Note: Descriptions are shown in the official language in which they were submitted.
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THERAPEUTIC SUBSTITUTED CYCL
FOR REDUCING INTRAOCULAR F
By Inventors
David W. Old, Vinh X. Ngo, Mark Holoboski and Mari F. Posner
CROSS REFERENCE
This application claims the benefit of U.S. Application serial number
60/947,904, filed July 03, 2007,
which is hereby incorporated by reference in its entirety.
BACKGROUND
[1] Ocular hypotensive agents are useful in the treatment of a number of
various ocular hypertensive
conditions, such as post-surgical and post-laser trabeculectomy ocular
hypertensive episodes, glaucoma, and
as presurgical adjuncts.
[2] Glaucoma is a disease of the eye characterized by increased intraocular
pressure. On the basis of its
etiology, glaucoma has been classified as primary or secondary. For example,
primary glaucoma in adults
(congenital glaucoma) may be either open-angle or acute or chronic angle-
closure. Secondary glaucoma
results from pre-existing ocular diseases such as uveitis, intraocular tumor
or an enlarged cataract.
[3] The underlying causes of primary glaucoma are not yet known. The increased
intraocular tension is
due to the obstruction of aqueous humor outflow. In chronic open-angle
glaucoma, the anterior chamber and
its anatomic structures appear normal, but drainage of the aqueous humor is
impeded. In acute or chronic
angle-closure glaucoma, the anterior chamber is shallow, the filtration angle
is narrowed, and the iris may
obstruct the trabecular meshwork at the entrance of the canal of Schlemm.
Dilation of the pupil may push the
root of the iris forward against the angle, and may produce pupilary block and
thus precipitate an acute attack.
Eyes with narrow anterior chamber angles are predisposed to acute angle-
closure glaucoma attacks of various
degrees of severity.
[4] Secondary glaucoma is caused by any interference with the flow of aqueous
humor from the posterior
chamber into the anterior chamber and subsequently, into the canal of Schlemm.
Inflammatory disease of the
anterior segment may prevent aqueous escape by causing complete posterior
synechia in iris bombe, and may
plug the drainage channel with exudates. Other common causes are intraocular
tumors, enlarged cataracts,
central retinal vein occlusion, trauma to the eye, operative procedures and
intraocular hemorrhage.
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[5] Considering all types together, glaucoma occurs in about 2% of all persons
over the age of 40 and
may be asymptotic for years before progressing to rapid loss of vision. In
cases where surgery is not indicated,
topical R-adrenoreceptor antagonists have traditionally been the drugs of
choice for treating glaucoma.
[6] Certain eicosanoids and their derivatives are currently commercially
available for use in glaucoma
management. Eicosanoids and derivatives include numerous biologically
important compounds such as
prostaglandins and their derivatives. Prostaglandins can be described as
derivatives of prostanoic acid which
have the following structural formula:
7 5 3 1
9 COOH
8 2/
14 16 18
12
11
[7] 13 15 17 19
[8] Various types of prostaglandins are known, depending on the structure and
substituents carried on the
alicyclic ring of the prostanoic acid skeleton. Further classification is
based on the number of unsaturated
bonds in the side chain indicated by numerical subscripts after the generic
type of prostaglandin [e.g.
prostaglandin El (PGEj), prostaglandin E2 (PGE2)], and on the configuration of
the substituents on the
alicyclic ring indicated by a or 0 [e.g. prostaglandin F2a (PGF20)].
DESCRIPTION OF THE INVENTION
[9] Disclosed herein are compounds having a formula
Ul
A Y
B
U2
wherein a dashed line represents the presence or absence of a bond;
2
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Y is an organic acid functional group, or an amide or ester thereof; or Y is
hydroxymethyl or an ether thereof;
or Y is a tetrazolyl functional group;
A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C=C-(CH2)3-, wherein 1 or 2
carbon atoms may be replaced
by S or 0; or A is -(CH2)m-Ar-(CH2)o- wherein Ar is interarylene or
heterointerarylene, the sum of m and o is
1, 2, 3, or 4, and wherein 1 -CH2- may be replaced by S or 0, and 1 -CH2-CH2-
may be replaced by -CH=CH-
or -C=C-;
U' and U2 are independently selected from -H, =0, -OH, -F, -Cl, and -CN; and
B is aryl or heteroaryl.
[10] These compounds are useful for the treatment of glaucoma and the
reduction of intraocular
pressure. The compound is incorporated into a dosage form or a medicament and
administered to the
mammal, such as a person, in need thereof. For example, a liquid composition
may be administered as an
eye drop or a solid or liquid dosage form may also be administered orally.
Other types of dosage forms and
medicaments are well known in the art, and may also be used here.
[11] Another embodiment is a composition comprising a compound disclosed
herein, wherein said
composition is a liquid which is ophthalmically acceptable.
[12] Another embodiment is a medicament comprising a compound disclosed
herein, wherein said
medicament is a liquid which is ophthalmically acceptable.
[13] Another embodiment is a method comprising administering a compound
disclosed herein to a
mammal for the treatment of glaucoma or elevated intraocular pressure.
[14] Another embodiment is a kit comprising a composition comprising compound
disclosed herein, a
container, and instructions for administration of said composition to a mammal
for the treatment of glaucoma
or elevated intraocular pressure.
[15] Methods of formulating compounds such as those disclosed herein for
ophthalmic and other
pharmaceutical preparations are well known in the art. For example, United
States Patent Application No.
10/599,046, filed on September 18, 2006, incorporated by reference herein,
describes typical formulation
methods.
[16] For the purposes of this disclosure, "treat," "treating," or "treatment"
refer to the use of a compound,
composition, therapeutically active agent, or drug in the diagnosis, cure,
mitigation, treatment, or prevention
of disease or other undesirable condition.
[17] Unless otherwise indicated, reference to a compound should be construed
broadly to include
pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms,
non-covalent complexes, and
combinations thereof, of a chemical entity of the depicted structure or
chemical name.
[18] A pharmaceutically acceptable salt is any salt of the parent compound
that is suitable for
administration to an animal or human. A pharmaceutically acceptable salt also
refers to any salt which may
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form in vivo as a result of administration of an acid, another salt, or a
prodrug which is converted into an acid
or salt. A salt comprises one or more ionic forms of the compound, such as a
conjugate acid or base,
associated with one or more corresponding counter-ions. Salts can form from or
incorporate one or more
deprotonated acidic groups (e.g. carboxylic acids), one or more protonated
basic groups (e.g. amines), or
both (e.g. zwitterions).
[19] A prodrug is a compound which is converted to a therapeutically active
compound after
administration. While not intending to limit the scope of the invention,
conversion may occur by hydrolysis of
an ester group or some other biologically labile group. Prodrug preparation is
well known in the art. For
example, "Prodrugs and Drug Delivery Systems," which is a chapter in Richard
B. Silverman, Organic
Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press:
Amsterdam, 2004, pp. 496-
557, provides further detail on the subject.
[20] Tautomers are isomers that are in rapid equilibrium with one another. For
example, tautomers may
be related by transfer of a proton, hydrogen atom, or hydride ion.
[21] Unless stereochemistry is explicitly depicted, a structure is intended to
include every possible
stereoisomer, both pure or in any possible mixture.
[22] Alternate solid forms are different solid forms than those that may
result from practicing the
procedures described herein. For example, alternate solid forms may be
polymorphs, different kinds of
amorphous solid forms, glasses, and the like.
[23] Non-covalent complexes are complexes that may form between the compound
and one or more
additional chemical species that do not involve a covalent bonding interaction
between the compound and the
additional chemical species. They may or may not have a specific ratio between
the compound and the
additional chemical species. Examples might include solvates, hydrates, charge
transfer complexes, and the
like.
[24] Since the compounds have several potential stereocenters, several
stereoisomers are possible.
Therefore, compounds such as those having the structures shown below are
contemplated.
U Ul Ul ~
A-Y
~\oA-Y AY
---- B
, - , ------- -B -----~B
U2 u2 u2
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Ul
,,\\\A-Y
-----~B
U2
[25] Double bonds can be cis or trans. Therefore, compounds according to the
structural depictions
below are contemplated.
Ul Ul
It
A Y A Y
B B
, - ~
U2 U2
[26] Since a dashed line represents the presence or absence of a bond,
compounds according to the
formula below are also contemplated.
Ul
A Y
~ B
~
~
[27] U 2
[28] Y is an organic acid functional group, or an amide or ester thereof; or Y
is hydroxymethyl or an ether
thereof; or Y is a tetrazolyl functional group. For the purposes of this
disclosure, Y is limited to from 0 to 14
carbon atoms and any necessary hydrogen atoms.
[29] An organic acid functional group is an acidic functional group on an
organic molecule. While not
intending to be limiting, organic acid functional groups may comprise an oxide
of carbon, sulfur, or
phosphorous. Thus, while not intending to limit the scope of the invention in
any way, in certain compounds
Y is a carboxylic acid, sulfonic acid, or phosphonic acid functional group.
[30] Esters and amides of organic functional groups are carbonyl groups
directly attached to a nitrogen
or oxygen atom. Thus, esters of amides of carboxylic acids, sulfonic acid, and
phosphonic acid functional
groups are depicted below.
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Acids Esters Amides
0 0 0
V OH V OR ~ NR'R2
carboxylic acid carboxylic acid ester carboxylic acid amide
0 % //' ~0 % //0
OH V/S\OR S\NR1R2
sulfonic acid sulfonic acid ester sulfonic acid amide
0~ ~O H ~O H ~~
~~ /O H
OH v---- P---- OR P-~' NR'R2
phosphonic acid phosphonic acid ester phosphonic acid amide
[31] An amide may also have a--S02- moiety. For example the amide -CONHS02R3,
wherein R3 is a
hydrocarbyl of from 1 to 14 carbon atoms, is contemplated. R, R1, R2, and R3
are hydrocarbyl subject to the
constraint that Y may not have more than 14 carbon atoms.
[32] An ether of hydroxymethyl is -CH2OR.
[33] An unsubstituted tetrazolyl functional group has two tautomeric forms,
which can rapidly interconvert
in aqueous or biological media, and are thus equivalent to one another. These
tautomers are shown below.
IIN NH
N ~/N
[34] H N
[35] Additionally, if R2 is C1-C6 alkyl, phenyl, or biphenyl, other isomeric
forms of the tetrazolyl functional
group such as the one shown below are also possible, unsubstituted and
hydrocarbyl substituted tetrazolyl up
to C12 are considered to be within the scope of the term "tetrazolyl."
N ~~ II
N
[36] R
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[37] In one embodiment, Y is C02R4, CONR5R6, CON(CH2CH2OH)2, CONH(CH2CH2OH),
CH2OH,
P(O)(OH)2, CONHS02R4, S02NR5R6,
N
N
II
N I
N
1 \
R4 or N R4;
wherein R4, R5 and R6 are independently H, C1-C6 alkyl, unsubstituted phenyl,
or unsubstituted biphenyl,
provided that Y has no more than 14 carbon atoms.
[38] A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C=C-(CH2)3-, wherein 1 or 2
carbon atoms may be
replaced by S or 0; or A is -(CH2)m-Ar-(CH2)o- wherein Ar is interarylene or
heterointerarylene, the sum of m
and o is 1, 2, 3, or 4, and wherein 1 -CH2- may be replaced by S or 0, and 1 -
CH2-CH2- may be replaced by -
CH=CH- or -C=C-.
[39] Thus, A may be -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C=C-(CH2)3-.
[40] Alternatively, A may be a group which is related to one of these three
moieties in that any carbon is
replaced with S or 0. For example, A may be a moiety where S replaces one or
two carbon atoms such as
one of the following or the like.
[41] Alternatively, A may be a moiety where 0 replaces one or two carbon atoms
such as one of the
following or the like.
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0
/110 All0'" 0-1~/
[42] Alternatively, A may have an 0 replacing one carbon atom and an S
replacing another carbon atom,
such as one of the following or the like.
A-1oA" sl-*'~~ o-1~~/
[43] Alternatively, in certain embodiments A is -(CH2)m-Ar-(CH2)o- wherein Ar
is interarylene or
heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein 1 -CH2-
may be replaced by S or 0, and 1
-CH2-CH2- may be replaced by -CH=CH- or -C=C-. In other words,
[44] in one embodiment A comprises:
1) a) 1, 2, 3, or 4 -CH2- moieties, or
b) 0, 1 or 2 -CH2- moieties and -CH=CH- or -C=C-; and
2) Ar;
e.g. -CH2-Ar-, -(CH2)2-Ar-, -CH=CH-Ar-, -C=C-Ar-, -CH2-Ar-CH2-, -CH2Ar-(CH2)2-
, -CH2Ar-CH=CH-, -
CH2Ar-C=C-, -(CH2)2-Ar-(CH2)2-, and the like;
[45] in another embodiment A comprises:
1) a) 0; and 0, 1, 2, or 3 -CH2- moieties; or
b) 0; and 0 or 1 -CH2- moieties and -CH=CH- or -C=C-; and
2) Ar;
e.g., -0-Ar-, -Ar-CH2-0-, -0-Ar-(CH2)2-, -OAr-CH=CH-, -0-Ar-C=C-,-0-CH2-Ar-, -
0-CH2-Ar-(CH2)2, -0-
CH2Ar-CH=CH-, -0-CH2Ar-C=C-,and the like; or
[46] in another embodiment A comprises:
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1) a) S; and 0, 1, 2, or 3 -CH2- moieties; or
b) S; and 0 or 1 -CH2- moieties and -CH=CH- or -C=C-; and
2) Ar;
e.g., -S-Ar-, -Ar-CH2-S-, -S-Ar-(CH2)2-, -SAr-CH=CH-, -S-Ar-C=C-,-S-CH2-Ar-, -
S-CH2-Ar-(CH2)2, -S-
CH2Ar-CH=CH-, -S-CH2Ar-C=C-, and the like.
[47] In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH2
may be replaced with S or
0 and 1 -CH2-CH2- may be replaced by -CH=CH- or -C=C-.
[48] In another embodiment, the sum of m and o is 3 wherein one CH2 may be
replaced with S or 0 and
1 -CH2-CH2- may be replaced by -CH=CH- or -C=C-.
[49] In another embodiment, the sum of m and o is 2 wherein one CH2 may be
replaced with S or 0 or 1
-CH2-CH2- may be replaced by -CH=CH- or -C=C-.
[50] In another embodiment, the sum of m and o is 4 wherein one CH2 may be
replaced with S or 0 and
1 -CH2-CH2- may be replaced by -CH=CH- or -C=C-.
[51] Interarylene or heterointerarylene refers to an aryl ring or ring system
or a heteroaryl ring or ring
system which connects two other parts of a molecule, i.e. the two parts are
bonded to the ring in two distinct
ring positions. Interarylene or heterointerarylene may be substituted or
unsubstituted. Unsubstituted
interarylene or heterointerarylene has no substituents other than the two
parts of the molecule it connects.
Substituted interarylene or heterointerarylene has substituents in addition to
the two parts of the molecule it
connects.
[52] In one embodiment, Ar is substituted or unsubstituted interphenylene,
interthienylene, interfurylene,
interpyridinylene, interoxazolylene, and interthiazolylene. In another
embodiment Ar is interphenylene (Ph).
In another embodiment A is -(CH2)2-Ph-. Substitutents of Ar each have from 0
to 4 carbon atoms, from 0 to 3
oxygen atoms, from 0 to 2 sulfur atoms, from 0 to 2 nitrogen atoms, from 0 to
3 fluorine atoms, from 0 to 1
chlorine atoms, from 0 to 1 bromine atoms, from 0 to 1 iodine atoms, and from
0 to 10 hydrogen atoms.
[53] In another embodiment A is -CH2-Ar-OCH2-. In another embodiment A is -CH2-
Ph-OCH2-. In
another embodiment, Ph is attached at the 1 and 3 positions, otherwise known
as m-interphenylene, such as
when A has the structure shown below.
H2C Cll CHA
I 2
[54]
[55] In another embodiment A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C=C-
(CH2)8-, wherein 1 or 2
carbon atoms may be replaced with S or 0; or A is -(CH2)2-Ph- wherein one -CH2-
may be replaced with S or
0.
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[56] In another embodiment A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C=C-
(CH2)8-, wherein 1 or 2
carbon atoms may be replaced with S or 0; or A is -(CH2)2-Ph-.
[57] In one embodiment, Ar is thienyl.
[58] In other embodiments, A has one of the following structures.
0
S 0
N-% N N
s S
tit-,,,, -,,(~ 0
V'0 %.'0 S j
V^o X S '`'.
oy~ ~ S~~ ~. ~ o~~ S
0 ~/'
N
o S
s o
[59] In another embodiment A is -CH2OCH2Ar-.
[60] In another embodiment A is -CH2SCH2Ar-.
[61] In another embodiment A is -(CH2)3Ar-.
[62] In another embodiment A is -CH2O(CH2)4-.
[63] In another embodiment A is -CH2S(CH2)4-.
[64] In another embodiment A is -(CH2)6-.
[65] In another embodiment A is cis -CH2CH=CH-(CH2)8-.
[66] In another embodiment A is -CH2C=C-(CH2)8-.
[67] In another embodiment A is -S(CH2)8S(CH2)2-.
[68] In another embodiment A is -(CH2)40CH2-.
[69] In another embodiment A is cis -CH2CH=CH-CH2OCH2-.
[70] In another embodiment A is -CH2CH=CH-CH2OCH2-.
[71] In another embodiment A is -(CH2)2S(CH2)8-.
[72] In another embodiment A is -CH2-Ph-OCH2-, wherein Ph is interphenylene,.
[73] In another embodiment A is -CH2-mPh-OCH2-, wherein mPh is m-
interphenylene.
[74] In another embodiment A is -CH2-0-(CH2)4-.
[75] In another embodiment A is -CH2-0-CH2-Ar-, wherein Ar is 2,5-
interthienylene.
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[76] In another embodiment A is -CH2-0-CH2-Ar-, wherein Ar is 2,5-
interfurylene.
[77] In another embodiment A is (3-methylphenoxy)methyl.
[78] In another embodiment A is (4-but-2-ynyloxy)methyl.
[79] In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.
[80] In another embodiment A is 2-(3-propyl)thiazol-5-yl.
[81] In another embodiment A is 3-(methoxymethyl)phenyl.
[82] In another embodiment A is 3-(3-propylphenyl).
[83] In another embodiment A is 3-methylphenethyl.
[84] In another embodiment A is 4-(2-ethyl)phenyl.
[85] In another embodiment A is 4-phenethyl.
[86] In another embodiment A is 4-methoxybutyl.
[87] In another embodiment A is 5-(methoxymethyl)furan-2-yl .
[88] In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.
[89] In another embodiment A is 5-(3-propyl)furan-2-yl.
[90] In another embodiment A is 5-(3-propyl)thiophen-2-yl.
[91] In another embodiment A is 6-hexyl.
[92] In another embodiment A is (Z)-6-hex-4-enyl.
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[93] U' and U2 are independently selected from -H, =0, -OH, -F, -Cl, and -CN.
Thus, the compounds
depicted in the structural formulas below are contemplated.
O F
A- Y A-Y rA-Y
~rB
B B
U2 U2 Uz
C N H
rA-Y A-Y A-Y
-B ----g
U2 Uz Uz
U U
A-Y
A-Y A-Y
----- B B ------B
O F
Ul Ul Ul
A- Y
A-Y A-Y
----- B B ----- -B
CI NC HO
[94] In one embodiment, U' is Cl and U2 is OH.
[95] B is substituted aryl or heteroaryl.
[96] Aryl is an aromatic ring or ring system such as phenyl, naphthyl,
biphenyl, and the like.
[97] Heteroaryl is aryl having one or more N, 0, or S atoms in the ring, i.e.
one or more ring carbons are
substituted by N, 0, and/or S. While not intending to be limiting, examples of
heteroaryl include thienyl,
pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, and the
like.
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[98] The substituents of B each have from 0 to 6 carbon atoms, from 0 to 3
oxygen atoms, from 0 to 2
sulfur atoms, from 0 to 2 nitrogen atoms, from 0 to 3 fluorine atoms, from 0
to 1 chlorine atoms, from 0 to 1
bromine atoms, from 0 to 1 iodine atoms, and from 0 to 14 hydrogen atoms.
[99] The substituents on B may be the same or different. For example, B might
have 2 chloro
substituents, or B might have a chloro and a hydroxymethyl substituent.
[100] The substituents of Ar and B are independent, but the types of
substituents contemplated are
similar. Thus, subject to the constraints described herein (i.e. limits on the
number of atoms for a
substituent), examples of substituents for Ar and B include, but are not
limited to:
[101] Hydrocarbyl, meaning a moiety consisting of carbon and hydrogen only,
including, but not limited to:
a. alkyl, meaning hydrocarbyl having no double or triple bonds, including, but
not limited to:
= linear alkyl, e.g. methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,
etc.,
= branched alkyl, e.g. iso-propyl, t-butyl and other branched butyl isomers,
branched pentyl
isomers, etc.,
= cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.,
= combinations of linear, branched, and/or cycloalkyl;
b. alkenyl, e.g. hydrocarbyl having 1 or more double bonds, including linear,
branched, or
cycloalkenyl
c. alkynyl, e.g. hydrocarbyl having 1 or more triple bonds, including linear,
branched, or
cycloalkenyl;
d. combinations of alkyl, alkenyl, and/or akynyl
[102] alkyl-CN, such as -CH2-CN, -(CH2)2-CN; -(CH2)3-CN, and the like;
[103] hydroxyalkyl, i.e. alkyl-OH, such as hydroxymethyl, hydroxyethyl, and
the like;
[104] ether substituents, including -0-alkyl, alkyl-0-alkyl, and the like;
[105] thioether substituents, including -S-alkyl, alkyl-S-alkyl, and the like;
[106] amine substituents, including -NH2, -NH-alkyl,-N-alkyl'alkyl2 (i.e.,
alkyl' and alkyl2 are the same or
different, and both are attached to N), alkyl-NH2, alkyl-NH-alkyl, alkyl-N-
alkyl'alkyl2, and the like;
[107] aminoalkyl, meaning alkyl-amine, such as aminomethyl (-CH2-amine),
aminoethyl, and the like;
[108] ester substituents, including -C02-alkyl, -C02_phenyl, etc.;
0
[109] other carbonyl substituents, including aldehydes; ketones, such as acyl
(i.e. ~(Khydrocarbyl
)and the like; in particular, acetyl, propionyl, and benzoyl substituents are
contemplated;
[110] phenyl or substituted phenyl;
[111] fluorocarbons or hydroflourocarbons such as -CFB, _CH2CF8, etc.; and
[112] -CN;
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[113] combinations of the above are also possible, subject to the constraints
defined;
[114] Alternatively, a substituent may be -F, -Cl, -Br, or -I.
[115] In particular, alkyl having from 1 to 6 carbon atoms is contemplated as
a substituent.
[116] Alternatively, alkyl having from 1 to 4 carbon atoms is contemplated;
[117] Substituents must be sufficiently stable to be stored in a bottle at
room temperature under a normal
atmosphere for at least 12 hours, or stable enough to be useful for any
purpose disclosed herein.
[118] If a substituent is a salt, for example of a carboxylic acid or an
amine, the counter-ion of said salt,
i.e. the ion that is not covalently bonded to the remainder of the molecule is
not counted for the purposes of
the number of heavy atoms in a substituent. Thus, for example, the salt -C02
Na+ is a stable substituent
consisting of 1 carbon atom and 2 oxygen atoms, i.e. sodium is not counted. In
another example, the salt -
NH(Me)2+CI- is a stable substituent consisting of 1 nitrogen atom, three
carbon atoms, and 7 hydrogen atoms,
i.e. chlorine is not counted.
[119] In one embodiment, B is substituted or unsubstituted phenyl or
pyridinyl.
[120] In one embodiment the substituents of B are Cl, F, CH3, CH2OH, or OH.
[121] Another embodiment is a compound having a formula
Ul
A Y
B
U2
wherein a dashed line represents the presence or absence of a bond;
Y is an organic acid functional group, or an amide or ester thereof; or Y is
hydroxymethyl or an ether thereof;
or Y is a tetrazolyl functional group;
A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C=C-(CH2)3-, wherein 1 or 2
carbon atoms may be replaced
by S or 0; or A is -(CH2)m-Ar-(CH2)o- wherein Ar is interarylene or
heterointerarylene, the sum of m and o is
1, 2, 3, or 4, and wherein 1-CH2- may be replaced by S or 0, and 1-CH2-CH2-may
be replaced by -CH=CH-
or -C=C-;
U' and U2 are independently selected from -H, =0, -OH, -F, -Cl, and -CN; and
B is aryl or heteroaryl,
provided that if U' is =0, U2 is not -OH or -H.
[122] Another embodiment is a compound having a formula
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Ul
A Y
B
U2
wherein a dashed line represents the presence or absence of a bond;
Y is an organic acid functional group, or an amide or ester thereof; or Y is
hydroxymethyl or an ether thereof;
or Y is a tetrazolyl functional group;
A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C=C-(CH2)3-, wherein 1 or 2
carbon atoms may be replaced
by S or 0; or A is -(CH2)m-Ar-(CH2)o- wherein Ar is interarylene or
heterointerarylene, the sum of m and o is
1, 2, 3, or 4, and wherein 1 -CH2- may be replaced by S or 0, and 1 -CH2-CH2-
may be replaced by -CH=CH-
or -C=C-;
U' is -H, -OH, -F, -Cl, or-CN;
U2 is -H, =0, -OH, -F, -Cl, or -CN; and
B is aryl or heteroaryl.
[123] Another embodiment is a compound having a formula
Ul
S
Y
B
U2
wherein a dashed line represents the presence or absence of a bond;
Y is an organic acid functional group, or an amide or ester thereof; or Y is
hydroxymethyl or an ether thereof;
or Y is a tetrazolyl functional group;
U' and U2 are independently selected from -H, =0, -OH, -F, -Cl, and -CN; and
B is aryl or heteroaryl.
[124] In another embodiment U' is =0.
[125] In another embodiment U' is -H.
[126] In another embodiment U' is -OH.
[127] In another embodiment U' is -F.
[128] In another embodiment U' is -Cl.
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[129] In another embodiment U' is -CN.
[130] In another embodiment U2 is =0.
[131] In another embodiment U2 is -H.
[132] In another embodiment U2 is -OH.
[133] In another embodiment U2 is -F.
[134] In another embodiment U2 is -Cl.
[135] In another embodiment U2 is -CN.
[136] Another embodiment is a compound having a formula
CI
,,O~\\A Y
B
HO
[137] In another embodiment, B is substituted with substituents selected from
F, Cl, C,_3 alkyl, and
hydroxyalkyl having from 1 to 3 carbon atoms.
[138] In another embodiment, B is selected from
CI ~
I ~ \ CI
CI
HO CI N
~ I CI / F
/ N
\ 1::
CI , and
[139] Another embodiment is a compound selected from:
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CI 0
OH CI O
O H
CI
H O CI
N
HO /
CI , N
CI 0 O
S C
\ OH S OH
CI \
HO
HO
HO , F
CI O CI 0
S S
\ / OH \ / OH
F CI
HO I HO
N
F , CI
CI 0
S CI 0
\ OH S OH
CI
HO I I \
/ HO
CI and
[140] Some hypothetical examples of useful compounds are shown below.
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CI 0 C C
S ,.~ S . S
/ OH / OH \ / OH
CI a
, \
CI` F I
N
CI CI CI
0
S .`` S OH ,,. S
/ OH ~ I OH
\ CI F CI
HO ,
HO I I/ F`
F
HO HO
CI
S S
OH a:s/OH
CI CI CI
O
N \
HO / N N
C N C
,X S ` \ S
OH S OH \ / OH
~
CI \
NC N HO I HO I/ N
/N
CI a G
CI C C
OH .`` S/ OH
F CI
HO HO
HO / OH HO /
F
F F F
C CI S
C O
S
~ OH S
OH
~ / OH F
HO H
HO O /
CN
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0 CI
c ~
OH JOH OH
CI CI CI
HO HO HO N
/N
CI CI CI O
C CI OH
CI
OH OH
N CH3
F ~ I \ CI ci
HO HO
HO
F HO F
C
C C S
OH S OH h OH
HO HO I / HO N
N N CI
C CI
CI S
``\ OH .`` OH
OH CI
I \ \ CI
CI
HO HO
HO N N
T7N/
SH C02H
CI N CI
CI S ,N \
` S OH H S/ OH
~ ~ ; I \ F F
HO
HO / HO
F F
CI CI
CI S
~S~ H/\ OH OH
~ ~\ r \
\ HO HO
HO NH2
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[141] Synthetic Methods
Scheme 1
HQ ~O
S COzMe S COzMe
MsC 0~~ TBAC, PhMe
~OTBS
THPO CHzCIz
THPO 2
1
ci ci
5:ro- S/ COzMe Swern
+ OH
THPO THPO 4
3
TBAF, THF
ci
S COzMe ci S COzMe
K2C03, DMF PPTs, MeOH
O ci
THPO PhsP, ~ ci THPO /
~
cl / 6 ci
CI
ci S ci
COzMe S COzMe
LiOH \
~ ci H20, THF ~ CI
7 ci 8 ci
Example 1
5-(3-((1 R,2R,3R,5R)-5-chloro-2-(3,5-dichlorostyryl)-3-hydroxycyclopentyl)prop-
1-enyl)thiophene-2-carboxylic
acid (8)
Step 1. Mesylation of 1 to give 2
Triethylamine (4.2 mL, 30.0 mmol) and methanesulfonyl chloride (1.9 mL, 24.1
mmol) were added
sequentially to a solution of 1(see US Prov. Pat. App. No. 60/805,285, 10.1 g,
19.9 mmol) in CH2CI2 (100
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mL) at 0 C. The reaction mixture was allowed to warm to room temperature and
stirred at room temperature
for 3 h. Saturated aqueous NaHCO3 (400 mL) was added and the mixture was
extracted with CH2CI2 (3x400
mL). The combined organic extracts were washed with water (200 mL) and brine
(200 mL), then dried
(MgS04), filtered and concentrated in vacuo to afford 11.5 g (-98%) of the
desired mesylate 2, which was
used without further purification.
Step 2. Conversion of mesylate 2 to chloride 3 and alcohol 4
Tetrabutylammonium chloride (26.5 g, 95.4 mmol) was added to a solution of 2
(11.5 g, 19.5 mmol) in toluene
(200 mL). The reaction mixture was heated at 45 C for 18 h. TLC analysis
indicated that much of the
starting mesylate remained, so the reaction mixture was heated at 50 C for 4
h. The cooled mixture was
partitioned between water (200 mL) and EtOAc (500 mL). The phases were
separated and the organic
phase was washed with water (4x200 mL). The combined aqueous phase was back-
extracted with EtOAc
(350 mL). The combined organic phase was dried (MgSOa), filtered and
concentrated in vacuo. Purification
of the crude residue by chromatography on 120 g silica gel (hexane -> EtOAc,
gradient) afforded 2.6 g (25%)
of chloride 3 and 1.8 g (22%) of alcohol 4.
Step 3. Desilylation of 3 to give alcohol 4
Tetrabutylammonium fluoride (14.7 mL of a 1.0 M THF solution, 14.7 mmol) was
added to a solution of 3 (2.6
g, 4.91 mmol) in THF (15 mL) at room temperature. After 18 h at room
temperature, the reaction mixture was
partitioned between EtOAc (50 mL) and water (50mL). The phases were separated
and the organic phase
was washed with water (3x5OmL). The combined aqueous phase was back-extracted
with EtOAc (100 mL).
The combined organic phase was dried (MgSOa), filtered and concentrated in
vacuo. Purification of the
crude residue by chromatography on 40 g silica gel (hexane -> EtOAc, gradient)
afforded 1.23 g (60%) of
alcohol 4.
Step 4. Oxidation of 4 to give 5
DMSO (1.5 mL, 21.1 mmol) was added to a solution of oxalyl chloride (4.4 mL of
a 2.0 M solution in CH2CI2,
8.8 mmol) in CH2CI2 (5 mL) at - 78 C. After 30 min, a solution of alcohol 4
(3.03 g, 7.30 mmol) in CH2CI2 (42
mL) was added slowly via syringe. After 15 min at - 78 C, triethylamine (9.0
mL, 64.6 mmol) was added.
After 1.5 h at - 78 C, the reaction was allowed to warm to room temperature.
After 2 h at room temperature
the reaction mixture was partitioned between saturated aqueous NaHCO3 (100 mL)
and CH2CI2 (300 mL).
The phases were separated and the aqueous phase was extracted with CH2CI2
(2x200 mL). The combined
extracts were dried (MgS04), filtered and concentrated in vacuo to afford -
3.0 g of crude aldehyde 5, which
was used without further purification.
Step 5. Wittig reaction of 5 to afford diene 6
Potassium carbonate (99.99%, 5.0 g, 36.2 mmol) and 3,5-
dichlorophenylmethyltriphenylphosphonium
chloride (see Cullen, et al., US 5,536,725, 6.7 g, 14.6 mmol) were added to a
solution of aldehyde 5 (crude
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from previous step, -3.0 g, -7.3 mmol) in DMF (73 mL) at room temperature.
After 18 h the reaction mixture
was partitioned between water (100 mL) and EtOAc (300 mL). The phases were
separated and the organic
phase was washed with water (9x100 mL). The combined aqueous phase was back-
extracted with EtOAc
(300 mL). The combined organic phase was dried (MgSOa), filtered and
concentrated in vacuo. Purification
of the crude residue by chromatography on silica gel (CH2CI2) afforded 3.0 g
(74%) of diene 6.
Step 6. Deprotection of 6 to give 7
Pyridinium p-toluenesulfonate (PPTs, 550 mg, 2.19 mmol) was added to a
solution of 6 (3.0 g, 5.40 mmol) in
methanol (100 mL) at room temperature under nitrogen. The solution was heated
at 40 C for 18 h, then
cooled and concentrated in vacuo. Purification of the crude residue by
chromatography on 12 g silica gel
(CH2CI2) afforded 1.7 g (67%) of alcohol 7 as a mixture of olefin isomers.
Step 7. Saponification of 7 to give 8
Lithium hydroxide (0.89 mL of a 1.0 M aqueous solution, 0.89 mmol) was added
to a solution of ester 7 (84
mg, 0.18 mmol) in THF (0.89 mL). The solution was heated at 40 C for 18 h,
then cooled to room
temperature. The mixture was partitioned between 1.0 M aqueous HCI (5 mL) and
EtOAc (5mL). The
phases were separated and the organic phase was washed with water (5 mL),
dried (MgS04), filtered and
concentrated in vacuo. Purification of the crude residue by chromatography on
4 g silica gel (CH2CI2 -> 10%
MeOH/ CH2CI2, gradient) afforded 48 mg (59%) of the title compound as a
mixture of olefin isomers.
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Scheme 2
cl cl
~`,= OCOzMe Swern ,,. \/ COzMe K2C03, DMF
\//~ ~ +
THP6 Ph3P^Ar
9 THPO 10 X-
CI CI
S COzMe COzMe
V \
Ar
THPO THPO
11 a-i 12a-i
PPTs, MeOH PPTs, MeOH
CI CI
S COzMe COzMe
Ar
^Ar
Hd Hd
13a-i 14a-i
LiOH, H20, THF LiOH, H20, THF
CI CI
S COzH COzH
Ar
Hd Hd
15a-i 16a-i
Example 2
5-(3-((1 R,2R,3R,5R)-5-chloro-2-(3-chloro-5-(hydroxymethyl)styryl)-3-
hydroxycyclopentyl)propyl)-thiophene-2-
carboxylic acid (15a)
Step 1. Oxidation of 9 to give 10
DMSO (32 L, 0.45 mmol) was added to a solution of oxalyl chloride (0.1 mL of
a 2.0 M solution in CH2CI2,
0.2 mmol) in CH2CI2 (0.3 mL) at - 78 C. After 30 min, a solution of alcohol 9
(see US Prov. Pat. App. No.
60/805,285, 70 mg, 0.17 mmol) in CH2CI2 (0.54 mL) was added via syringe. After
15 min at- 78 C,
triethylamine (187 L, 1.34 mmol) was added and the reaction was allowed to
warm to room temperature.
After 5 h at room temperature the reaction mixture was partitioned between
saturated aqueous NaHCO3 (10
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mL) and CH2CI2 (20 mL). The phases were separated and the aqueous phase was
extracted with CH2CI2
(2x10 mL). The combined organic phase was dried (MgSOa), filtered and
concentrated in vacuo to afford 69
mg of crude aldehyde 10, which was used without further purification.
Step 2. Wittig reaction of 10 to afford 11a
Potassium carbonate (99.99%, 232 mg, 1.68 mmol) was added to a solution of
aldehyde 10 (crude from
previous step, 69 mg, -0.17 mmol) and 3-chloro-5-
(hydroxymethyl)benzyltriphenylphosphonium chloride
(Preparation 1, 150 mg, 0.33 mmol) in DMF (1.6 mL) at room temperature. After
18 h the reaction mixture
was partitioned between water (30 mL) and EtOAc (50 mL). The phases were
separated and the organic
phase was washed with water (3x30 mL) and brine (30 mL) then dried (MgS04),
filtered and concentrated in
vacuo. Purification of the crude residue by chromatography on 4 g silica gel
(hexane -> EtOAc, gradient)
afforded 35 mg (38%) of alkene 11a (contaminated with -5% cis-olefin 12a).
Step 3. Deprotection of 11a to give 13a
PPTs (16 mg, 0.006 mmol) was added to a solution of 11a (35 mg, 0.06 mmol) in
methanol (0.6 mL) at room
temperature under nitrogen. The solution was heated at 40 C for 18 h, then
cooled and concentrated in
vacuo. Purification of the crude residue by chromatography on 4 g silica gel
(hexane -> EtOAc, gradient)
afforded 28 mg (94%) of alcohol 13a (contaminated with -5% cis-olefin 14a).
Step 4. Saponification of 13a to give 15a
Lithium hydroxide (0.04 mL of a 1.0 M aqueous solution, 0.04 mmol) was added
to a solution of ester 13a (5
mg, 0.011 mmol) in THF (0.05 mL). After 18 h, the mixture was partitioned
between 1.0 M aqueous HCI (1
mL) and CH2CI2 (5 mL). The phases were separated and the aqueous phase was
extracted with CH2CI2 (5
mL). The combined organic phase was dried (MgS04), filtered and concentrated
in vacuo. Purification of the
crude residue by chromatography on 4 g silica gel (CH2CI2 -> 20% MeOH/ CH2CI2,
gradient) afforded 3 mg
(62%) of the title compound (contaminated with -5% cis-olefin 16a).
Example 3
5-(3-((1 R,2R,3R,5R)-5-chloro-2-((E)-2-(5-chloropyridin-3-yl)vinyl)-3-
hydroxycyclopentyl)propyl)-thiophene-2-
carboxylic acid (15b)
Step 1. Wittig reaction of 10 to afford 11 b
In accordance with the procedure of example 2, step 2, aldehyde 10 (190 mg,
0.46 mmol) and ((5-chloro-3-
pyridinyl)methyl)triphenylphosphonium chloride (Preparation 2, 100 mg, 0.24
mmol) were converted into 104
mg (84%) of alkene 11b (contaminated with -5% cis-olefin 12b).
Step 2. Deprotection of 11 b to give 13b
In accordance with the procedure of example 2, step 3, THP-ether 11 b(104 mg,
0.20 mmol) was converted
into 40 mg (46%) of alkene 13b (contaminated with -5% cis-olefin 14b).
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Step 3. Saponification of 13b to give 15b
In accordance with the procedure of example 2, step 4, ester 13b (10 mg, 0.023
mmol) was converted into 3
mg (31%) of the title compound (contaminated with -5% cis-olefin 16b).
Example 4
5-(3-((1 R,2R,3R,5R)-5-chloro-2-((E)-2-(2,6-dichloropyridin-4-yl)vinyl)-3-
hydroxycyclopentyl)propyl)-thiophene-
2-carboxylic acid (15c)
Step 1. Wittig reaction of 10 to afford 11c and 12c
In accordance with the procedure of example 2, step 2, aldehyde 10 (290 mg,
0.70 mmol) and ((2,6-dichloro-
4-pyridinyl)methyl)triphenylphosphonium chloride (Preparation 3, 325 mg, 0.71
mmol) were converted into
200 mg (51%) of alkene 11c and 8 mg (2%) of alkene 12c and 108 mg (28%) of a
mixture of 11c and 12c.
Step 2. Deprotection of 11c112c to give 13c114c
In accordance with the procedure of example 2, step 3, a mixture of 11c and
12c (229 mg, 0.41 mmol) was
converted into 169 mg (87%) of alkene 13c and 22 mg (11%) of alkene 14c.
Step 3. Saponification of 13c to give 15c
Lithium hydroxide (0.23 mL of a 1.0 M aqueous solution, 0.23 mmol) was added
to a solution of ester 13c (14
mg, 0.029 mmol) in THF (0.46 mL). After 66 h, the mixture was concentrated
under a stream of nitrogen,
diluted with water (2 mL) and acidified with 1.0 M aqueous HCI (1 mL). The
mixture was extracted with
EtOAc (3xlOmL). The combined organic phase was washed with brine (5 mL), dried
(Na2S04), filtered and
concentrated in vacuo. Purification of the crude residue by chromatography on
4 g silica gel (CH2CI2 -> 15%
MeOH/ CH2CI2, gradient) afforded 4.5 mg (33%) of the title compound.
Example 5
5-(3-((1 R,2R,3R,5R)-5-chloro-2-((Z)-2-(2,6-dichloropyridin-4-yl)vinyl)-3-
hydroxycyclopentyl)propyl)-thiophene-
2-carboxylic acid (16c)
In accordance with the procedure of example 4, step 3, ester 14c (22 mg, 0.046
mmol) was converted into
3.5 mg (16%) of the title compound, employing a reaction time of 18 h.
Example 6
5-(3-((1 R,2R,3R,5R)-5-chloro-2-((E)-3,5-difluorostyryl)-3-
hydroxycyclopentyl)propyl)thiophene-2-carboxylic
acid (15d)
Step 1. Wittig reaction of 10 to afford 11d and 12d
In accordance with the procedure of example 2, step 2, aldehyde 10 (250 mg,
0.60 mmol) and ((3,5-
difluorophenyl)methyl)triphenylphosphonium chloride (Preparation 4, 422 mg,
0.90 mmol) were converted
into 200 mg (63%) of an inseparable mixture of alkenes 11d and alkene 12d.
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Step 2. Deprotection of 11d112d to give 13d114d
In accordance with the procedure of example 2, step 3, a mixture of 11d and
12d (200 mg, 0.38 mmol) was
converted into 120 mg (71 %) of alkene 13d and 20 mg (12%) of alkene 14d.
Step 3. Saponification of 13d to give 15d
In accordance with the procedure of example 2, step 4, ester 13d (20 mg, 0.045
mmol) was converted into 5
mg (26%) of the title compound.
Example 7
5-(3-((1 R,2R,3R,5R)-5-chloro-2-((Z)-3,5-difluorostyryl)-3-
hydroxycyclopentyl)propyl)thiophene-2-carboxylic
acid (16d)
In accordance with the procedure of example 2, step 4, ester 14d (20 mg, 0.045
mmol) was converted into
3.9 mg (20%) of the title compound.
Example 8
5-(3-((1 R,2R,3R,5R)-5-chloro-2-(3,5-dimethylstyryl)-3-
hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid
(15e)
Step 1. Wittig reaction of 10 to afford 11e
In accordance with the procedure of example 2, step 2, aldehyde 10 (250 mg,
0.60 mmol) and ((3,5-
dimethylphenyl)methyl)triphenylphosphonium chloride (Preparation 5, 375 mg,
0.90 mmol) were converted
into 250 mg (80%) of alkene 11e (contaminated with -10% cis-olefin 12e).
Step 2. Deprotection of 11e to give 13e
In accordance with the procedure of example 2, step 3, 11e (250 mg, 0.48 mmol)
was converted into 195 mg
(93%) of alkene 13e (contaminated with -10% cis-olefin 14e).
Step 3. Saponification of 13e to give 15e
In accordance with the procedure of example 2, step 4, ester 13e (10 mg, 0.023
mmol) was converted into 3
mg (31 %) of the title compound (contaminated with -10% cis-olefin 16e).
Preparation 1
(3-Chloro-5-(hydroxymethyl)benzyl)triphenylphosphonium chloride
Step 1. Methyl 3-chloro-5-(hydroxymethyl)benzoate
Sodium borohydride (1.1 g, 29.1 mmol) was added to a solution of dimethyl 5-
chloroisophthalate (2.0 g, 8.7
mmol) in methanol (10 mL) and CH2CI2 (10 mL). The reaction mixture was heated
at 35 C for 18 h then
cooled to room temperature. The mixture was treated with water (50 mL) and
extracted with CH2CI2 (3x200
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mL). The combined organic phase was dried (MgSOa), filtered and concentrated
in vacuo to afford crude
methyl 3-chloro-5-(hydroxymethyl)benzoate that was used without further
purification.
Step 2. Methyl 3-((tert-butyldimethylsilyloxy)methyl)-5-chlorobenzoate
Imidazole (3.6 g, 52.9 mmol) and TBSCI (4.0 g, 26.5 mmol) were added to a
solution of crude methyl 3-
chloro-5-(hydroxymethyl)benzoate (-8.7 mmol) in DMF (100 mL). After 18 h the
reaction mixture was
partitioned between water (100 mL) and EtOAc (200 mL). The phases were
separated and the organic
phase was washed with water (4x100 mL) and brine (100 mL) then dried (MgSOa),
filtered and concentrated
in vacuo to afford crude methyl 3-((tert-butyldimethylsilyloxy)methyl)-5-
chlorobenzoate that was used without
further purification.
Step 3. (3-((tert-Butyldimethylsilyloxy)methyl)-5-chlorophenyl)methanol
Sodium borohydride (1.1 g, 29.1 mmol) was added to a solution of crude methyl
3-((tert-
butyldimethylsilyloxy)methyl)-5-chlorobenzoate (-8.7 mmol) in methanol (10 mL)
and CH2CI2 (10 mL). After
18 h at room temperature, the reaction mixture was concentrated in vacuo.
Citric acid (5% aqueous, 50 mL)
was added and the mixture was extracted with CH2CI2 (50 mL). The organic phase
was washed with water
(50 mL) and brine (50 mL), then dried (MgSOa), filtered and concentrated in
vacuo. Purification of the crude
residue by chromatography on 12 g silica gel (hexanes -> EtOAc, gradient)
afforded 920 mg (37% over
three steps) of (3-((tert-butyldimethylsilyloxy)methyl)-5-
chlorophenyl)methanol.
Step 4. tert-B utyl-(3-chloro-5-(chloromethyl)benzyloxy)d imethylsi lane
Triethylamine (0.78 mL, 5.6 mmol) and methanesulfonyl chloride (0.31 mL, 4.0
mmol) were added to a
solution of (3-((tert-butyldimethylsilyloxy)methyl)-5-chlorophenyl)methanol
(460 mg, 1.6 mmol) in CH2CI2 (1.6
mL) at 0 C and the mixture was allowed to warm to room temperature. After 18 h
at room temperature, the
reaction was treated with saturated aqueous NaHCO3 (50 mL) and extracted with
CH2CI2 (3x20 mL). The
combined organic phase was dried (MgS04), filtered and concentrated in vacuo.
Purification of the crude
residue by chromatography on 4 g silica gel (hexanes -> EtOAc, gradient)
afforded 100 mg (20%) of tert-
butyl-(3-chloro-5-(ch loromethyl)benzyloxy)di methylsi lane.
Step 5. 3-Chloro-5-(hydroxymethyl)benzyl)triphenylphosphonium chloride
Triphenylphosphine (128 mg, 0.49 mmol) was added to a solution of tert-butyl-
(3-chloro-5-
(chloromethyl)benzyloxy)d i methylsi lane (100 mg, 0.33 mmol) in toluene (0.6
mL) and the reaction mixture
was heated to 100 C. After 18 h the reaction was cooled to room temperature
and the solid material was
isolated by filtration. After washing with excess toluene and drying in vacuo,
150 mg (quant.) of the title
compound was isolated as a colorless solid.
Preparation 2
((5-Chloro-3-pyridinyl)methyl)triphenylphosphonium chloride
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Step 1. Methyl 5-chloronicotinate
Concentrated H2S04 (105 L, 1.26 mmol) was added to a solution of 5-
chloronicotinic acid (1.0 g, 6.35 mmol)
in methanol (12.7 mL) and the mixture was heated at reflux. After 18 h, the
mixture was cooled to room
temperature then partitioned between water (200 mL) and CH2CI2 (200 mL) and
carefully neutralized with
solid K2CO3. The phases were separated and the aqueous phase was extracted
with CH2CI2 (200 mL). The
combined organic phase was dried (MgSOa), filtered and concentrated in vacuo
to afford 1.2 g of crude
methyl 5-chloronicotinate that was used without further purification.
Step 2. (5-Chloropyridin-3-yl)methanol
Sodium borohydride (790 mg, 20.9 mmol) was added to a solution of crude methyl
5-chloronicotinate (-6.35
mmol) in methanol (10 mL) and CH2CI2 (10 mL). After 18 h at room temperature,
the reaction mixture was
concentrated in vacuo. Water (50 mL) was added and the mixture was extracted
with CH2CI2 (3x50 mL).
The organic phase was dried (MgSOa), filtered and concentrated in vacuo. .
Purification of the crude residue
by chromatography on 40 g silica gel (hexanes -> EtOAc, gradient) afforded 510
mg (56% over two steps) of
(5-chloropyridin-3-yl)methanol.
Step 3. 3-Chloro-5-(chloromethyl)pyridine
Triethylamine (1.75 mL, 12.6 mmol) and methanesulfonyl chloride (0.69 mL, 8.9
mmol) were added to a
solution of (5-chloropyridin-3-yl)methanol (510 mg, 3.6 mmol) in CH2CI2 (3.5
mL) at 0 C and the reaction was
allowed to warm to room temperature. After 18 h at room temperature, the
reaction was partitioned between
water (50 mL) and CH2CI2 (50 mL). The phases were separated and the organic
phase was extracted with
CH2CI2 (20 mL). The combined organic phase was dried (MgS04), filtered and
concentrated in vacuo.
Purification of the crude residue by chromatography on 12 g silica gel
(hexanes -> EtOAc, gradient) afforded
300 mg (52%) of 3-chloro-5-(chloromethyl)pyridine.
Step 4. ((5-Chloro-3-pyridinyl)methyl)triphenylphosphonium chloride
In accordance with the procedure of preparation 1, step 5, 3-chloro-5-
(chloromethyl)pyridine (300 mg, 1.85
mmol) was converted into 100 mg (13%) of the title compound.
Preparation 3
((2,6-Dichloro-4-pyridinyl)methyl)triphenylphosphonium chloride
In accordance with the procedure of preparation 1, step 5, 2,6-dichloro-4-
(chloromethyl)pyridine (1.0 g, 5.1
mmol) was converted into 2.0 g (86%) of the title compound.
Preparation 4
((3,5-Difluorophenyl)methyl)triphenylphosphonium chloride
In accordance with the procedure of preparation 1, step 5, 1-(bromomethyl)-3,5-
difluorobenzene
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(1.0 g, 4.8 mmol) was converted into 1.8 g (79%) of the title compound.
Preparation 5
((3,5-Dimethylphenyl)methyl)triphenylphosphonium chloride
Step 1. 1-(Chloromethyl)-3,5-dimethylbenzene
Triethylamine (7.2 mL, 51.7 mmol) and methanesulfonyl chloride (2.86 mL, 36.8
mmol) were added to a
solution of (3,5-dimethylphenyl)methanol (2.0 g, 14.7 mmol) in CH2CI2 (25 mL)
at 0 C and the mixture was
allowed to warm to room temperature. After 18 h at room temperature, the
reaction was treated with
saturated aqueous NaHCO3 (100 mL) and extracted with CH2CI2 (3x100 mL). The
combined organic phase
was washed with brine (100 mL), dried (MgS04), filtered and concentrated in
vacuo. Purification of the crude
residue by chromatography on 40 g silica gel (hexanes -> EtOAc, gradient)
afforded 1.5 g (66%) of 1-
(chloromethyl)-3,5-dimethylbenzene.
Step 2. ((3,5-dimethylphenyl)methyl)triphenylphosphonium chloride
In accordance with the procedure of preparation 1, step 5, 1-(chloromethyl)-
3,5-dimethylbenzene (1.5 g, 9.7
mmol) was converted into 600 mg (15%) of the title compound.
This procedure may be readily adapted by a person of ordinary to obtain a
variety of other
compounds. For example, United States Provisional Patent Application Serial
No. 60/806,947, filed on July
11, 2006, incorporated by reference herein, describes methods that may be
adapted to prepare compounds
with a variety of different moieties for A, U' and U2.
Preparation 6
((3-(But-3-enyl)phenyl)methyl)triphenylphosphonium chloride
Step 1. (3-(but-3-enyl)phenyl)methanol
LiAIH4 (10.0 mL of a 1.0 M solution in THF, 10.0 mmol) was added to a 0 C
solution of ethyl 3-(but-3-
enyl)benzoate (commercially available from Reike Metals, Inc., 1.94 g, 9.5
mmol) in THF (35 mL). After 2 h
at 0 C the reaction was carefully quenched with water (50 mL). 10% aqueous
NaOH (50 mL) was added
and the mixture was extracted with CH2CI2 (3x50 mL). The extracts were washed
with brine (50 mL) then
dried (MgS04), filtered and concentrated in vacuo. Purification of the crude
residue by chromatography on 40
g silica gel (hexanes -> EtOAc, gradient) afforded 1.7 g (somewhat impure,
quant. crude) of (3-(but-3-
enyl)phenyl)methanol.
Step 2. 1-(but-3-enyl)-3-(chloromethyl)benzene
Triethylamine (2.0 mL, 14.4 mmol) and methanesulfonyl chloride (0.90 mL, 11.6
mmol) were added to a
solution of (3-(but-3-enyl)phenyl)methanol (- 9.5 mmol) in CH2CI2 (20 mL) at 0
C and the mixture was
allowed to warm to rt. After 18 h at rt, the reaction was treated with
saturated aqueous NaHCO3 (50 mL) and
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extracted with CH2CI2 (3x50 mL). The combined organic phase was washed with
brine (50 mL), dried
(MgSOa), filtered and concentrated in vacuo. Purification of the crude residue
by chromatography on 40 g
silica gel (hexanes -> EtOAc, gradient) afforded 1.6 g (93%) of 1-(but-3-enyl)-
3-(chloromethyl)benzene.
Step 3. ((3-(but-3-enyl)phenyl)methyl)triphenylphosphonium chloride
In accordance with the procedure of preparation 1, step 5, 1-(but-3-enyl)-3-
(chloromethyl)benzene (1.6 g, 8.9
mmol) was converted into 2.2 g (56%) of the title compound.
Example 9
5-(3-((1 R,2R,3R,5R)-2-(3-(but-3-enyl)styryl)-5-chloro-3-
hydroxycyclopentyl)propyl)thiophene-2-carboxylic
acid (15f)
Step 1. Wittig reaction of 10 to afford 11f
In accordance with the procedure of example 2, step 2, aldehyde 10 (250 mg,
0.60 mmol) and ((3-(but-3-
enyl)phenyl)methyl)triphenylphosphonium chloride (Preparation 6, 450 mg, 1.02
mmol) were converted into
220 mg (67%) of alkene 11f (contaminated with -5% cis-olefin 12f).
Step 2. Deprotection of 11f to give 13f
In accordance with the procedure of example 2, step 3, THP-ether 11f (220 mg,
0.41 mmol) was converted
into 164 mg (88%) of alkene 13f (contaminated with -5% cis-olefin 14f).
Step 3. Saponification of 13f to give 15f
In accordance with the procedure of example 2, step 4, ester 13f (30 mg, 0.065
mmol) was converted into 8.3
mg (29%) of the title compound (15f, contaminated with -5% cis-olefin 16f).
Preparation 7
(E)-(3-chloro-5-(prop-l-enyl)benzyl)triphenylphosphonium bromide
Step 1. methyl 3-chloro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)benzoate
Dihydropyran (1.5 mL, 16.4 mmol) and PPTs (290 mg, 1.15 mmol) were added to a
solution of methyl 3-
chloro-5-(hydroxymethyl)benzoate (see preparation 1, step 1, 1.30 g, 6.5 mmol)
in CH2CI2 (20 mL). The
mixture was heated at 40 C. After 18 h, the reaction mixture was cooled,
concentrated in vacuo, and
purified by chromatography on 40 g silica gel (hexanes -> EtOAc, gradient) to
afford 1.80 g, (98%) of methyl
3-ch loro-5-((tetrahydro-2 H-pyran-2-yloxy)methyl )benzoate.
Step 2. (3-chloro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)methanol
Sodium borohydride (834 mg, 22.0 mmol) was added to a solution of methyl 3-
chloro-5-((tetrahydro-2H-
pyran-2-yloxy)methyl)benzoate (1.80 g, 6.3 mmol) in methanol (20 mL) and
CH2CI2 (20 mL). After 3 d at rt,
the reaction mixture was concentrated in vacuo. Water (100 mL) was added and
the mixture was extracted
with CH2CI2 (3xlOOmL). The organic phase was washed with brine (100 mL), dried
(MgS04), filtered and
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concentrated in vacuo. Purification of the crude residue by chromatography on
40 g silica gel (hexanes ~
EtOAc, gradient) afforded 790 mg (49%) of (3-chloro-5-((tetrahydro-2H-pyran-2-
yloxy)methyl)phenyl)methanol.
Step 3. 3-chloro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)benzaldehyde
DMSO (0.70 mL, 9.06 mmol) was added to a solution of oxalyl chloride (2.0 mL
of a 2.0 M solution in CH2CI2,
4.0 mmol) in CH2CI2 (3 mL) at - 78 C. After 1 h at - 78 C, a solution of (3-
chloro-5-((tetrahydro-2H-pyran-
2-yloxy)methyl)phenyl)methanol (600 mg, 2.33 mmol) in CH2CI2 (6 mL) was added
slowly via syringe. After 5
min at - 78 C, triethylamine (2.4 mL, 17.2 mmol) was added and the reaction
was allowed to warm to room
temperature. After 3 h the reaction mixture was partitioned between saturated
aqueous NaHCO3 (50 mL)
and CH2CI2 (150 mL). The phases were separated and the aqueous phase was
extracted with CH2CI2 (2x50
mL). The combined extracts were dried (MgS04), filtered and concentrated in
vacuo to afford of crude 3-
chloro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)benzaldehyde, which was used
without further purification.
Step 4. (E)-2-(3-chloro-5-(prop-l-enyl)benzyloxy)tetrahydro-2H-pyran
Potassium t-butoxide (1.11 g, 9.89 mmol) was added to a solution of
ethyltriphenylphosphonium bromide
(2.39 g, 6.44 mmol) in THF (20 mL) at 0 C. To this red/orange mixture was
added a solution of crude 3-
chloro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)benzaldehyde (- 2.33 mmol) in
THF (20 mL) at 0 C. After 5
min, the reaction mixture was partitioned between 0.1 N HCI (50 mL) and CH2CI2
(200 mL). The phases
were separated and the aqueous phase was extracted with CH2CI2 (3x100 mL). The
combined organic
phase was washed with brine (100 mL), dried (MgSOa), filtered and concentrated
in vacuo. Purification of the
crude residue by chromatography on 40 g silica gel (hexanes -> EtOAc,
gradient) afforded 400 mg (64%) of
(E)-2-(3-chloro-5-(prop-l-enyl)benzyloxy)tetrahydro-2H-pyran.
Step 5. (E)-(3-chloro-5-(prop-l-enyl)phenyl)methanol
In accordance with the procedure of example 2, step 3, (E)-2-(3-chloro-5-(prop-
l-enyl)benzyloxy)tetrahydro-
2H-pyran (470 mg, 1.76 mmol) was converted into 240 mg (75%) of (E)-(3-chloro-
5-(prop-1-
enyl)phenyl)methanol.
Step 6. (E)-1 -(bromomethyl)-3-chloro-5-(prop-1 -enyl)benzene
Bromine (72 L, 1.40 mmol) was added to a solution of triphenylphosphine (415
mg, 1.58 mmol) and
imidazole (110 mg, 1.62 mmol) in CH2CI2 (1.5 mL) at 0 C. After 15 min, a
solution of (E)-(3-chloro-5-(prop-l-
enyl)phenyl)methanol (240 mg, 1.31 mmol) in CH2CI2 (4.5 mL) was added. After
30 min at 0 C, the reaction
mixture was concentrated in vacuo. Purification of the crude residue by
chromatography on 40 g silica gel
(hexanes -> EtOAc, gradient) afforded 240 mg (74%) of (E)-1-(bromomethyl)-3-
chloro-5-(prop-1-
enyl)benzene.
Step 7. (E)-(3-chloro-5-(prop-l-enyl)benzyl)triphenylphosphonium bromide
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In accordance with the procedure of preparation 1, step 5, (E)-1-(bromomethyl)-
3-chloro-5-(prop-l-
enyl)benzene (240 mg, 0.98 mmol) was converted into 430 mg (87%) of the title
compound.
Example 10
5-(3-((1 R,2R,3R,5R)-5-chloro-2-((E)-3-chloro-5-((E)-prop-1-enyl)styryl)-3-
hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid (15g)
Step 1. Wittig reaction of 10 to afford 11 g
In accordance with the procedure of example 2, step 2, aldehyde 10 (250 mg,
0.60 mmol) and (E)-(3-chloro-
5-(prop-l-enyl)benzyl)triphenylphosphonium bromide (Preparation 7, 430 mg,
0.85 mmol) were converted
into 204 mg (60%) of a mixture of alkenes 11g and 12g.
Step 2. Deprotection of 11g and 12g to give 13g and 14g
In accordance with the procedure of example 2, step 3, THP-ethers 11g and 12g
(204 mg, 0.36 mmol) were
converted into 107 mg (62%) of alkene 13g and 21 mg (12%) of alkene 14g.
Step 3. Saponification of 13g to give 15g
In accordance with the procedure of example 2, step 4, ester 13g (49 mg, 0.10
mmol) was converted into 35
mg (74%) of the title compound (15g).
Example 11
5-(3-((1 R,2R,3R,5R)-5-chloro-2-((Z)-3-chloro-5-((E)-prop-1-enyl)styryl)-3-
hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid (16g)
In accordance with the procedure of example 2, step 4, ester 14g (Example 10,
step 2, 21 mg, 0.044 mmol)
was converted into 10 mg (49%) of the title compound (16g).
Example 12
5-(3-((1 R,2R,3R,5R)-5-chloro-3-hydroxy-2-(3-
methylstyryl)cyclopentyl)propyl)thiophene-2-carboxylic acid
(15h and 16h)
Step 1. Wittig reaction of 10 to afford 11 h
In accordance with the procedure of example 2, step 2, aldehyde 10 (250 mg,
0.60 mmol) and (3-
methylbenzyl)triphenylphosphonium chloride (483 mg, 1.20 mmol) were converted
into 210 mg (69%) of
alkene 11h (contaminated with -10% of cis-alkene 12h).
Step 2. Deprotection of 11 h to give 13h
In accordance with the procedure of example 2, step 3, impure THP-ether 11h
(207 mg, 0.41 mmol) was
converted into 166 mg (96%) of alkene 13h (contaminated with -10% of cis-
alkene 14h).
Step 3. Saponification of 13h to give 15h
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In accordance with the procedure of example 2, step 4, impure ester 13h (45
mg, 0.11 mmol) was converted
into 5 mg (11 %) of the title compound (15h, contaminated with -10% of cis-
alkene 16h).
Preparation 8
((2-Propylpyridin-4-yl)methyl)triphenylphosphonium bromide
Step 1. Methyl 2-propylisonicotinate [In accordance with the procedures of
Furstner, et al Angew. Chem Int.
Ed. 2002, 41, 609-612]
At 0 C, n-propylmagnesium chloride (16.0 mL of a 2.0 N solution in THF, 32.0
mmol) was added to a
solution of methyl 2-chloroisonicotinate (4.77 g, 27.8 mmol), Fe(acac)3 (610
mg, 1.73 mmol), THF (150 mL)
and NMP (17 mL) at 0 C. After 1 h, the reaction was diluted with MTBE (200 mL)
and slowly quenched with
1.0 N HCI (20 mL). The mixture was diluted with water (50 mL) and the phases
were separated. The
aqueous phase was extracted with MTBE (2x200 mL). The combined organic phase
was dried (MgSOa),
filtered and concentrated in vacuo. Purification of the crude residue by flash
column chromatography on 200
g silica gel (20% hexanes/EtOAc) afforded 2.3 g (46%) of methyl 2-
propylisonicotinate.
Step 2. (2-propylpyridin-4-yl)methanol
In accordance with the procedures of preparation 6, step 1, methyl 2-
propylisonicotinate (2.15 g, 12.0 mmol)
was converted into 1.2 g (66%) of (2-propylpyridin-4-yl)methanol.
Step 3. 4-(bromomethyl)-2-propylpyridine
In accordance with the procedures of preparation 7, step 6, (2-propylpyridin-4-
yl)methanol (700 mg, 4.63
mmol) was converted into 600 mg (61%) of 4-(bromomethyl)-2-propylpyridine.
Step 4. ((2-Propylpyridin-4-yl)methyl)triphenylphosphonium bromide
In accordance with the procedure of preparation 1, step 5, 4-(bromomethyl)-2-
propylpyridine (350 mg, 1.64
mmol) was converted into 710 mg (91%) of the title compound.
Example 13
5-(3-((1 R,2R,3R,5R)-5-chloro-3-hydroxy-2-((E)-2-(2-propylpyridin-4-
yl)vinyl)cyclopentyl)propyl)thiophene-2-
carboxylic acid (15i)
Step 1. Wittig reaction of 10 to afford 11 i
In accordance with the procedure of example 2, step 2, aldehyde 10 (250 mg,
0.60 mmol) and ((2-
propylpyridin-4-yl)methyl)triphenylphosphonium bromide (430 mg, 0.90 mmol)
were converted into 250 mg
(78%) of a alkene 11 i(contaminated with -10% of cis-alkene 12i).
Step 2. Deprotection of 11 i to give 13i
In accordance with the procedure of example 2, step 3, impure THP-ether 11i
(250 mg, 0.47 mmol) was
converted into 201 mg (95%) of alkene 13i (contaminated with -10% of cis-
alkene 14i).
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Step 3. Saponification of 13i to give 15i
In accordance with the procedure of example 2, step 4, impure ester 13i (20
mg, 0.045 mmol) was converted
into 8 mg (41 %) of the title compound (15i, contaminated with -10% of cis-
alkene 16i).
Scheme 3
0
O~/J HO MsO
LiAIH4, THF -,-,OH MsCI, Et3N OMs KSAc
OTBS CHZCIZ ~OTBS DMF
q-.,-OTBS z -,
THPO THPO THPO
17 18 19
Ms0 ~SAc BrN Y21 CZEt Ms0 ~S\ N COZEt TBAC, Et3N
~OTBS ~OTBSS/~
PhMe
P(n-Bu)3, K2C03
THPO THPO
20 EtOH 22
CI CI
~,,=~S SN~COZEt TBAF, THF L.,.~S~ ~N/ COZEt
\//,1~OTBS `//,1~OH (S/~
THPO THPO
23 24
Preparation 9
ethyl 2-(2-((1 R,2S,3R,5R)-5-chloro-2-(hydroxymethyl)-3-(tetrahydro-2H-pyran-2-
yloxy)cyclopentyl)ethylthio)thiazole-4-carboxylate (24)
Step 1. Reduction of lactone 17 to diol 18
LiAIH4 (13.5 mL of a 1.0 M solution in THF, 13.5 mmol) was slowly added to a
solution of lactone 17 (5.0 g,
13.5 mmol) in THF (45 mL) at 0 C under nitrogen (vigorous gas evolution was
observed). After 3 h at 0 C,
tlc analysis showed the reaction was complete and water (50 mL) was added
slowly. Upon warming to rt,
CH2CI2 (250 mL) was added, followed by 15% aqueous NaOH (100 mL). The phases
were separated and
the aqueous phase was extracted CH2CI2 (3x100 mL). The combined organic phase
was washed with brine,
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dried (MgSOa), filtered and concentrated in vacuo. The resulting crude diol 18
(-5 g) was used in the next
reaction with out further purification.
Step 2. Mesylation of diol 18 to afford di-mesylate 19
Triethylamine (4.4 mL, 31.6 mmol) and methanesulfonyl chloride (1.8 mL, 23.2
mmol) were added
sequentially to a solution of 18 (3.57 g, 9.53 mmol) in CH2CI2 (100 mL) at 0
C. The reaction mixture was
allowed to warm to rt and stirred at rt for 3 d (note: this reaction time can
be as short as 1 d). Saturated
aqueous NaHCO3 (100 mL) was added and the mixture was extracted with CH2CI2
(300 mL). The organic
phase was washed with brine (50 mL) then dried (MgSOa), filtered and
concentrated in vacuo. Purification of
the crude residue by flash column chromatography on 80 g silica gel (hexane ->
EtOAc, gradient) afforded
4.44 g (88%) of di-mesylate 19.
Step 3. Conversion of mesylate 19 to thioacetate 20
Potassium thioacetate (1.51 g, 13.2 mmol) was added to a solution of di-
mesylate 19 (4.44 g, 8.37 mmol) in
DMF (100 mL) at rt. After stirring 18 h at rt, the mixture was partitioned
between EtOAc (400 mL) and water
(50 mL). The phases were separated and the organic phase was washed with water
(10x100 mL), dried
(MgSOa), filtered and concentrated in vacuo. Purification of the crude residue
by traditional flash column
chromatography on silica gel (30% EtOAc/hexanes) afforded 2.93 g (69%) of
thioacetate 20.
Step 4. Reaction of 20 with 21 to give thiazole 22
Tri-n-butylphosphine (0.25 mL, 1.0 mmol) was added to a solution of
thioacetate 20 (2.42 g, 4.74 mmol) in
absolute EtOH (20 mL). After 5 min at rt under nitrogen, ethyl 2-bromothiazole-
4-carboxylate (21,
commercially available from CombiBlocks, Inc., 1.30 g, 5.51 mmol) and
potassium carbonate (1.09 g, 7.89
mmol) were added in rapid succession. A nitrogen atmosphere was re-established
and mixture was heated
at 40 C overnight. The mixture was cooled to rt and then partitioned between
EtOAc (700 mL) and water
(200 mL). The phases were separated and the organic phase was washed with
brine (100 mL), dried
(MgS04), filtered and concentrated in vacuo. Purification of the crude residue
by flash column
chromatography on 80 g silica gel (hexane -> EtOAc, gradient) afforded 1.10 g
(37%) of thiazole 22.
Step 5. Conversion of mesylate 22 to chloride 23
Triethylamine (2.5 mL, 17.9 mmol) and tetrabutylammonium chloride (2.5 g, 9.0
mmol) were added to a
solution of 22 (1.10 g, 1.76 mmol) in toluene (20 mL). The reaction mixture
was heated at 40 C for 18 h.
TLC analysis of the cooled mixture showed the reaction to be incomplete. More
triethylamine (1.2 mL, 8.6
mmol) and tetrabutylammonium chloride (1.2 g, 4.3 mmol) were added and the
mixture was heated at 40 C
for 18 h. The cooled mixture was diluted with water (100 mL) and extracted
with EtOAc (300 mL). The
organic phase was washed with brine (50 mL), dried (MgS0a), filtered and
concentrated in vacuo.
Purification of the crude residue by flash column chromatography on 40 g
silica gel (hexane -> EtOAc,
gradient) afforded 720 mg (72%) of chloride 23.
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Step 6. Desilylation of 23 to give alcohol 24
Tetrabutylammonium fluoride (1.8 mL of a 1.0 M solution in THF, 1.8 mmol) was
added to a solution of 23
(720 mg, 1.28 mmol) in THF (7 mL) at rt. After 1 h at rt, the reaction mixture
was partitioned between EtOAc
(200 mL) and H20 (100 mL). The phases were separated and the organic phase was
washed with brine
(2x50 mL) then dried (MgS04), filtered and concentrated in vacuo. Purification
of the crude residue by flash
column chromatography on 12 g silica gel (hexane -> EtOAc, gradient) afforded
510 mg (89%) of the title
compound (24).
Scheme 4
ci
,~S` NCO2Et Swern ci
r`~S` NCO2Et K2CO3, DMF
OH S/ ~%O S + n
THPO 24 THPO Ph3P Ar
cl ci
,,S N COZEt ~,SYN COZEt
.~ y + y
~ Ar S Ar S
THPO THPO
26a,b 27a,b
PPTs, MeOH PPTs, MeOH
ci ~ ci
S N COZEt J~,=`\iS'~N ~ COZEt
S/ (\/~I~/Ar (S'
Ar
HO HO
28a,b 29a,b
LiOH, H20, THF LiOH, H20, THF
ci
\iS SNrC02H ci
\iS\ /NY CO2H
v V Ar Ar '
HO HO
30a,b 31a,b
Example 14
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2-(2-((1 R,2R,3R,5R)-5-chloro-2-(3,5-dichlorostyryl)-3-
hydroxycyclopentyl)ethylthio)thiazole-4-carboxylic acid
(30a)
Step 1. Swern oxidation of 24 to give 25
In accordance with the procedure of example 2, step 1, alcohol 24 (Preparation
9, 150 mg, 0.34 mmol) was
converted into crude aldehyde 25 which was used without further purification
in the next step.
Step 2. Wittig reaction of 25 to afford 26a and 27a
In accordance with the procedure of example 2, step 2, aldehyde 24 (-0.17
mmol) and 3,5-
dichlorophenylmethyltriphenylphosphonium chloride (210 mg, 0.46 mmol) were
converted into 91 mg (33%)
of an inseparable mixture of alkenes 26a and 27a.
Step 3. Deprotection of 26a and 27a to give 28a and 29a
In accordance with the procedure of example 2, step 3, THP-ethers 26a and 27a
(91 mg, 0.15 mmol) were
converted into 40 mg (51 %) of alkene 28a and 21 mg (27%) of alkene 29a.
Step 4. Saponification of 28a to give 30a
In accordance with the procedure of example 2, step 4, ester 28a (10 mg, 0.020
mmol) was converted into 2
mg (21 %) of the title compound (30a).
Example 15
2-(2-((1 R,2R,3R,5R)-2-((E)-3-(but-3-enyl)-5-chlorostyryl)-5-chloro-3-
hydroxycyclopentyl)ethylthio)thiazole-4-
carboxylic acid (30b)
Step 1. Wittig reaction of 25 to afford 26b and 27b
In accordance with the procedure of example 2, step 2, aldehyde 25 (141 mg,
0.31 mmol) and 3-(but-3-
enyl)phenyl)methyl)triphenylphosphonium chloride (Preparation 6, 317 mg, 0.72
mmol) were converted into
105 mg (58%) of a mixture of alkenes 26b and 27b.
Step 2. Deprotection of 26b and 27b to give 28b and 29b
In accordance with the procedure of example 2, step 3, THP-ethers 26b and 27b
(105 mg, 0.18 mmol) was
converted into 67 mg (75%) of alkene 28b and 12 mg (13%) of alkene 29b.
Step 3. Saponification of 28b to give 30b
In accordance with the procedure of example 2, step 4, ester 28b (67 mg, 0.14
mmol) was converted into 30
mg (47%) of the title compound (30b).
Example 16
2-(2-((1 R,2R,3R,5R)-2-((Z)-3-(but-3-enyl)-5-chlorostyryl)-5-chloro-3-
hydroxycyclopentyl)ethylthio)thiazole-4-
carboxylic acid (31 b)
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In accordance with the procedure of example 2, step 4, ester 29b (12 mg, 0.24
mmol) was converted into 5
mg (44%) of the title compound (31 b).
Scheme 5
O TESO
C02Me Li = Ph S C02Me HF-pyridine
AIMe3 0 C
TBSO 32 TESOTf TBSO Ph
33
0 0
S C02Me S CO2Me
+ X /I
TBSO Ph TBSO Ph
34 35
HF-pyridine HF-pyridine
0 Ctort 0 Ctort
O
S C02Me S C02Me
HO Ph HO Ph
36 37
rabbit liver esterase rabbit liver esterase
pH 7.2 buffer, DMSO pH 7.2 buffer, DMSO
O
CO2H S CO2H
HO \ Ph HO Ph
38 39
Example 17
5-(3-((1 R,2S,3R)-3-hydroxy-5-oxo-2-
(phenylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid (38)
Step 1. Conjugate addition and silylation to afford 33
Trimethylaluminum (4.1 mL of a 2.0 M solution in toluene, 8.2 mmol) was added
to a flask containing THF (20
mL), and the flask was cooled to -78 C. Lithium phenylacetylide (8.2 mL of a
1.0 M solution in THF, 8.2
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mmol) was added and the reaction was stirred for 30 min at -78 C. Another
flask was charged with enone
32 (see W02007/115020 which is hereby incorporated by reference in its
entirety) in THF (20 mL), cooled to
-78 C, and TESOTf (1.80 g, 6.81 mmol) was added (it is important to cool the
enone to -78 C prior to
TESOTf addition). After having stirred for 30 min at -78 C, the contents of
the aluminum containing flask
were transferred via cannula to the second flask (containing the enone) at -
78 C, and the reaction was
allowed to stir for 30 min. The reaction was warmed to approximately -10 C
and saturated aqueous
Rochelle's Salt (200 mL) was added (5 min after quenching, the reaction
effervesced; the final flask must be
large enough to allow for this action). Robust stirring of the contents
continued for several hours and the
contents were transferred to a separatory funnel and were washed once with
Et20 and CH2CI2. The
combined organic phase was dried (Na2S04) and combiflash chromatography
provided 1.20 g of pure
product, and 784 mg of product contaminated with 5% ketone (- 75%).
Step 2. Deprotection of 33 to give 34 and 35
Silyl enol ether 33 (260 mg, 0.43 mmol) and MeCN (10 mL) were added to a
plastic bottle and cooled to 0 C.
HF-pyridine (0.05 mL) was added and the reaction was stirred for 2 h at 0 C.
The reaction was then
quenched slowly with saturated aqueous NaHCO3, and the mixture was extracted
once with EtOAc and once
with CH2CI2. The combined organic phase was dried (Na2S04), concentrated and
Combiflash
chromatography gave 75 mg (35%) of ketone 34 followed by followed by 28.7 mg
(14%) of the slower moving
isomer ketone 35.
Step 3. Deprotection of 34 to give 36
Silyl ether 34 (75 mg, 0.15 mmol) and MeCN (3 mL) were added to a plastic vial
and cooled to 0 C.
HF-pyridine (0.05 mL) was added and the reaction was allowed to warm to room
temperature overnight with
stirring. The reaction was then quenched slowly with saturated aqueous NaHCO3,
and the mixture was
extracted once with EtOAc and once with CH2CI2. The combined organic phase was
dried (Na2S04),
concentrated and Combiflash chromatography gave 45.6 mg (79%) of ketone 36.
Step 4. Saponification of 36 to give 38
Ester 36 (10 mg, 0.026 mmol), DMSO (0.5 mL), and pH 7.2 phosphate buffer (50
mL) were added to a 100
mL round bottomed flask followed by the addition of rabbit liver esterase
(RLE, commercially available from
Sigma, 500 units). After having stirred for 12 h at room temperature, the
reaction was concentrated in vacuo.
Purification of the crude residue by flash column chromatography (50%
EtOAc/hexanes -> 1% AcOH in
EtOAc) afforded 7.3 mg (76%) of the title compound (38).
Example 18
5-(3-((1 S,2S,3R)-3-hydroxy-5-oxo-2-
(phenylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid (39)
Step 1. Deprotection of 35 to give 37
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In accordance with the procedure of example 17, step 3, silyl ether 35 (28.7
mg, 0.058 mmol) was converted
to 17.1 mg (77%) of ketone 37.
Step 4. Saponification of 37 to give 39
In accordance with the procedure of example 17, step 4, ester 37 (17.1 mg,
0.045 mmol) was converted to
14.4 mg (87%) of the title compound (39).
Scheme 6
O HO S
S/ COZMe L-Selectride COZMe DAST
TBSO TBS6
Ph Ph
34 40
F F F
oS COZMe S COZMe LiOH S COZH
HF-pyridine
H20, THF
TBSO Ph HO HO
Ph Ph
41 42 43
Example 19
5-(3-((1 R,2S,3R,5R)-5-fluoro-3-hydroxy-2-
(phenylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid (43)
Step 1. Reduction of 34 to give 40
L-Selectride (1.14 mL of a 1.0 M solution in THF, 1.14 mmol) was added to a
solution of ketone 34 (170 mg,
0.34 mmol) in THF (5 mL) at-78 C. After 1 h, 3% H202 (25mL) was added and the
reaction was warmed to
room temperature. After 0.5 h of stirring at room temperature, saturated
aqueous NH4CI was added and the
mixture was extracted with EtOAc (3x). The combined organic phase was washed
with brine, dried
(Na2SO4), and concentrated. Purification of the crude residue by flash column
chromatography afforded 150
mg (88%) of the desired alcohol 40.
Step 2. Conversion of alcohol 40 to fluoride 41
(Diethylamino)sulfur trifluoride (DAST, 17 L, 0.13 mmol) was added to a
solution of alcohol 40 (30 mg, 0.060
mmol) in CH2CI2 (3 mL) at -78 C. After stirring for 30 min, the mixture was
diluted with water, extracted with
CH2CI2 (3x) and hexanes (lx). The combined organic phase was washed with
brine, dried (Na2SO4), and
concentrated. Purification of the crude residue by combiflash chromatography
afforded 23 mg (76%) of
fluoride 41.
Step 3. Deprotection of 41 to give 42
HF pyridine (0.15 mL) was added to a solution of 41 (23 mg, 0.046 mmol) in
MeCN (2 mL) in a plastic vial.
After stirring 16 h, the mixture was quenched with saturated aqueous NaHCO8
and extracted with EtOAc.
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The organic phase was washed with brine, dried (Na2SO4), filtered and
concentrated in vacuo. Purification of
the crude residue by combiflash chromatography afforded 16 mg (90%) of alcohol
42.
Step 4. Saponification of 42 to give 43
Lithium hydroxide (6.5 mg, 0155 mmol) was added to a solution of ester 11 (8
mg, 0.021 mmol) in a 1:0.5
THF/water solution (1.5 mL). After having stirred 72 h, purification of the
residue by flash column
chromatography provided 8 mg (quant.) of the title compound (43).
Scheme 7
HO Ms0
S COZMe MsCI, Et3N S COZMe TBAC
CHZCIZ
TBSO ~ Ph TBSO ~ Ph
40 44
CI S COZMe CI COZMe LiOH CI SCOZR
HF-pyridine \/
H20, THF
TBSO Ph HO \ Ph HO
Ph
45 46 47 R=H
i-Pr-I ~ ( )
DBU
acetone 48 (R=i-Pr)
Example 20
5-(3-((1 R,2S,3R,5R)-5-chloro-3-hydroxy-2-
(phenylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid (47)
Step 1. Mesylation of 40 to give 44
Methanesulfonyl chloride (37 L, 0.48 mmol) was added to a solution of alcohol
40 (120 mg, 0.24 mmol) and
triethylamine (0.10 mL, 0.72 mmol) in CH2CI2 (3 mL). After stirring 1 hour at
room temperature, the mixture
was quenched with saturated aqueous NaHCO8. The organic phase was separated
and washed with brine,
dried (Na2SO4), filtered and concentrated. Purification of the crude residue
by flash column chromatography
provided 110 mg (79%) of mesylate 44.
Step 2. Conversion of mesylate 44 to chloride 45
TBAC (245mg, 0.88 mmol) was added to a solution of mesylate 44 (50 mg, 0.087
mmol) in toluene (2 mL)
and the mixture was then stirred at 45 C for 6 h. The mixture was then cooled
to room temperature and
water was added. The aqueous layer was extracted with EtOAc, and the organic
phase was washed with
brine, dried (Na2SO4), filtered and concentrated. Purification of the crude
residue by combiflash
chromatography provided 45 mg (quant.) of chloride 45.
Step 3. Deprotection of 45 to give 46
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In accordance with the procedure of example 19, step 3, silyl ether 45 (45 mg,
0.087 mmol) was converted to
31 mg (89%) of alcohol 46.
Step 4. Saponification of 46 to give 47
In accordance with the procedure of example 19, step 4, ester 46 (31 mg, 0.077
mmol) was converted to 15.8
mg (53%) of the title compound (47).
Example 21
Isopropyl 5-(3-((1 R,2S,3R,5R)-5-chloro-3-hydroxy-2-
(phenylethynyl)cyclopentyl)propyl)thiophene-2-
carboxylate (48)
2-lodopropane (passed through a short column of activated basic, Brockman I,
standard grade, 150 mesh
Alumina just prior to use, 43 mg, 0.26 mmol) was added to a mixture of acid 47
(5 mg, 0.013 mmol) and DBU
(7.8 mg, 0.051 mmol) in acetone (0.4 mL). After stirring for 16 h, the mixture
was concentrated, extracted
with EtOAc. The organic phase was washed with 1% aqueous HCI, saturated
aqueous NaHCO3, brine, then
dried (Na2S04), filtered and concentrated in vacuo. Purification of the crude
residue by combiflash
chromatography afforded 2.9 mg (52%) of the title compound (48).
Scheme 8
Ms0 NC
""CO2Me KCN S/ CO2Me
~ ~ HF-pyridine
TBSO "
Qs%z~ -
Ph TBSO Ph
44 49
NC CO Me
2 LiOH NC " COZH
~ I
HO H20, THF
Ph HO Ph
50 51
Example 22
5-(3-((1 S,2S,3R,5R)-5-cyano-3-hydroxy-2-
(phenylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid (51)
Step 1. Conversion of mesylate 44 into nitrile 49
Potassium cyanide (68 mg, 1.04 mmol) was added to a solution of mesylate 44
(60 mg, 0.104 mmol) in
DMSO (5 mL), and the mixture was then heated at to 65 C for 24 h. The mixture
was cooled to room
temperature, diluted with water/brine, and extracted with CHCI3 (4x) & EtOAc.
The combined organic phase
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was washed with brine, dried (Na2S04), filtered and concentrated in vacuo.
Purification of the crude residue
by combiflash chromatography provided 13 mg (25%) of nitrile 49.
Step 2. Deprotection of 49 to give 50
In accordance with the procedure of example 19, step 3, silyl ether 49 (13 mg,
0.026 mmol) was converted to
7.3 mg (72%) of alcohol 50.
Step 3. Saponification of 50 to give 51
In accordance with the procedure of example 19, step 4, ester 50 (7.3 mg,
0.019 mmol) was converted to 5
mg (71 %) of the title compound (51).
Scheme 9
O \ S/ COZMe CF3TMS TMSO,,. CF3 COZMe
KZC03
TBSO \ Ph TBSO
Ph
34 52
0
HO3
., CF3 g COZMe Me02C" 0',, CF3 S
COZMe Bu SnH
CIC(O~OZMe 3
TBSO Ph TBSO Ph
53 54
F3C
S COZMe F3C S COZR F3C S
\ / HF-pyridine ' \ / COZR
+ \ /
TBSO 55 Ph HO
Ph HO Ph
LiOHC 56 (R=Me) LiOHC 57 (R=Me)
H20 H20
THF 58 (R=H) THF 59 (R=H)
Example 23
5-(3-((1 R,2S,3R)-3-hydroxy-2-(phenylethynyl)-5-(trifl
uoromethyl)cyclopentyl)propyl)thiophene-2-carboxylic
acid (faster eluting HPLC diastereomer 58)
Step 1. Conversion of 34 into 52
Trifluoromethyl trimethylsilane (Fluka, 8 mL of a 2.0 M solution in THF, 16
mmol) was added to a solution of
ketone 34 (300 mg, 0.60 mmol) in THF (17 mL) at room temperature, followed by
the addition of 4 drops of
tetrabutylammonium fluoride (TBAF, 1.0 M in THF); the reaction turned light
yellow. After 45 min, the
reaction was quenched slowly with saturated aqueous NH4CI and extracted with
EtOAc (3x). The combined
43
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organic phase was washed with brine, dried (Na2S04), filtered and
concentrated. The crude silane 52 was
dried under high vacuum for 12 hours prior to the following reaction.
Step 2. Desilylation of 52 to give 53
Solid K2CO3 (248 mg, 1.79 mmol) was added to crude silane 52 in MeOH (40 mL)
and the mixture was stirred
for 4 h. The reaction was then diluted with saturated aqueous N H4CI, and
extracted with EtOAc, The
organic phase was washed with brine, dried (Na2S04), filtered and
concentrated. Purification of the crude
residue by combiflash chromatography afforded 170 mg (50% over two steps) of
alcohol 53.
Step 3. Conversion of alcohol 53 into ester 54
Methyl oxalyl chloride (183 mg, 1.49 mmol) was added slowly to a mixture of
alcohol 53 (170 mg, 0.30 mmol),
pyridine (0.73 mL, 9.0 mmol), 4-N,N-dimethylaminopyridine (220 mg, 1.80 mmol),
and CH2CI2 (8 mL). After
stirring 1.5 h, the mixture was quenched with water, diluted with
EtOAc/hexanes (4:1; 20 mL), and partitioned.
The organic phase was washed again with water (20 mL), then dried (Na2S04),
filtered and concentrated in
vacuo. Purification of the crude residue by combiflash chromatography afforded
162 mg (83%) of ester 54.
Step 4. Conversion of ester 54 into 55
A mixture of oxalyl ester 54 (162 mg, 0.25 mmol), AIBN (40 mg) and toluene (2
mL) was bubbled with
nitrogen gas for 20 min. Separately, a solution of Bu3SnH (727 mg, 2.50 mmol)
in toluene (10 mL) was
bubbled with nitrogen gas for 20 min, and then brought to 120 C. The AIBN
containing mixture was quickly
added dropwise. After 20 min, TLC indicated no starting material and the
reaction was concentrated to afford
129 mg (- 94%) of crude 55.
Step 5. Deprotection of 55 to give 56 and 57
In accordance with the procedure of example 19, step 3, crude silyl ether 55
(129 mg, - 0.234 mmol) was
converted to 4 mg (4%) of faster eluting alcohol 56 and 10.4 mg (10%) of
slower eluting alcohol 57 after
HPLC separation (EtOAc/hex; 1:3).
Step 6. Saponification of 56 to give 58
In accordance with the procedure of example 19, step 4, ester 56 (4 mg, 0.009
mmol) was converted to 2.2
mg (57%) of the title compound (58).
Example 24
5-(3-((1 R,2S,3R)-3-hydroxy-2-(phenylethynyl)-5-(trifl
uoromethyl)cyclopentyl)propyl)thiophene-2-carboxylic
acid (slower eluting HPLC diastereomer 59)
In accordance with the procedure of example 19, step 4, ester 57 (10.4 mg,
0.024 mmol) was converted to 5
mg (50%) of the title compound (59).
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Scheme 10
/
ci O ci O S COZMe x p(O)(OMe)2 ;.= \ S/ COZMe X-Ar
\//,1 ~ TsN3, K2CO3 Pd(MeCN)2CI2
THPO MeOH, MeCN THPO H XPhos, Cs2CO3
60 THF
ci ci ci S
COZMe S COZMe /S` /COZH
C / PPTs, MeOH ~ / LiOH (\J/
H20, THF
THPO Ar HO Ar HO ~ Ar
61a-h 62a-h 63a-h
Example 25
5-(3-((1 R,2S,3R,5R)-5-chloro-2-((3,5-dichlorophenyl)ethynyl)-3-
hydroxycyclopentyl)propyl)thiophene-2-
carboxylic acid (63a)
Step 1. Reaction of 10 to give 60 (in accordance with the procedures of Roth,
et al., Synthesis 2004, 59-62).
To a mixture of tosyl azide (240 mg, 1.22 mmol) and potassium carbonate (415
mg, 3.0 mmol) in MeCN (15
mL) was added dimethyl-2-oxopropylphosphonate (166 L, 1.20 mmol). After 2 h
of stirring at room
temperature, a solution of crude aldehyde 10 (prepared in accordance with the
procedure of example 2, step
1, -1.0 mmol) in MeOH (3 mL) was added by cannula. The mixture was allowed to
stir overnight at room
temperature then was concentrated in vacuo. Water (10 mL) was added and the
mixture was extracted with
EtOAc (20 mL). The organic phase was washed with water (10 mL) and brine (10
mL), then dried (Na2S04),
filtered and concentrated in vacuo. Purification of the crude residue by
chromatography on 40 g silica gel
(hexanes -> EtOAc, gradient) afforded 203 mg (49%, slightly contaminated with
tosyl amide) of alkyne 60.
Step 2. Arylation of 60 to give 61a (in accordance with the procedures of
Gelman and Buchwald, Angew.
Chem. Int. Ed. 2003, 42, 5993-5996)
Cesium carbonate (80 mg, 0.25 mmol), bis(acetonitrile)palladium (II) chloride
(1.6 mg, 0.006 mmol), 2-
dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 8.8 mg, 0.018
mmol) and 1-bromo-3,5-
dichlorobenzene (27.5 mg, 0.12 mmol) were combined in a 1 dram vial. The
mixture was purged with
nitrogen, stirred at room temperature for 25 min, then a solution of alkyne 60
(50 mg, 0.12 mmol) in MeCN
(0.25 mL) was added. After 3 h at room temperature, tlc analysis showed very
little reaction had occurred so
the vial was sealed under nitrogen and heated at 50 C. After 18 h, the
mixture was cooled, diluted with
EtOAc and filtered through celite. The filtrate was concentrated in vacuo.
Purification of the crude residue by
chromatography on 12 g silica gel (hexanes -> EtOAc, gradient) afforded 34.5
mg (51 %) of 61a.
Step 3. Deprotection of 61a to give 62a
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In accordance with the procedures of example 2, step 3, THP-ether 61a (34 mg,
0.061 mmol) was converted
into 25 mg (87%) of alcohol 62a.
Step 4. Saponification of 62a to give 63a
In accordance with the procedures of example 4, step 3, ester 62a (25 mg,
0.053 mmol) was converted into
16.5 mg (68%) of the title compound (63a).
Example 26
5-(3-((1 R,2S,3R,5R)-5-chloro-2-((3-ethylphenyl)ethynyl)-3-
hydroxycyclopentyl)propyl)thiophene-2-carboxylic
acid (63b)
Step 1. Arylation of 60 to give 61b
In accordance with the procedures of example 24, step 2, 60 (50 mg, 0.12
mmol)and 1-bromo-3-
ethylbenzene (26 mg, 0.14 mmol) were converted into 41 mg (65%) of 61b after
heating at 70 C for 4 h.
Step 2. Deprotection of 61 b to give 62b
In accordance with the procedures of example 2, step 3, THP-ether 61 b (41 mg,
0.080 mmol) was converted
into 30 mg (87%) of alcohol 62b.
Step 3. Saponification of 62b to give 63b
In accordance with the procedures of example 4, step 3, ester 62b (30 mg,
0.070 mmol) was converted into
27 mg (93%) of the title compound (63b) after heating at 40 C for 18 h.
Example 27
5-(3-((1 R,2S,3R,5R)-2-((3-(but-3-enyl)phenyl)ethynyl)-5-chloro-3-
hydroxycyclopentyl)propyl)thiophene-2-
carboxylic acid (63c)
Step 1. Arylation of 60 to give 61c
In accordance with the procedures of example 24, step 2, 60 (36 mg, 0.088
mmol)and 1-bromo-3-(but-3-
enyl)benzene (18.5 mg, 0.088 mmol) were converted into 42 mg (89%) of 61c
after heating at 50 C for 18 h.
Step 2. Deprotection of 61c to give 62c
In accordance with the procedures of example 2, step 3, THP-ether 61c (42 mg,
0.078 mmol) was converted
into 24 mg (68%) of alcohol 62c.
Step 3. Saponification of 62c to give 63c
In accordance with the procedures of example 4, step 3, ester 62c (24 mg,
0.070 mmol) was converted into
16 mg (69%) of the title compound (63c) after heating at 40 C for 18 h.
Example 28
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5-(3-((1 R,2S,3R,5R)-5-chloro-3-hydroxy-2-(thiophen-2-
ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic
acid (63d)
Step 1. Arylation of 60 to give 61d
In accordance with the procedures of example 24, step 2, 60 (65 mg, 0.16 mmol)
and 2-chlorothiophene (15
pL, 0.16 mmol) were converted into 15 mg (19%) of 61d after heating at 50 C
for 18 h.
Step 2. Deprotection of 61d to give 62d
In accordance with the procedures of example 2, step 3, THP-ether 61d (15 mg,
0.030 mmol) was converted
into 10 mg (80%) of alcohol 62d.
Step 3. Saponification of 62d to give 63d
In accordance with the procedures of example 4, step 3, ester 62d (5 mg, 0.012
mmol) was converted into 2
mg (41 %) of the title compound (63d) after heating at 40 C for 18 h and
purification by preparative thin layer
chromatography eluting with 20% MeOH/CH2CI2.
Example 29
5-(3-((1 R,2S,3R,5R)-5-chloro-3-hydroxy-2-(thiophen-3-
ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic
acid (63e)
Step 1. Arylation of 60 to give 61e
In accordance with the procedures of example 24, step 2, 60 (65 mg, 0.16 mmol)
and 3-chlorothiophene (15
pL, 0.16 mmol) were converted into 25 mg (32%) of 61e after heating at 50 C
for 18 h.
Step 2. Deprotection of 61e to give 62e
In accordance with the procedures of example 2, step 3, THP-ether 61e (25 mg,
0.051 mmol) was converted
into 20 mg (96%) of alcohol 62e.
Step 3. Saponification of 62e to give 63e
In accordance with the procedures of example 4, step 3, ester 62e (10 mg,
0.024 mmol) was converted into 1
mg (10%) of the title compound (63e) after heating at 40 C for 18 h and
purification by preparative thin layer
chromatography eluting with 20% MeOH/CH2CI2.
Example 30
5-(3-((1 R,2S,3R,5R)-5-chloro-3-hydroxy-2-(pyridin-2-
ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid
(63f)
Step 1. Arylation of 60 to give 61f
In accordance with the procedures of example 24, step 2, 60 (107 mg, 0.26
mmol) and 2-bromopyridine (50
pL, 0.52 mmol) were converted into 74 mg (58%) of 61f after heating at 60 C
for 18 h.
Step 2. Deprotection of 61f to give 62f
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In accordance with the procedures of example 2, step 3, THP-ether 61f (74 mg,
0.15 mmol) was converted
into 22 mg (36%) of alcohol 62f.
Step 3. Saponification of 62f to give 63f
In accordance with the procedures of example 4, step 3, ester 62f (10 mg,
0.025 mmol) was converted into 5
mg (52%) of the title compound (63f) after purification by preparative thin
layer chromatography eluting with
30% MeOH/CH2CI2.
Example 31
5-(3-((1 R,2S,3R,5R)-5-chloro-3-hydroxy-2-(pyridin-3-
ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid
(63g)
Step 1. Arylation of 60 to give 61g
In accordance with the procedures of example 24, step 2, 60 (150 mg, 0.37
mmol) and 3-bromopyridine (116
mg, 0.73 mmol) were converted into 93 mg (52%) of 61g after heating at 65 C
for 18 h.
Step 2. Deprotection of 61g to give 62g
In accordance with the procedures of example 2, step 3, THP-ether 61g (93 mg,
0.19 mmol) was converted
into 34 mg (44%) of alcohol 62g after a second equivalent portion of PPTs was
added after 18 h and heating
at 45 C for an additional 24 h was conducted.
Step 3. Saponification of 62g to give 63g
In accordance with the procedures of example 4, step 3, ester 62g (11 mg,
0.027 mmol) was converted into 7
mg (66%) of the title compound (63g) after purification by preparative thin
layer chromatography eluting with
30% MeOH/CH2CI2.
Example 32
5-(3-((1 R,2S,3R,5R)-5-chloro-3-hydroxy-2-(pyridin-4-
ylethynyl)cyclopentyl)propyl)thiophene-2-carboxylic acid
(63h)
Step 1. Arylation of 60 to give 61h
In accordance with the procedures of example 24, step 2, 60 (134 mg, 0.33
mmol) and 4-bromopyridine
hydrochloride (111 mg, 0.57 mmol) were converted into 107 mg (67%) of 61h
after heating at 65 C for 18 h
and using 3.5 equivalents of Cs2C03.
Step 2. Deprotection of 61 h to give 62h
In accordance with the procedures of example 2, step 3, THP-ether 61h (107 mg,
0.22 mmol) was converted
into 109 mg of impure crude alcohol 62h after a second equivalent portion of
PPTs was added after 18 h and
heating at 50 C for an additional 24 h was conducted.
Step 3. Saponification of 62h to give 63h
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In accordance with the procedures of example 4, step 3, impure ester 62h (15
mg, -0.037 mmol) was
converted into 8 mg (-55%) of the title compound (63h) after purification by
preparative thin layer
chromatography eluting with 20% MeOH/CH2CI2.
Scheme 11
ci C02Me ci
S CO2Me X-Ar
PPTs, MeOH
THPO Pd(MeCN)2CI2
H HO H XPhos, Cs2CO3
THF
60 64
ci ci
S CO2Me S CO2H
1. TBAF, THF
2. LiOH, H20, THF
Hd \ OTBS Hd OH
62i 63i
Preparation 10
(3-(3-bromophenyl)propoxy)(tert-butyl)dimethylsilane
Step 1. 3-(3-bromophenyl)propan-l-ol
A solution of 1-allyl-3-bromobenzene (998 mg, 5.1 mmol) in THF (2 mL + 0.5 mL)
was added to a solution of
9-BBN dimer (806 mg, 3.3 mol) in THF (6.6 mL). The mixture was stirred
overnight at room temperature,
then 3.0 M NaOH (2 mL) and 30% H202 (2 mL) were added while cooling the
reaction mixture in an ice bath
to control the exotherm. The mixture was stirred at room temperature for 4 h
and then partitioned between
brine (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous
phase was extracted with
EtOAc (20 mL). The combined organic phase was dried (Na2S04), filtered and
concentrated in vacuo.
Purification of the crude residue by chromatography on 80 g silica gel
(hexanes -> 60% EtOAc/hexanes,
gradient) afforded 637 mg (58%) of 3-(3-bromophenyl)propan-l-ol.
Step 2. (3-(3-bromophenyl)propoxy)(tert-butyl)d i methylsi lane
t-Butyldimethylsilyl chloride (3.26 g, 21.7 mmol) was added to a solution of 3-
(3-bromophenyl)propan-l-ol
(3.15 g, 14.7 mmol), triethylamine (4.1 mL, 29.4 mmol) and DMAP (364 mg, 3.0
mmol) in CH2CI2 (30 mL).
After stirring at room temperature for 18 h, the reaction was quenched with
saturated aqueous NaHCO3 (100
mL) and the mixture was extracted with CH2CI2 (50 mL). The organic phase was
washed with brine (100 mL)
and then was dried (Na2S04), filtered and concentrated in vacuo. Purification
of the crude residue by
49
CA 02692572 2010-01-05
WO 2009/006370 PCT/US2008/068716
chromatography on 120 g silica gel(10% EtOAc/hexanes -> 35% EtOAc/hexanes,
gradient) afforded 4.36 g
(90%) of the title compound.
Example 33
5-(3-((1 R,2S,3R,5R)-5-chloro-3-hydroxy-2-((3-(3-
hydroxypropyl)phenyl)ethynyl)cyclopentyl)propyl)thiophene-
2-carboxylic acid (63i)
Step 1. Deprotection of 60 to give 64
In accordance with the procedures of example 2, step 3, THP-ether 60 (121 mg,
0.29 mmol) was converted
into 62 mg (65%) of alcohol 64 after purification on 40 g silica gel (hexane -
> 50% EtOAc/hexanes, gradient).
Step 2. Arylation of 64 to give 62i
In accordance with the procedures of example 24, step 2, 64 (292 mg, 0.89
mmol) and (3-(3-
bromophenyl)propoxy)(tert-butyl)dimethylsilane (preparation 10, 286 mg, 0.87
mmol) were converted into 321
mg (64%) of 62i after purification on 40 g silica gel (hexane -> 45%
EtOAc/hexanes, gradient).
Step 3. Deprotection and saponification of 62i to give 63i
TBAF (0.10 mL of a 1.0 M solution in THF, 0.10 mmol) was added to a solution
of 62i (13 mg, 0.023 mmol) in
THF (0.10 mL). After stirring 21 h at room temperature, the reaction was
partitioned between saturated
aqueous NH4CI (10 mL) and EtOAc (20 mL). The layers were separated and the
aqueous phase was
extracted with EtOAc (20 mL). The combined organic phase was dried (Na2S04),
filtered and concentrated in
vacuo. The crude material was then treated in accordance with the procedures
of example 4, step 3, to
afford 5 mg (49%) of the title compound (63i) after heating at 60 C for 18 h
and after purification by
chromatography thin layer chromatography eluting with 7.5% MeOH/CH2CI2.
Scheme 12
ci O ci ~O S SN\ /COZMe x~P(O)(OMe)2 ,,=~S SN~CO2Me X-Ar
1 TsN3, K2CO3 Pd(MeCN)2CI2
THPO MeOH, MeCN THPO ~ H XPhos, Cs2CO3
THF
25 65
ci ci ci ~S` N/ COZMe ~S N /COZMe ;,.~5 SCOZH
PPTs, MeOH SJ/ LiOH Y /
THPO HpO,THF -
H~66z \ Ar HO Ar
66a,b 67a,b 68a,b
Example 34
CA 02692572 2010-01-05
WO 2009/006370 PCT/US2008/068716
2-(2-((1 R,2S,3R,5R)-5-chloro-2-((3,5-dichlorophenyl)ethynyl)-3-
hydroxycyclopentyl)ethylthio)thiazole-4-
carboxylic acid (68a)
Step 1. Reaction of 25 to give 65
In accordance with the procedures of example 24, step 1, crude aldehyde 25
(prepared in accordance with
the procedure of examples 2 and 14, step 1, -5.85 mmol) was converted to 600
mg (23%) of alkyne 65.
Step 2. Arylation of 65 to give 66a
In accordance with the procedures of example 24, step 2, 65 (100 mg, 0.23
mmol) and 1-bromo-3,5-
dichlorobenzene (102 mg, 0.45 mmol) were converted into 21 mg (16%) of 66a
after heating at 60 C for 18
h.
Step 3. Deprotection of 66a to give 67a
In accordance with the procedures of example 2, step 3, THP-ether 66a (21 mg,
0.036 mmol) was converted
into 4 mg (22%) of alcohol 67a.
Step 4. Saponification of 67a to give 68a
In accordance with the procedures of example 4, step 3, ester 67a (3 mg, 0.059
mmol) was converted into 2
mg (71 %) of the title compound (68a) after purification by preparative thin
layer chromatography eluting with
20% MeOH/CH2CI2.
Example 35
2-(2-((1 R,2S,3R,5R)-5-chloro-3-hydroxy-2-
(phenylethynyl)cyclopentyl)ethylthio)thiazole-4-carboxylic acid
(68b)
Step 1. Arylation of 65 to give 66b
In accordance with the procedures of example 24, step 2, 65 (100 mg, 0.23
mmol) and bromobenzene (47
pL, 0.45 mmol) were converted into 20 mg (17%) of 66b after heating at 60 C
for 18 h.
Step 2. Deprotection of 66b to give 67b
In accordance with the procedures of example 2, step 3, THP-ether 66b (20 mg,
0.038 mmol) was converted
into 11 mg (66%) of alcohol 67b
Step 3. Saponification of 67b to give 68b
In accordance with the procedures of example 4, step 3, ester 67b (6 mg, 0.014
mmol) was converted into 4
mg (71 %) of the title compound (68b) after purification by preparative thin
layer chromatography eluting with
20% MeOH/CH2CI2.
51
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WO 2009/006370 PCT/US2008/068716
In vitro testing
United States Patent Application Serial No. 11/553,143, filed on October 26,
2006, incorporated by
reference herein in its entirety, describes the methods used to obtain the in
vitro data in the table below.
---- -- ---- -- --- - -- - ---
EP~ cEata ' EP4 data c3thatRec ptars {ECSi] en n{V!}
---------------------------------------- ......
Exanople; ', SiruCEure iBipr cA A9P fl:pr
tfi #SI hFP hEPi hEP3A hTP hEP hD3'
_ -_-_____ EC~4 E~59
. _
. ,t . =..,v' Y :~- { ; ---- ... ............ -------------
~
37 0.2 2.2 10t1D0 i 44i; L N ~ , rl.^~ { 1 [] q ~..30C 44
\
......
.--
------------
-- ---.... -- ..
1 [F71. 135 h1.1 NA , NA NIA N,G i[S0.}
.. .+
_____ .... - _.._. ...... . } _.... . _....
101 a 10 168S3 303 NA NA NA r3A NA NA
~~.`.
-..
-- ..;
----
~ -
,
4 qq 1 flv z.3 5556 tYt NA NA NA NA fihl NA
__ ..
----------- ------ - --------------... ... -----
~l . .
3 eE ;?x i3ae NA N A 2A N, W
A zHs
9 N
52
CA 02692572 2010-01-05
WO 2009/006370 PCT/US2008/068716
--- - -- -- ---- ---- -- ----- - - - - ---
i~2 d~ka ~P f cÃata Qther REcapO rs (~G5 O rn nMJ
~xarn#ale# Stnre#r:rC taipr cA419~' ps
Fti FCi hFP hEF!4 ItEF'3A hTP h4fi hOP
------------ - ------------------
--...
.- ......................... __
00; 8?Ei NA NØ NA 9i53G;i NA NA
22 U,"a >700
ci
. =
. =
.. . =
= = :
, r = , .
...... ---- - ............. - - -- --- ....
{ ---~ - _ ----
7 l F ~1 s5 2 7 42~ 3213 NA ~lA. NA 1,15 NA f363
..FS=
........ ............. - ____,..-.-.. - = ....... . ---_._ _____ _______
.......
..____..
z: 328 14 8 86 NA NA N7 NA W A
---------------- --------------------
G 0~ 53.7 17;39s NA NA 5763 1A NA Y3A
---- _. .....,.... ---- -------
.... ........... ....
?
: P
7~ r 1542 1 1d =,1O}GO ~. !A o ~;.''. NA NA NA NA
;J
, =
, = =
., , . :
53
CA 02692572 2010-01-05
WO 2009/006370 PCT/US2008/068716
---- --------- -------------- ~pF daia EP4 daim r~r r~tec~~iAra aEC50EFS nm)
- ......
E~ana~Ee~ ~S~tl~ts~t~ flr~ r oAd~i#' ipr
Ki EÃ9 #AF3 hEK'4 izMd4 1a3'P it@P = Rpp
......: ------ -. _.::. .. ~~~~ . .......... E~~atl ---
1 t ~- 1:N 1i hfi s;3 rf y;: hZ 1A f NA
j=~ - ._.
1:2'. 17 9+7,i ~'.4 NA ~M7; 3 ~,~3 iJ~. FC`*4
:..........:::.. ~ = . . . ; ; ~
-- a , ..........._........... ~ ...
............ .......
.............. .. _ . ..._ . . __ ____________
i ].A c >'FQVC r b; ~ l'iA 3~1:~. NA hi+~~~5 ?k:M
,,.. ~,:=
---
- --- = - ._. ........ .
"
~
'=r '`~~~ ' . [i L'a1 ' 1ti i+f.?i `~;e7. 5 R.3 SA RA NA
7;>=
,õ p:ilt NA 1 ~^L)., G . NA = N.t ~1;jChil}
.,..... ................................... ._... _ ___ -
~2 craia EP4i$tA t5
thirResptcrs{EC56trr lZiti')
..................... ....... . ---_
Exste!gis# SRr~~vturE i9ipt aA4 fEpr
to;,R u," K3 ; K4 ttKP hEPE hEP3A 37TP h9P hEDP
....----- -....... .. --------------------------
i? 2.rwi IJr 'liiG~+~ ?~~ 'd.* F3A =`p,",(tv
-- ------ -----
------------ ------- ------------
~
} % ..
33 d3 7i.1
L} ?0, NA 9Nc NA Ptn NA
.-
n
W2 .?ti P;>, *]r+ ~ N
+: iA
`~ ..
___ _ ________
- .__ _ _ _
rf
J ~ 4~`~ .. ~+k t 4 26604 102?: FLA N-A NA he: NA
.............:. -------------------- .........
..,.. ....... ..__. .... . . . ... .... ........ ...._
__.. _ =. .. ..._. ___ ------------
- ____________ __________
=
= ..~ .~ = . . t
] 9 NA szM ^1 4027 NA NA y3 0 i1
-------------- ---------------------------------------
54
CA 02692572 2010-01-05
WO 2009/006370 PCT/US2008/068716
.._..__ .__.. . _
Lf~2 c9 iG~ ~f~ E Lfeln ~S~FI~f ROaNgAAGts (~OSd~ 3f f7'Edl}
- .:: . .... ... _..
Exomr-O' stncc ur;s M~~ ...... CAMP ... ............fil#r
Ki 3d! hFP hP, hEP,sAf hTP MP hOg
.... ........ .... - __ ..
..........
.
Y~=- ` ~~\ "'~x5
22
2<5 fi ER 13 :'2~', ::`~,,-= ;J{x? f~f;~ ..t~u.;~; NA `JA hiA.
#V ;i FWi NA NA Pdr"s
e 10' 4 NA N H r~A. NA NA
P;&
--- - a -- - - -_ _____ ---
-------------------------- ____________ __________,___________,
----
~.. , ;
'I dth 266 N R: r2<, ?3 I r. a: i:t
i.G =\ '--~ -- 41: ,: t;~ 'tl.:i Z9$ .':n rJA. NA P.~~ t* ?iA `~ah
CA 02692572 2010-01-05
WO 2009/006370 PCT/US2008/068716
-- -------- ................ ..... ..... ---- ------ _
--
i aPz data EP$ r18:az Ot.##or RerWc rs { Ei rG Eoz i]Atf}
ExamRfa# Strtrtieerb fitNr eAP ---- _ #~F
Kf Sfl Wp ht P hEP3A!tY`P hIP hDP
ECK k0`.*~...... ___AXQ ....
cy~ u
27 fP .liz . 1 llim" :1 NA 1J : n KA NA Pa i ?;.:c
.. '\ . q,:` 1:'= .
, .... ........ .._... .......
~:=y ,.
L.~ .. v.1,.a :.
NLa ,S~4
., .,
l$"F *J ~ NA ~FA NA NA
........ ..... ................................ ....... ........ - ------ --
------------
~1 cr
4 Cvtti NA NA y R:r NA
---- ------------ - ,...... . ....... ....... __--------
;.> s^.=. 4 4 1S44 NA '3A JA ?3~ NA S
------------------
............ .....................'....................... ...,. .. -- . . .
...
EP2 n~a¾a Fi~ rktta '1t#~c~r 3~~cat~tqrs (ECSt3 m rtSR)
.. ..
JxxstqlO .trractG.re #aps c1149P i Kf F~ Fil tlr1 h..P7' hEg?A h'fP NP EiOP
-----_-- ------- ...................... Efi533--'- ;..iqri(E
: ......
'~-._ . ..,~ =_..o
i ~} ~i;Y ?t3 t A~X, NA N,: KA .'cr'! gr. ti:t
-----------------
-
-- ...... _ ---- ------ ---
ZFi 3\ 7.~2 : ih24 Kt; NA NA NA i^J?is:
.... ....
,
----------- ....... ---------
N;Sl 2:7 6. M1EA? N 1 143 i
~..i ~
....... .. -. :: ...
_ .......... .........
:::..__. . .__.. __.___ .
..
, ... , .
~.
0 i 1,! ii ?Jrt N:i Us Y+\ ~~ it7
. ..`,.
56
