2H); 6.91 (d, 2H); 7.98 (d, 2H); 13C (CDC13) 6(ppm):
31.89, 51.81, 59.88, 65.50, 114.06, 122.67, 131.57, 162.60, 166.84.
Example 46
Synthesis of 4-[3-(tert-Butyldimethylsilanyloxy)propoxy]benzoic acid methyl
ester
TBSCI
imidazole
DMF
O O
To a 50 mL flask was added Example 4A (300 mg, 1.4 mmol), anhydrous
dimethylformamide (4 mL), tert-butyldimethylsilyl chloride (317 mg, 2.1 mmol), and
imidazole (146 mg, 2.1 mmol). The resulting solution was stirred for 2 hours. At
this point the reaction was diluted with ethyl acetate and transferred to a separatory
funnel. The organic phase was washed with aqueous 0.1 N hydrochloric acid(2x),
water(2x), then brine. The organic layer was then dried over magnesium sulfate,
filtered, and concentrated. Column chromatography [silica gel; eluent hexanes-ethyl
acetate (9.5:1)] provided the desired product (413 mg, 91 %). 'H (CDC13) 5(ppm):
0.03 (s, 6H); 0.87 (s, 9H); 1.97-2.01 (m, 2H); 3.79 (t, 2H); 3.87 (s, 3H); 4.11 (t, 2H);
6.90 (d, 2H); 7.97 (d, 2H); 13C (CDC13) 8(ppm): 18.30, 25.89, 32.3, 51.78, 59.27,
-42-
64.67, 114.08, 122.43, 131.56, 162.90, 166.90
Example 4C
Synthesis of {4-[3-(tert-Butyldimethylsilanyloxy)propoxy]phenyl}methanol
LAH
ether
O
Example 4B (396 mg, 1.22 mmol) was added to a dry 50 mL flask along with
anhydrous diethyl ether (10 mL). The flask was lowered into an ice bath. Lithium
aluminum hydride (93 mg, 2.44 mmol) was added in portions to the reaction flask.
The mixture was allowed to stir in the bath for 2 hours. The reaction was quenched
with water (0.093 mL), aqueous 15 % sodium hydroxide (0.093 mL) then water
(0.279 mL). The white solid was filtered off and the filtrate was dried over
magnesium sulfate, filtered, and concentrated to give, the desired product (291 mg, 80
%). 'H(CDC13) 5(ppm): 0.04 (s, 6H); 0.88 (s, 9H); 1.95-1.99 (m, 2H); 3.79 (t, 2H);
4.05 (t, 2H); 4.60 (s, 2H); 6.88-6.89 (m, 2H); 7.25-7.27 (m, 2H); (CDC13) 8(ppm):
18.30, 25.91, 32.41, 59.50, 64.57, 65.10, 114.59, 128.60, 132.97, 158.75.
Example 4D
Synthesis of 2-tert-butyl-4-chloro-5-{4-[3-(tertbutyldimethylsilanyloxy)
propoxy]benzyloxy}-2H-pyridazin-3-one
o
To a dry 25 mL flask was added Example 4C (211 mg, 0.71 mmol) and
anhydrous tetrahydrofuran (3 mL). The flask was cooled in an ice bath. To the flask
was added triphenylphosphine (187 mg, 0.71 mmol) and 2-tert-butyl-4-chloro-5-
hydroxy-2H-pyridazin-3-one (142 mg, 0.71 mmol). Lastly, diisopropyl
azodicarboxylate (144 mg, 0.71 mmol) was added. The reaction mixture was
allowed to stir in the ice bath for 1 hour. At this point the mixture was diluted with
diethyl ether and transferred to a separatory funnel. The organic solution was washed
with water and then brine, dried over magnesium sulfate, filtered, and concentrated
under reduced pressure. Column chromatography [silica gel; eluent hexanes-ethyl
acetate (9:1)] provided the desired product (106 mg, 31 %). *H (CDC13) 8(ppm): 0.03
(s, 6H); 0.87 (s, 9H); 1.62 (s, 9H); 1.95-1.99 (m, 2H); 3.79 (t, 2H); 4.06 (t, 2H); 5.23
-43-
(s, 2H); 6.91-6.92 (m, 2H); 7.30-7.31 (m, 2H); 7.72 (s, 1H); 13C (CDC13) 5(ppm):
18.29, 25.90, 27.87, 32.34, 59.41, 64.63, 66.30, 71.89, 114.90, 118.34, 125.34,
126.68, 128.92, 153.79, 159.07, 159.55
Example 4E
Synthesis of 2-tert-butyl-4-chloro-5-[4-(3-hydroxypropoxy)-benzyloxy]-2Hpyridazin-
3-one
O TBAF o yNN-o- ^ -F
To a scintillation vial containing a suspension of Example 4F (4.5 mg, 8.64 x
10"3 mmol) in anhydrous acetonitrile (0.25 mL) was added a solution of potassium
fluoride (1.6 mg, 4.07 x 10"2 mmol) and kryptofix (15.0 mg, 4.07 x 10~2 mmol) in
anhydrous acetonitrile (0.25 mL). The vial was capped and lowered into a 90 °C oil
bath. The reaction was allowed to stir for 40 minutes. The reaction was cooled and
concentrated under reduced pressure. Preparatory thin layer chromatography [silica
gel; eluent pentane-ethyl acetate (3:2)] provided the desired product (0.8 mg, 25 %).
'H(CDC13) 8(ppm): 1.62 (s, 9H); 2.14-2.20 (m, 2H); 4.09-4.11 (m, 2H); 4.60 (t, 1H);
4.68 (t, 1H); 5.24 (s, 2H); 6.92 (d, 2H); 7.32 (d, 2H); 7.72 (s, 1H); 19F(CDC13, CFC13
as internal standard) 8(ppm): -222.66 (t of t, J = 28.2, -50.4}
Example 5A
Synthesis of 4-(2-hydroxyethoxymethyl)benzoic acid methyl ester
CO2Me CO2Me
BF3- Et20
"OH
To a two-neck round bottom flask, which was equipped with a Dewar
condenser, a solution of 4-hydroxymethylbenzoic acid methyl ester (2.50 g, 0.015
mol) in anhydrous dichloromethane (30 mL) was cooled to -10 °C in a salt/ice bath.
Ethylene oxide (1.10 mL) was added to the cooled stirring solution dropwise
followed by the addition of boron trifluoride etherate (0.51 ml). The reaction mixture
-45-
was stirred for 45 minutes and then warmed to room temperature for 30 minutes to
boil off any excess of ethylene oxide in the reaction mixture. The reaction mixture
was then diluted with brine. The aqueous layer was extracted with dichloromethane
(3 times). All of the organic layers were combined, dried over Na2SC>4, filtered, and
concentrated to provide an oil. The crude material was purified using silica gel
chromatography (4:1 pentane:ethyl acetate) to provide the desired product (537 mg,
2.56 mmol) in 17% yield. !H (CDC138.36, 600 MHz): 8 (2H, d, 7=8.4 Hz), 7.41
(2H, d, 7=8.5 Hz), 4.62 (3H, s), 3.92 (2H, s), 3.78 (m, 2H), 3.63 (2H, m); 13C
(CDC13167.1, 143.5, 130.0, 129.8, 127.5, 72.9, 72.0,, 150 MHz): 5 62.1, 52.3.
Example 5B
Synthesis of 4-[2-(terM>utyldimethylsilanyloxy)ethoxymethyl]benzoic acid
methyl ester
CO2Me CO2Me
TBDMS-CI,
Imidazole, DMF
OTBDMS
To a solution of the product of Example 5A (544.5 mg, 2.59 mmol) in
anhydrous DMF (26 mL) was added imidazole (264 mg, 3.89 mmol) and TBDMS-CI
(586 mg, 3.89 mmol). The reaction mixture stirred at room temperature overnight
and was quenched with water. The aqueous layer was extracted with ethyl acetate
(3x). All combined organic layers were dried over Na2SC>4, filtered, and
concentrated. The crude material was purified using silica gel chromatography (4:1
pentane:ethyl acetate) to provide the desired product (677.5 mg, 2.19 mmol) in 84%
yield. 'H (CDC138.01, 600 MHz): 8 (2H, d, 7=8.3 Hz), 7.42 (2H, d, 7=8.4 Hz), 4.63
(2H, s), 3.91 (2H, s), 3.82 (2H, t, 7=5.0), 3.58 (2H, t, 7=5.1 Hz), 0.91 (9H, s), 0.07
(6H, s); 13C (CDC13166.5, 143.5, 129.2, 128.8, 126.5, 72.1, 71.6,, 150 MHz): 8 62.3,
51.5,25.4, 17.9,-5.8.
-46-
Example SC
Synthesis of {4-[2-(^rt-butyldimethylsilanyIoxy)ethoxymethy!]phenyl}methanoi
CO2Me
LAH, THF,
.OTBDMS k ^\ ^OTBDMS
•ry
To a solution of the product of Example 5B (670 mg, 2.18 mmol) dissolved in
anhydrous THF (22 mL) was added a solution of LAH (1.0 M solution in THF, 2.18
mL, 2.18 mmol) dropwise. After completion of addition the reaction mixture was
stirred at room temperature for 3 hours. The reaction mixture was diluted with water.
The aqueous layer was extracted with ethyl acetate (3x). All combined organic layers
were dried over Na2SO4, filtered, and concentrated to provide an oil (587 mg, 1.98
mmol), which was used in the next step without any further purification (91% yield).
1H (CDC13 7,34 (4H, s), 4.68 (2H, s), 4.57 (2H, s), 3.80, 600 MHz): 5 (2H, t, .7=5.2
Hz), 3.56 (2H, t, 7=5.3 Hz), 1.69 (1H, br s), 0.90 (9H, s), 0.07 (6H, s); !3C (CDCI3
140.4,138.3, 128.0, 127.2, 73.2,71.9, 65.4,, 150 MHz): 5 63.0, 26.2, 18.6, -5.O..
Example 5D
Synthesis of 2-tert'buty]-5-{4-[2-(tertbutyldimethylsilanyIoxy)
ethoxymethyl]benzyloxy}-4-chloro-2flr-pyridazin-3-one
o
•.THF.PPhg \/ 11 r,
OTBDMS i i »n ' i n
N*
To solution of the product of Example 5C (437 mg, 1.48 mmol) and 2-tertbutyj-
4-chloro-5-hydroxy-2//-pyridazin-3-one (250 mg, 1.23 mmol) dissolved in
anhydrous THF (12 mL) was added solid PPh3 (485 mg, 1.85 mmol) and diisopropyl
azodicarboxylate (DIAD, 0.358 mL. 1.85 mmoJ). After completion of addition the
reaction mixture continued to stir at room temperature. After 20 hours, the reaction
mixture was diluted with water. The aqueous layer was separated and extracted with
ethyl acetate (3x). All combined organic layers were dried over Na2SO4, filtered, and
concentrated to provide an oil. The crude material was purified using silica gel
-47-
chromatography (4:1 pentane: ethyl acetate) to provide the desired product 528 mg,
1.10 mmol) in 89% yield. ]H (CDC13 7.70 (1H, s), 7.38 (4H, m), 5.30 (2H, s), 4.58,
600 MHz): 8 (2H, s), 3.80 (2H, t, J= 5.4 Hz), 3.57 (2H, t, 7=5.4 Hz), 1.63 (9H, br s),
0.90 (9H, s), 0.07 (6H, s); 13C (CDC13159.0, 153.7, 138.8, 134.4, 128.3, 127.3,, 150
MHz): 8 125.1, 118.5, 72.8, 71.7, 71.6, 66.4, 61.9, 29.7, 27.9, 25.6, -5.1.; HRMS
calcd for C24H37ClN2O4Si: 481.228389, found 481.2282.
Example 5E
Synthesis of 2- te/?-butyl-4-chloro-5-[4-(2-hydroxyethoxymethyl)benzyloxy]-2//-
pyridazin-3-one
OTBDMS
TBAF, THF
To a solution of the product of Example 5D (528 mg, 1.09 mmol) dissolved in
anhydrous THF (11 mL) was added a solution of TBAF (1.0 M solution in THF, 1.65
mL, 1.65 mmol) dropwise. After completion of addition the reaction was stirred at
room temperature for 1 hour and then quenched with water. The aqueous layer was
separated and extracted with ethyl acetate (3x). All combined organic layers were
dried over Na2SC>4, filtered, and concentrated to provide an oil. The crude material
was purified using silica gel chromatography (4:1 hexanes: ethyl acetate) to provide
the desired product (311 mg, 0.850 mmol) in 78% yield. 'H (CDC13, 600 MHz): 8
7.70 (1H, s), 7.38 (4H, m), 5.30 (2H, s), 4.56 (2H, s), 3.76 (2H, t, 7=4.9 Hz), 3.60
(2H, t, 7=4.8 Hz), 2.00 (1H, br s), 1.61 (9H, br s); 13C (CDC13159.0, 153.6,, 150
MHz): 8 138.8, 134.4, 128.2, 127.2, 125.1, 118.3, 72.8, 71.6, 71.6, 66.4, 61.9, 27.8;
HRMS calcd for C18H23C1N2O4: 367.141911, found 367.1419.
Example 5F
Synthesis of toluene-4-sulfonic acid 2-[4-(l-fc?/f-butyl-5-chloro-6-oxo-l,6-
dihydro-pyridazin-4-yloxymethyl)-benzyloxy]-ethyl ester
TsCI, TEA,
DMAP, DCM
To a solution of the product of Example 5E (200 mg, 0.546 mmol) dissolved
OTs
-48-
in anhydrous dichloromethane (5.50 mL) was added TsCl (125 mg, 0.656 mmol),
DMAP (100 mg, 0.819 mmol) and triethylamine (0.091 mL, 0.656 mmol). The
reaction mixture continued stirring at room temperature. After 22 hours the reaction
mixture was diluted with water. The aqueous layer was separated and extracted with
ethyl acetate (3x). All combined organic layers were dried over Na2SC>4, filtered, and
concentrated to provide an oil. The crude material was purified using silica gel
chromatography (3:2 pentane:ethyl acetate) to provide the desired product (232 mg,
0.447 mmol) in 82% yield. ]H (CDC137.79, 600 MHz): 5 (2H, d, 7=8.3 Hz), 7.71
(1H, s), 7.38 (2H, d, 7=8.2 Hz), 7.32 (4H, m), 5.30 (2H, s), 4.50 (2H, s), 4.21 (2H,
m), 3.69 (2H, m), 2.43 (3H, s), 1.63 (9H, br s); 13C (CDC13 159.0, 153.7, 144.8,
138.8,, 150 MHz): 5 134.4, 133.1, 129.8, 128.1, 128.0, 127.2, 125.1, 118.4,72.8,
71.7, 69.2, 67.8, 66.4, 27.9, 21.6; HRMS calcd for C25H29C1N2O6: 521.150762, found
521.1503.
Example 5G
Synthesis of 2-terf-butyl-4-chloro-5- [4-(2-fluoro-ethoxymethyl)-benzyloy]-2//-
pyridazin-3-one
OTs
KF, Kryptofix,
ACN
To a solution of the product of Example 5F (50 mg, 0.096 mmol) in
anhydrous acetonitrile (1.0 mL) was added KF (1 1.2 mg, 0.192 mmol) and Kryptofix
(72.4 mg, 0.192 mmol). After completion of addition the reaction mixture was
heated to 90 °C. After 10 minutes, the reaction mixture was cooled down to room
temperature and diluted with water. The aqueous layer was separated and extracted
with ethyl acetate (3x). All combined organic layers were dried over Na2SO4,
filtered, and concentrated to provide an oil. The crude material was purified using
silica gel chromatography (4:1 pentane: ethyl acetate) to provide the desired product
(28 mg, 0.076 mmol) in 79% yield. !H (DMSO-d6, 600 MHz): 8 8.22 (1H, s), 7.45
(2H, d, 7=8.20 Hz), 7.39 (2H, d, 7=8.24 Hz), 5.42 (2H, s), 4.60 (1H, m), 4.54 (2H,
s), 4.52 (1H, m), 3.71 (1H, m), 3.66 (1H, m), 1.57 (9H, s); 13 157.8, 153.8, 138.6,C
(DMSO-d6, 150MHz): 8 134.6, 127.8, 127.7, 126.2, 115.6, 83.5 (82.4), 71.6, 71.2,
69.1 (69.0), 65.3, 27.4; I9F (DMSO-d6-221.74 (IF, m)., 564 MHz): 8 HRMS calcd
-49-
for s: 369.137575, found 369.1377.
Example 6A
Synthesis of l-(4-hydroxymethyIphenoxy)propan-2-one
o
Acetone
To a stirred solution of 4-hydroxybenzyl alcohol (1.0 g, 8.06 mmol) in
acetone (80 mL) was added potassium carbonate (1.34 g, 9.68 mmol) and
chloroacetone (0.771 mL, 9.68 mmol). After completion of addition the reaction
mixture was heated to reflux. After 20 hours the reaction mixture was cooled down
to room temperature and the solvent was removed. Water and ethyl acetate were
added to the crude material. The aqueous layer was separated and extracted with
ethyl acetate (3x, 100 mL). All combined organic layers were dried over Na2SC>4,
filtered, and concentrated to provide an oil. The crude material was purified using
silica gel chromatography (gradient from 4:1 to 1:1 pentane:ethyl acetate) to provide
the desired product (0.981 g, 5.45 mmol) in 98% yield. 1H (CDC13, 600 MHz): 5
7.30 (2H, d, 7=8.7 Hz), 6.87 (2H, d, 7=8.7 Hz), 4.63 (2H, d, 7=5.7 Hz), 4.54 (2H, s),
2.27 (3H, s), 1.66 (1H, t, 7=5.8 Hz); 13C (CDC13, 150 MHz): 5 205.7, 157.3, 134.3,
128.8,114.6,73.1,64.8,26.6.
Example 6B
Synthesis of l-(4-hydroxymethyl-phenoxy)-propan-2-ol:
.OH
NaBH4, MeOH
To a solution of l-(4-hydroxymethylphenoxy)-propan-2-one (1.26 g, 6.99
mmol) dissolved in methanol (60 mL) was added solid NaBHU (0.32 g, 8.39 mmol).
-50-
After completion of addition the reaction mixture was stirred at room temperature
overnight. The reaction mixture was diluted with water, and the aqueous layer was
extracted with ethyl acetate (3x). All combined organic layers were dried over
Na2SC>4, filtered, and concentrated to provide an oil (1.24 g, 6.81 mmol), which was
used in the next step without any further purification (98% yield). *H (CDCl3?.29,
600 MHz): 5 (2H, d, 7=8.4 Hz), 6.90 (2H, d, 7=8.5 Hz), 4.62 (2H, s), 4.21 (1H, m),
3.94 (1H, dd, 7=9.2, 3.1 Hz), 3.82 (1H, m), 1.29 (3H, d, 7=6.4 Hz).
Example 6C
Synthesis of 2-terf-butyl-4-chloro-5- [4-(2-hydroxypropoxy)benzyloxy] -2Hpyridazin-
3-one
o
To solution of the product of Example 6B (269 mg, 1.48 mmol) and 2-tertbutyl-
4-chloro-5-hydroxy-2//-pyridazin-3-one (250 mg, 1.23 mmol) dissolved in
anhydrous THF (18.5 mL) was added solid PPh3 (485 mg, 1.85 mmol) and DIAD
(0.358 mL, 1.85 mmol). After completion of addition the reaction mixture continued
to stir at room temperature. After 20 hours, the reaction mixture was diluted with
water. The aqueous layer was separated and extracted with ethyl acetate (3x). All
combined organic layers were dried over NaaSC^, filtered, and concentrated to
provide an oil. The crude material was purified using silica gel chromatography (1:1
pentane:ethyl acetate) to provide the desired product (234 mg, 0.634 mmol) in 51%
yield. 'H (CDC13 7.71 (1H, s), 7.33 (2H, d,, 600 MHz): 5 7=8.7 Hz), 6.94 (2H, d,
7=8.7 Hz), 5.24 (2H, s), 4.19 (1H, m), 3.95 (1H, dd, 7=9.2, 3.1 Hz), 3.81 (1H, dd,
7=9.2, 7.7 Hz), 1.62 (9H, s) 1.29 (3H, d, 7=6.4 Hz).

CLAIMS
1. A low dielectric loss material comprising a plurality of polyolefin tapes forming
a sheet and a coating disposed onto said sheet, wherein said coating
5 comprises an epoxy resin
2. The material of claim 1 wherein said plurality of polyolefin tapes comprises at
least one woven layer of tapes.
3. The material of any one of the preceding claims wherein the polyolefin tapes
comprise ultra high molecular weight polyethylene tapes.
10 4. The material of any one of the preceding claims wherein the tensile strength of
the polyolefin tapes is at least 0.3 GPa.
5. The material of any one of the preceding claims wherein said sheet is a
multilayered sheet comprising a plurality of monolayers containing tapes.
6. The material of any one of the preceding claims wherein said sheet is free of
15 any matrix or binder.
7. The material of any one of the preceding claims wherein said sheet is a
consolidated sheet.
8. A low dielectric loss material comprising a plurality of polyolefin tapes forming
a sheet, said sheet containing at least one primed surface, said at least one
20 primed surface being primed with a primer comprising a thermosetting resin,
wherein a coating is disposed onto said primed surface of said sheet, wherein
said coating comprises an epoxy resin.
9. The material of claim 5 wherein the primer is a one-component aqueous
adhesive primer which contains little or no volatile organic compounds.
25 10. An assembly comprising a high frequency antenna emitting and/or receiving a
high frequency electromagnetic radiation and an antenna housing comprising
walls and an opening to allow at least part of the electromagnetic radiation to
be received and/or emitted by said antenna without interference with said
walls wherein said opening is at least partially covered by the material of any
30 one of claims 1-6.