NZ617402B2 - Epoxyeicosatrienoic acid analogs and methods of making and using the same - Google Patents
Epoxyeicosatrienoic acid analogs and methods of making and using the same Download PDFInfo
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- NZ617402B2 NZ617402B2 NZ617402A NZ61740212A NZ617402B2 NZ 617402 B2 NZ617402 B2 NZ 617402B2 NZ 617402 A NZ617402 A NZ 617402A NZ 61740212 A NZ61740212 A NZ 61740212A NZ 617402 B2 NZ617402 B2 NZ 617402B2
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- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/51—Y being a hydrogen or a carbon atom
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/43—Y being a hetero atom
- C07C323/44—X or Y being nitrogen atoms
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
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- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
- C07D277/593—Z being doubly bound oxygen or doubly bound nitrogen, which nitrogen is part of a possibly substituted oximino radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
- C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
- C07D291/04—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
Abstract
Disclosed are compounds which are analogs of epoxyeicosatrienoic acid (EET) for example 1-(11-(2-hydroxyphenylthio)undec-5(Z)-enyl)-3-n-pentylurea and compositions containing these compounds. The compounds act as EET agonists and are intended for use as medications in the treatment of drug-induced nephrotoxicity, hypertension and other related conditions. Also disclosed are methods of making and using the compounds and compositions comprising the compounds. ephrotoxicity, hypertension and other related conditions. Also disclosed are methods of making and using the compounds and compositions comprising the compounds.
Description
EPOXYEICOSATRIENOIC ACID ANALOGS AND METHODS OF MAKING AND
USING THE SAME
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Appn. No. 61/472,410, filed
April 6, 2011, and U.S. Provisional Appn. No. 61/608,361 filed March 8, 2012, both of which
are hereby incorporated by reference herein for all purposes
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
This invention was made with government support under DK38226, HL59699,
GM31278, and HL51055 awarded by the National Institutes of Health. The government has
certain rights in the invention.
FIELD OF THE INVENTION
This invention relates generally to analogs of epoxyeicososatrienoic acid (EET).
More particularly, the present invention is directed to EET analogs that act as EET agonists and
are useful as medications in the treatment of drug-induced nephrotoxicity, hypertension and
other related conditions.
BACKGROUND OF THE INVENTION
Epoxyeicosatrienoic acids (EETs) are signaling molecules that can act as short-range
hormones, (i.e. they are autocrine and paracrine mediators) of the cardiovascular system and
kidney. They produce vasorelaxation as well as anti-inflammatory and pro-fibrinolytic effects.
Hypertension and Related Conditions. Cardiovascular disease afflicts 81 million
of the 300 million people in the United States, and 75 million of these people have hypertension.
CYP epoxygenase metabolites have biological actions that implicate them as important
contributors to cardiovascular function and blood pressure control.
One of the first biological activities described for epoxyeicosatrienoic acids (EETs)
was inhibition of renal tubular sodium reabsorption. Subsequently, EETs were determined to
dilate blood vessels and were identified as endothelium-derived hyperpolarizing factors (EDHF).
These biological actions are consistent with the idea that EETs would be eicosanoids that
contribute to lowering of blood pressure and prevent salt-sensitive hypertension.
Altered levels of EETs may contribute to hypertension in humans. A single
nucleotide polymorphism in a CYP epoxygenase gene is associated with hypertension.
Experimental studies in rodents have also demonstrated hypertension in conditions where kidney
CYP epoxygenase enzyme and/or EET levels were decreased. Increasing EET levels with
11,12-EET-SI, a 11,12-EET analog, improved renal afferent arteriolar function in vitro.
Currently, soluble epoxide hydrolase inhibitors (sEHI) are used in vivo to increase
EET levels and this results in a generalized increase in 11,12-EET and 14,15-EET and to a lesser
extent 8,9-EET. Recent in vivo studies have demonstrated that EET analogs lower blood
pressure in hypertensive rats, and also ameliorate the metabolic syndrome phenotype in heme-
oxygenase 2 deficient mice and prevent the adiposity-related vascular and renal damage. It does
appear as if some of the EET agonists like NUDSA may also inhibit sEH and increase CYP2C
epoxygenase expression. This type of combinational activity described for NUDSA could
provide added beneficial effects. As a whole, these findings have generated interest in targeting
the CYP epoxygenase pathway and EETs for the treatment of hypertension.
Even though EETs have actions on renal tubular transport and vascular function that
are essential for blood pressure regulation it has become apparent that additional biological
actions ascribed to EETs made them an excellent therapeutic target for other cardiovascular
diseases. These additional activities demonstrated for EETs include inhibition of platelet
aggregation and anti-inflammation. EETs also have been found to have effects on vascular
migration and proliferation, including promoting angiogenesis. Thus, EETs have become a
therapeutic target for end organ damage associated with cardiovascular diseases, cardiac
ischemic injury, atherosclerosis, and stroke.
The therapeutic potential for EET agonists and sEHIs could extend beyond
hypertension and cardiovascular diseases. Neural protection from ischemic injury has been
attributed to sEHI actions on blood vessels and neurons. There is growing evidence that sEHIs
provide protection from ischemic damage in the brain and heart through effects on apoptotic
signaling cascades. EET agonists and sEHIs have also been demonstrated to modulate pain in
various experimental animal models. Other possible therapeutic applications for EET agonists
are sure to be discovered when these agents are tested in other disease models.
Accordingly, there is a need in the art for novel EET agonists that are active as
therapeutic agents against hypertension and related cardiovascular and neural disease.
Drug-Induced Nephrotoxicity. A common side-effect of many drugs used in the
treatment of various conditions is nephrotoxicity. For instance, cisplatin, a platinum-based
inorganic compound, is one of the most potent and widely used chemotherapy agents available to
treat a variety of malignancies, including ovarian, lung, testicular and bladder cancers. Although,
cisplatin is used as an important chemotherapy drug in the clinic, it has potentially lethal adverse
effects. The most common of this adverse effect is nephrotoxicity (25-40% of cisplatin treated
patients develop acute renal failure), which limits the safe and effective use of this widely used
chemotherapeutic agent. The pathophysiology of cisplatin-induced nephrotoxicity involves
enhanced oxidative stress, inflammation, increased endoplasmic reticulum (ER) stress and renal
cell apoptosis.
EET is an important lipid mediator that exerts a number of biological actions
including anti-inflammatory, anti-oxidative and anti-apoptotic activities. A numbers of studies
demonstrated that with anti-inflammatory, anti-apoptotic and anti-oxidative activities, EET
possess strong organ protective potential. For instance, increased EET bioavailability resulted
from reduced conversion of EET to its less active form by soluble epoxide hydrolase (sEH)
inhibitor provides kidney protection in a number of preclinical models of human diseases. These
studies demonstrated that the kidney protective effect of EET was related to anti-inflammatory
and anti-oxidative effects of EET. Indeed, there is strong evidence that EET have anti-
inflammatory effects against acute and chronic inflammation. Apart from inflammation, EET
also protect cells from apoptosis. Thus, there are strong evidences of EET’s ability to protect
organ by mechanisms involve its anti-inflammatory, anti-apoptotic and anti-oxidative activities.
However, it is known that endogenously produced EETs are chemically and
metabolically labile. Also, rapid metabolism, low solubility and storage issue limit the
therapeutic prospect of EET. As such considerable interest has arisen in developing strategies to
enhance the bioavailability of EET. In this effort, attempts have been made to develop EET
analogs that possess EET-mimetic activity along with several key features important for stability
and bio-availability. Several of such EET analogs have demonstrated a number of biological
activities including organ protection.
In the present study we have investigated the kidney protective effect of two newly
developed orally active EET analogs in cisplatin-induced nephrotoxicity. We have demonstrated
that EET analogs offered marked reno-protection during cisplatin administration and this effect
was related to their anti-oxidative, anti-inflammatory, anti-ER stress and anti-apoptotic activities.
We have further demonstrated that while protecting the kidney from the deleterious nephrotoxic
effects of cisplatin, these EET analogs did not compromise cisplatin’s chemotherapeutic effect.
Acordingly, there is a need in the art for novel EET analogs that are active as
therapeutic agents against the deleterious nephrotoxic effects of cisplatin.
It is an object of the present invention to go someways towards fulfilling these needs
and/or to provide the public with a useful choice.
SUMMARY OF THE INVENTION
Here, the inventors demonstrate novel compositions of epoxyeicosatrienoic acids
(EET) analogs and uses thereof in the manufacture of a medicament for the treatment of
cardiovascular disease, particularly the use of such compositions as as anti-hypertensive agents.
Accordingly, the invention encompasses in a first aspect certain compounds that are
14,15-EET analogs. In certain embodiments, the compound has the structure of any one of the
following compounds.
In one embodiment, the invention comprises compound 7 or 30.
Also described is a method of making any of compounds 1-33 as described and
claimed herein.
Compounds according to the invention are, in certain embodiments, provided in the
form of a composition comprising a compound as described and claimed herein in combination
with a pharmaceutically acceptable carrier.
The present invention further encompasses methods of providing treatment of
hypertension in a non-human subject, resulting in a reduction of blood pressure in said non-
human subject. Such methods include steps of administering to a subject a therapeutically
effective amount of any of compounds 1-33, alone or in combination, as described and claimed
herein, whereby blood pressure in the subject is reduced. In one embodiment, the method
comprises administering compound 7. In an alternate embodiment the method comprises
administering compound 30.
In another embodiment, the present invention provides EET analogs having the
structures selected from the group consisting of
(EET-A) or (EET-B).
In yet another embodiment, the invention encompasses the use of any of the 14,15-
EET analogs described above for the manufacture of a medicament for treating hypertension in a
subject. As well, the present invention further contemplates compounds according to the
invention for use in treating hypertension in a subject.
The present invention further encompasses methods of treating drug-induced
nephrotoxicity in a non-human subject. In one embodiment, the invention comprises providing
treatment for the deleterious nephrotoxic effects of cisplatin in said non-human subject. Such
methods include steps of administering to a non-human subject a therapeutically effective
amount of a compound as described and claimed herein, whereby the deleterious nephrotoxic
effects of the drug in the subject are reduced.
Other objects, features and advantages of the present invention will become apparent
after review of the specification, claims and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1A depicts the chemical structure SRD-I9, which corresponds to EET
analog compound 26 of Table 1. Figure 1B shows mean measured blood pressure as a function
of days of treatment in spontaneously hypertensive rats administered a composition containing
vehicle or compound 26. Figure 1C shows mean measured blood pressure at day 0, day 7, and
day 14 in spontaneously hypertensive rats administered a composition containing vehicle or
compound 26.
Figure 2A depicts the chemical structure LGK-I15, which corresponds to EET
analog compound 20 of Table 1. Figure 2B shows mean measured blood pressure as a function
of days of treatment in spontaneously hypertensive rats administered a composition containing
vehicle or compound 20. Figure 2C shows mean measured blood pressure at day 0, day 7, and
day 14 in spontaneously hypertensive rats administered a composition containing vehicle or
compound 20.
Figure 3A depicts the chemical structure JLJ-I6, which corresponds to EET
analog compound 7 of Table 1. Figure 3B shows mean measured blood pressure as a function of
days of treatment in spontaneously hypertensive rats administered a composition containing
vehicle or compound 7. The data is graphed as 12 hour averages. Compounds were delivered i.p.
for 14 days. Figure 3C shows mean measured blood pressure at day 0, day 7, and day 14 relative
to initial treatment in spontaneously hypertensive rats administered a composition containing
vehicle or compound 7.
Figure 4A depicts the chemical structure MV-IV20, which corresponds to EET
analog compound 30 of Table 1. Figure 4B shows mean measured blood pressure as a function
of days of treatment in spontaneously hypertensive rats administered a composition containing
vehicle or compound 30. The data is graphed as 12 hour averages. Figure 3C shows mean
measured blood pressure at day 0, day 7, and day 14 in spontaneously hypertensive rats
administered a composition containing vehicle or compound 30.
Figure 5A shows mean measured blood pressure as a function of days of treatment
inangiotensin II induced hypertensive rats administered a composition containing vehicle or
compound 7. The data is graphed as 12 hour averages. Figure 5B shows mean measured blood
pressure at day 0, day 7, and day 14 in angiotensin II induced hypertensive rats administered a
composition containing vehicle or compound 7.
Figure 6A shows mean measured blood pressure as a function of days of treatment in
angiotensin II induced hypertensive rats administered a composition containing vehicle or
compound 30. The data is graphed as 12 hour averages. Figure 6B shows mean measured blood
pressure at day 0, day 7, and day 14 in angiotensin II induced hypertensive rats administered a
composition containing vehicle or compound 30.
Figure 7: (a) Plasma creatinine, (b) Blood urea nitrogen (BUN), (c) kidney injury
molecule-1, and (d) urinary NA Gin cisplatin administered rats pretreated with either EET
analogs, EET-A andEET-B or vehicle. *p<0.05 vs. normal Wistar Kyotorat; #p<0.05 vs. vehicle
treated rat administered cisplatin. Data expressed as mean ±SEM,n=5-7.
Figure 8A: Representative photomicrographs of Periodicacid-Schiff(PAS) Staining
(200x) depicting tubular cast formation along with the calculated cast are a fraction (%) in the
renal cortical sections of different experimental groups. *p<0.05 vs. normal Wistar Kyotorat;
#p<0.05 vs. vehicle treated rat. Data expressed as mean ±SEM, n=5-7.
Figure 8B: Representative photomicrographs of Periodicacid-Schiff(PAS) Staining
200x) depicting tubular cast formation along with the calculated cast area fraction (%) in the
renal medullary sections of different experimental groups. *p<0.05 vs. normal Wistar Kyoto rat;
#p<0.05 vs. vehicle treated rat. Data expressed as mean ±SEM,n=5-7.
Figure 9: RT-PCR analysis form RNA expressions of (a) NOX1, (b) gp91Phox, (d)
SOD1, (e) SOD2, (f) SOD3 and (c) measurements of kidney thiobarbituric acid-reactive
substances(TBARS) in cisplatin administered rats treated with either EET analogs A, B or
vehicle. *p<0.05vs. normal Wistar Kyoto rat;# p<0.05 vs. vehicle pretreated rat administered
cisplatin. Data expressed as mean ±SEM,n=5-7.
Figure 10: Renal expression of inflammatory marker genes TNF-α(a), IL-6 (b) and
IL-1β (c) in cisplatinadministered rats pretreated with either EET analogs EET-A and EET-B or
vehicle. *p<0.05 vs. normal Wistar Kyoto rat; #p<0.05 vs. vehicle pretreated rat administered
cisplatin. Data expressed as mean ±SEM, n=5-7.
Figure 11: Renal expression of endoplasmic reticulum stress marker genes
GRP78/BiP(a) and caspase12 (b) in cisplatin administered rats treated with either EET analogs
EET-A and EET-B or vehicle. *p<0.05 vs. normal WistarKyoto rat; #p<0.05 vs. vehicle treated
rat administered. Data expressed as mean ±SEM, n=5-7.
Figure 12: Renal cortical caspase 3 activity (a) andrenal expression of anti-apoptotic
gene Bcl2 (b) in different experimental groups. The ratios between the renal expression of anti-
apoptotic gene Bcl2 and the apoptotic genes Bak (c) and Bax (d) in different experimental
groups. *p<0.05 vs. normal Wistar Kyoto rat; #p<0.05 vs. vehicle treated rat administered
cisplatin. Data expressed as mean ±SEM, n=5-7.
Figure 13A: Cytotoxic effect of cisplatin in normal kidney cell (HEK293) and cancer
cells (Hela, U87, NCCIT).
Figure 13B: Effect of EET analog EET-A on the cell growth of HEK293, Hela, U87,
NCCIT. EET-A does not effect the chemotherapeutic effect of cisplatin in NCCIT cancer cells.
Data expressed as mean±SEM, n=5-7.
Figure 14: Structure of EET analogs EET-A and EET-B.
Figure 15: Synthesis of EET-B.
Figure 16A: Synthesis of EET-A.
Figure 16B: Alternate synthesis of EET-A.
DETAILED DESCRIPTION OF THE INVENTION
I. IN GENERAL
Before the present materials and methods are described, it is understood that this
invention is not limited to the particular methodology, protocols, materials, and reagents
described, as these may vary. It is also to be understood that the terminology used herein is for
the purpose of describing particular embodiments only, and is not intended to limit the scope of
the present invention which will be limited only by any later-filed nonprovisional applications.
It must be noted that as used herein and in the appended claims, the singular forms
“a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. As
well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably
herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used
interchangeably.
The term "comprising" as used in this specification and claims means "consisting at
least in part of", that is to say when interpreting independent claims including that term, the
features prefaced by that term in each claim all need to be present but other features can also be
present.
Unless defined otherwise, all technical and scientific terms used herein have the same
meanings as commonly understood by one of ordinary skill in the art to which this invention
belongs. Although any methods and materials similar or equivalent to those described herein can
be used in the practice or testing of the present invention, the preferred methods and materials
are now described. All publications and patents specifically mentioned herein are incorporated
by reference for all purposes including describing and disclosing the chemicals, instruments,
statistical analysis and methodologies which are reported in the publications which might be
used in connection with the invention. All references cited in this specification are to be taken as
indicative of the level of skill in the art. Nothing herein is to be construed as an admission that
the invention is not entitled to antedate such disclosure by virtue of prior invention.
II. THE INVENTION
Disclosed herein are novel EET analogs, EET agonists, and other related lipid
compounds, and compositions comprising such compounds, as well as methods of synthesizing
such compounds and the use of such compositions in treating hypertension and related
conditions in treating the deleterious effects of cisplatin nephrotoxicity and related conditions.
The inventors' have shown that several of the compounds exhibit anti-hypertensive effects and
are well-tolerated in relevant rat models. A number of different delivery options are possible,
including intraperitoneal injections, blood injections, or oral delivery. Liposomes, mycelles, and
emulsifiers can be used in to make these preparations more soluble.
As used herein, "subject" means mammals and non-mammals. “Mammals” means
any member of the class Mammalia including, but not limited to, humans, non-human primates
such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses,
sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals
including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals
include, but are not limited to, birds, and the like. The term "subject" does not denote a particular
age or sex.
As used herein, “administering” or “administration” includes any means for
introducing a compound of the present invention into the body, preferably into the systemic
circulation. Examples include but are not limited to oral, buccal, sublingual, pulmonary,
transdermal, transmucosal, as well as subcutaneous, intraperitoneal, intravenous, and
intramuscular injection.
A "therapeutically effective amount" means an amount of a compound that, when
administered to a subject for treating a disease or condition, is sufficient to effect such treatment
for the disease. The "therapeutically effective amount" will vary depending on the compound, the
disease state being treated, the severity or the disease treated, the age and relative health of the
subject, the route and form of administration, the judgment of the attending medical or veterinary
practitioner, and other factors.
For purposes of the present disclosure, “treating” or “treatment” describes the
management and care of a patient for the purpose of combating the disease, condition, or
disorder. The terms embrace both preventative, i.e., prophylactic, and palliative treatments.
Treating includes the administration of a compound of present invention to prevent the onset of
the symptoms or complications, alleviating the symptoms or complications, or eliminating the
disease, condition, or disorder.
A compound is administered to a patient in a therapeutically effective amount. A
compound can be administered alone or as part of a pharmaceutically acceptable composition.
In addition, a compound or composition can be administered all at once, as for example, by a
bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly
over a period of time, as for example, using transdermal delivery. Further, the dose of the
compound can be varied over time. A compound can be administered using an immediate
release formulation, a controlled release formulation, or combinations thereof. The term
"controlled release" includes sustained release, delayed release, and combinations thereof.
A pharmaceutical composition of the invention can be prepared, packaged, or sold in
bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is
discrete amount of the pharmaceutical composition comprising a predetermined amount of the
active ingredient. The amount of the active ingredient is generally equal to the dosage of the
active ingredient that would be administered to a patient or a convenient fraction of such a
dosage such as, for example, one-half or one-third of such a dosage.
The relative amounts of the active ingredient, the pharmaceutically acceptable carrier,
and any additional ingredients in a pharmaceutical composition of the invention will vary,
depending upon the identity, size, and condition of the human treated and further depending
upon the route by which the composition is to be administered. By way of example, the
composition can comprise between 0.1% and 100% (w/w) active ingredient. A unit dose of a
pharmaceutical composition of the invention will generally comprise from about 100 milligrams
to about two grams of the active ingredient, and preferably comprises from about 200 milligrams
to about 1.0 gram of the active ingredient.
A preferred dosage for humans would be in the low mg/kg range administered orally
once daily. Twice daily would also be acceptable.
To improve water solubility, the preferred compounds can be formulated with
cyclodextrins or cyclodextrin-derived products, derivatized with substituents such as
polyethylene glycols or other polar functionality, or included in liposomes. For oral delivery, the
compounds may be modified with lipophilic functionality or conjugated to actively absorbed
molecules. Other approaches are discussed in "Strategies to improve oral drug bioavailability",
Isabel Gomez-Orellana,Expert Opinion on Drug Delivery, May 2005, Vol. 2, No. 3 : Pages 419-
433, which is incorporated by reference herein.
Also described is a kit comprising a pharmaceutical composition of the invention and
instructional material. Instructional material includes a publication, a recording, a diagram, or
any other medium of expression which is used to communicate the usefulness of the
pharmaceutical composition of the invention for one of the purposes set forth herein in a human.
The instructional material can also, for example, describe an appropriate dose of the
pharmaceutical composition of the invention. The instructional material of the kit of the
invention can, for example, be affixed to a container which contains a pharmaceutical
composition of the invention or be shipped together with a container which contains the
pharmaceutical composition. Alternatively, the instructional material can be shipped separately
from the container with the intention that the instructional material and the pharmaceutical
composition be used cooperatively by the recipient.
Also described is a kit comprising a pharmaceutical composition of the invention and
a delivery device for delivering the composition to a human. By way of example, the delivery
device can be a squeezable spray bottle, a metered-dose spray bottle, an aerosol spray device, an
atomizer, a dry powder delivery device, a self-propelling solvent/powder-dispensing device, a
syringe, a needle, a tampon, or a dosage- measuring container. The kit can further comprise an
instructional material as described herein. The kit also comprises a container for the separate
compositions, such as a divided bottle or a divided foil packet. Additional examples of
containers include syringes, boxes, bags, and the like. Typically, a kit comprises directions for
the administration of the separate components. The kit form is particularly advantageous when
the separate components are preferably administered in different dosage forms (e.g., oral and
parenteral), are administered at different dosage intervals, or when titration of the individual
components of the combination is desired by the prescribing physician.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers
next to the tablets or capsules whereby the numbers correspond with the days of the regimen that
the tablets or capsules so specified should be ingested. Another example of such a memory aid is
a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . .
Second Week, Monday, Tuesday," etc. Other variations of memory aids will be readily apparent.
A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given
day.
Also described is a dispenser designed to dispense the daily doses one at a time in the
order of their intended use.. Preferably, the dispenser is equipped with a memory aid, so as to
further facilitate compliance with the dosage regimen. An example of such a memory aid is a
mechanical counter, which indicates the number of daily doses that have been dispensed.
Another example of such a memory aid is a battery-powered micro-chip memory coupled with a
liquid crystal readout, or audible reminder signal which, for example, reads out the date that the
last daily dose has been taken and/or reminds one when the next dose is to be taken.
The compounds of the present invention, optionally comprising other
pharmaceutically active compounds, can be administered to a patient either orally, rectally,
parenterally, (for example, intravenously, intramuscularly, or subcutaneously) intracisternally,
intravaginally, intraperitoneally, intravesically, locally (for example, powders, ointments or
drops), or as a buccal or nasal spray. Other contemplated formulations include projected
nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and
immunologically-based formulations.
Parenteral administration of a pharmaceutical composition includes any route of
administration characterized by physical breaching of a tissue of a human and administration of
the pharmaceutical composition through the breach in the tissue. Parenteral administration thus
includes administration of a pharmaceutical composition by injection of the composition, by
application of the composition through a surgical incision, by application of the composition
through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral
administration includes subcutaneous, intraperitoneal, intravenous, intraarterial, intramuscular, or
intrasternal injection and intravenous, intraarterial, or kidney dialytic infusion techniques. For
example, the compositions of the present invention can be administered to a subject by brain (via
vPAG) injections, intrathecal injections, intraperitoneal injections, or blood injections.
Compositions suitable for parenteral injection comprise the active ingredient
combined with a pharmaceutically acceptable carrier such as physiologically acceptable sterile
aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, or may comprise
sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of
suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, isotonic
saline, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable
mixtures thereof, triglycerides, including vegetable oils such as olive oil, or injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a
coating such as lecithin, by the maintenance of the required particle size in the case of
dispersions, and/or by the use of surfactants. Such formulations can be prepared, packaged, or
sold in a form suitable for bolus administration or for continuous administration. Injectable
formulations can be prepared, packaged, or sold in unit dosage form, such as in ampules, in
multi-dose containers containing a preservative, or in single-use devices for auto-injection or
injection by a medical practitioner.
Formulations for parenteral administration include suspensions, solutions, emulsions
in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable
formulations. Such formulations can further comprise one or more additional ingredients
including suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for
parenteral administration, the active ingredient is provided in dry (i.e. powder or granular) form
for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral
administration of the reconstituted composition.
The pharmaceutical compositions can be prepared, packaged, or sold in the form of a
sterile injectable aqueous or oily suspension or solution. This suspension or solution can be
formulated according to the known art, and can comprise, in addition to the active ingredient,
additional ingredients such as the dispersing agents, wetting agents, or suspending agents
described herein. Such sterile injectable formulations can be prepared using a non-toxic
parenterally-acceptable diluent or solvent, such as water or 1,3-butanediol, for example. Other
acceptable diluents and solvents include Ringer's solution, isotonic sodium chloride solution, and
fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations
which are useful include those which comprise the active ingredient in microcrystalline form, in
a liposomal preparation, or as a component of a biodegradable polymer systems. Compositions
for sustained release or implantation can comprise pharmaceutically acceptable polymeric or
hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer,
or a sparingly soluble salt.
The compounds according to the present invention may also contain adjuvants such
as preserving, wetting, emulsifying, and/or dispersing agents, including, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic
agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable
pharmaceutical compositions can be brought about by the use of agents capable of delaying
absorption, for example, aluminum monostearate and/or gelatin. In particular, liposomes,
mysomes and emulsifiers can be used in to make the present compounds more soluble for
delivery.
Dosage forms can include solid or injectable implants or depots. In preferred
embodiments, the implant comprises an effective amount of an active agent and a biodegradable
polymer. In preferred embodiments, a suitable biodegradable polymer can be selected from the
group consisting of a polyaspartate, polyglutamate, poly(L-lactide), a poly(D,L-lactide), a
poly(lactide-co-glycolide), a poly(ε-caprolactone), a polyanhydride, a poly(beta-hydroxy
butyrate), a poly(ortho ester) and a polyphosphazene. In other embodiments, the implant
comprises an effective amount of active agent and a silastic polymer. The implant provides the
release of an effective amount of active agent for an extended period of about one week to
several years.
Solid dosage forms for oral administration include capsules, tablets, powders, and
granules. In such solid dosage form, the active compound is admixed with at least one inert
customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or
extenders, as for example, starches, lactose, sucrose, mannitol, or silicic acid; (b) binders, as for
example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, or acacia; (c)
humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, or sodium
carbonate; (e) solution retarders, as for example, paraffin; (f) absorption accelerators, as for
example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol or
glycerol monostearate; (h) adsorbents, as for example, kaolin or bentonite; and/or (i) lubricants,
as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage forms may also
comprise buffering agents.
A tablet comprising the active ingredient can, for example, be made by compressing
or molding the active ingredient, optionally with one or more additional ingredients.
Compressed tablets can be prepared by compressing, in a suitable device, the active ingredient in
a free-flowing form such as a powder or granular preparation, optionally mixed with one or more
of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded
tablets can be made by molding, in a suitable device, a mixture of the active ingredient, a
pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture.
Pharmaceutically acceptable excipients used in the manufacture of tablets include
inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents.
Known dispersing agents include potato starch and sodium starch glycolate. Known surface
active agents include sodium lauryl sulfate. Known diluents include calcium carbonate, sodium
carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate,
and sodium phosphate. Known granulating and disintegrating agents include corn starch and
alginic acid. Known binding agents include gelatin, acacia, pre-gelatinized maize starch,
polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include
magnesium stearate, stearic acid, silica, and talc.
Tablets can be non-coated or they can be coated using known methods to achieve
delayed disintegration in the gastrointestinal tract of a human, thereby providing sustained
release and absorption of the active ingredient. By way of example, a material such as glyceryl
monostearate or glyceryl distearate can be used to coat tablets. Further by way of example,
tablets can be coated using methods described in U.S. Pat. Nos. 4,256,108; 4,160,452; and
4,265,874 to form osmotically-controlled release tablets. Tablets can further comprise a
sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of
these in order to provide pharmaceutically elegant and palatable preparation.
Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared
with coatings or shells, such as enteric coatings and others well known in the art. They may also
contain opacifying agents, and can also be of such composition that they release the active
compound or compounds in a delayed manner. Examples of embedding compositions that can
be used are polymeric substances and waxes. The active compounds can also be in micro-
encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Solid compositions of a similar type may also be used as fillers in soft or hard filled
gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight
polyethylene glycols, and the like. Hard capsules comprising the active ingredient can be made
using a physiologically degradable composition, such as gelatin. Such hard capsules comprise
the active ingredient, and can further comprise additional ingredients including, for example, an
inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin. Soft gelatin capsules
comprising the active ingredient can be made using a physiologically degradable composition,
such as gelatin. Such soft capsules comprise the active ingredient, which can be mixed with
water or an oil medium such as peanut oil, liquid paraffin, or olive oil.
Oral compositions can be made, using known technology, which specifically release
orally-administered agents in the small or large intestines of a human patient. For example,
formulations for delivery to the gastrointestinal system, including the colon, include enteric
coated systems, based, e.g., on methacrylate copolymers such as poly(methacrylic acid, methyl
methacrylate), which are only soluble at pH 6 and above, so that the polymer only begins to
dissolve on entry into the small intestine. The site where such polymer formulations disintegrate
is dependent on the rate of intestinal transit and the amount of polymer present. For example, a
relatively thick polymer coating is used for delivery to the proximal colon (Hardy et al., Aliment.
Pharmacol. Therap. (1987) 1:273-280). Polymers capable of providing site-specific colonic
delivery can also be used, wherein the polymer relies on the bacterial flora of the large bowel to
provide enzymatic degradation of the polymer coat and hence release of the drug. For example,
azopolymers (U.S. Pat. No. 4,663,308), glycosides (Friend et al., J. Med. Chem. (1984) 27:261-
268) and a variety of naturally available and modified polysaccharides (see PCT application
PCT/GB89/00581) can be used in such formulations.
Pulsed release technology such as that described in U.S. Pat. No. 4,777,049 can also
be used to administer the active agent to a specific location within the gastrointestinal tract.
Such systems permit drug delivery at a predetermined time and can be used to deliver the active
agent, optionally together with other additives that my alter the local microenvironment to
promote agent stability and uptake, directly to the colon, without relying on external conditions
other than the presence of water to provide in vivo release.
Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the
liquid dosage form may contain inert diluents commonly used in the art, such as water or other
solvents, isotonic saline, solubilizing agents and emulsifiers, as for example, ethyl alcohol,
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene
glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, almond oil, arachis oil,
coconut oil, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil,
MIGLYOL , glycerol, fractionated vegetable oils, mineral oils such as liquid paraffin,
tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of
these substances, and the like.
Besides such inert diluents, the compounds of the present invention can also include
adjuvants, such as wetting agents, emulsifying and suspending agents, demulcents, preservatives,
buffers, salts, sweetening, flavoring, coloring and perfuming agents. Suspensions, in addition to
the active compound, may contain suspending agents, as for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol or sorbitan esters, microcrystalline cellulose, hydrogenated
edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, agar-agar, and
cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, aluminum metahydroxide, bentonite, or mixtures of these
substances, and the like. Liquid formulations of a pharmaceutical composition of the invention
that are suitable for oral administration can be prepared, packaged, and sold either in liquid form
or in the form of a dry product intended for reconstitution with water or another suitable vehicle
prior to use.
Known dispersing or wetting agents include naturally-occurring phosphatides such as
lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic
alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived
from a fatty acid and a hexitol anhydride (e.g. polyoxyethylene stearate,
heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene
sorbitan monooleate, respectively). Known emulsifying agents include lecithin and acacia.
Known preservatives include methyl, ethyl, or n-propyl-para-hydroxybenzoates, ascorbic acid,
and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol,
sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for
example, beeswax, hard paraffin, and cetyl alcohol.
Liquid solutions of the active ingredient in aqueous or oily solvents can be prepared
in substantially the same manner as liquid suspensions, the primary difference being that the
active ingredient is dissolved, rather than suspended in the solvent. Liquid solutions of the
pharmaceutical composition of the invention can comprise each of the components described
with regard to liquid suspensions, it being understood that suspending agents will not necessarily
aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example,
water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl
alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils,
and mineral oils such as liquid paraffin.
Compositions for rectal or vaginal administration can be prepared by mixing a
compound of the present invention and any additional compounds with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are
solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the
rectum or vaginal cavity and release the active ingredient. Such a composition can be in the
form of, for example, a suppository, a retention enema preparation, and a solution for rectal or
colonic irrigation. Suppository formulations can further comprise various additional ingredients
including antioxidants and preservatives. Retention enema preparations or solutions for rectal or
colonic irrigation can be made by combining the active ingredient with a pharmaceutically
acceptable liquid carrier. As is known in the art, enema preparations can be administered using,
and can be packaged within, a delivery device adapted to the rectal anatomy of a human. Enema
preparations can further comprise various additional ingredients including antioxidants and
preservatives.
A pharmaceutical composition of the invention can be prepared, packaged, or sold in
a formulation suitable for vaginal administration. Such a composition can be in the form of, for
example, a suppository, an impregnated or coated vaginally-insertable material such as a tampon,
a douche preparation, or a solution for vaginal irrigation.
Dosage forms for topical administration of a compound according to the present
invention include ointments, powders, sprays and inhalants. The compounds are admixed under
sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers, and/or
propellants that may be required. Formulations suitable for topical administration include liquid
or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such
as creams, ointments or pastes, and solutions or suspensions. Topically-administrable
formulations can, for example, comprise from about 0.1% to about 10% (w/w) active ingredient,
although the concentration of the active ingredient can be as high as the solubility limit of the
active ingredient in the solvent. Formulations for topical administration can further comprise one
or more of the additional ingredients described herein.
Ophthalmic formulations, eye ointments, powders, and solutions are also
contemplated as being within the scope of this invention. Such formulations can, for example,
be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution or suspension of
the active ingredient in an aqueous or oily liquid carrier. Such drops can further comprise
buffering agents, salts, or one or more other of the additional ingredients described herein. In
other embodiments, ophthalmalmically administrable formulations comprise the active
ingredient in microcrystalline form or in a liposomal preparation.
Pharmaceutical compositions of the invention formulated for pulmonary delivery can
provide the active ingredient in the form of droplets of a solution or suspension. Such
formulations can be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or
suspensions, optionally sterile, comprising the active ingredient, and can conveniently be
administered using any nebulization or atomization device. Such formulations can further
comprise one or more additional ingredients including a flavoring agent such as saccharin
sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as
methylhydroxybenzoate. The droplets provided by this route of administration preferably have
an average diameter in the range from about 0.1 to about 200 nanometers.
A pharmaceutical composition of the invention can be prepared, packaged, or sold in
a formulation suitable for buccal administration. Such formulations can, for example, be in the
form of tablets or lozenges made using conventional methods, and can, for example, comprise
0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable or degradable
composition and, optionally, one or more of the additional ingredients described herein.
Alternately, formulations suitable for buccal administration can comprise a powder or an
aerosolized or atomized solution or suspension comprising the active ingredient. Such powdered,
aerosolized, or atomized formulations, when dispersed, preferably have an average particle or
droplet size in the range from about 0.1 to about 200 nanometers, and can further comprise one
or more of the additional ingredients described herein.
For parenteral administration in non-human animals, the compounds of the present
invention may be prepared in the form of a paste or a pellet and administered as an implant,
usually under the skin of the head or ear of the animal. Paste formulations can be prepared by
dispersing a compound or compounds in pharmaceutically acceptable oil such as peanut oil,
sesame oil, corn oil or the like. Pellets containing a therapeutically effective amount of a
compound or compounds can be prepared by admixing the compound with a diluent such as a
carbowax, carnauba wax, and the like, and a lubricant, such as magnesium or calcium stearate,
can be added to improve the pelleting process. It is, of course, recognized that more than one
pellet may be administered to an animal to achieve the desired dose level. Moreover, it has been
found that such implants may also be administered periodically during the animal treatment
period in order to maintain the proper active agent level in the animal's body.
The compounds of the present invention and the pharmaceutically acceptable salts of
the same, can be administered to a patient at dosage levels in the range of from about 0.01 to
about 1,000 mg per day. For a normal adult human having a body weight of about 70 kg, a
dosage in the range of from about 0.01 to about 300 mg is typically sufficient, with 1-10 mg/kg a
preferred dosage. However, some variability in the general dosage range may be required
depending upon the age and weight of the subject being treated, the intended route of
administration, the particular compound being administered and the like. The determination of
dosage ranges and optimal dosages for a particular patient is well within the ability of one of
ordinary skill in the art having the benefit of the instant disclosure. It is also noted that the
compounds of the present invention can be used in sustained release, controlled release, and
delayed release formulations, which forms are also well known to one of ordinary skill in the art.
It is not critical whether the compounds of the present invention are administered
directly to the cell, to a tissue comprising the cell, a body fluid that contacts the cell, or a body
location from which the compound can diffuse or be transported to the cell. It is sufficient that
the compound is administered to the patient in an amount and by a route whereby an amount of
the compound sufficient to mobilize lipids in the cell arrives, directly or indirectly at the cell.
The minimum amount varies with the identity of the compounds.
The specific dosage and dosage range that can be used depends on a number of
factors, including the requirements of the patient, the severity of the condition being treated, and
the pharmacological activity of the compound being administered. The determination of dosage
ranges and optimal dosages for a particular patient is well within the ordinary skill of one in the
art in view of this disclosure. It is understood that the ordinarily skilled physician or veterinarian
will readily determine and prescribe an effective amount of the compound to mobilize lipid
stores, induce weight loss, or inhibit appetite in the patient. In so proceeding, the physician or
veterinarian can, for example, prescribe a relatively low dose at first, subsequently increasing the
dose until an appropriate response is obtained. It is further understood, however, that the specific
dose level for any particular human will depend upon a variety of factors including the activity of
the specific compound employed, the age, body weight, general health, gender, and diet of the
human, the time of administration, the route of administration, the rate of excretion, any drug
combination, and the severity of any disorder being treated.
Various exemplary embodiments of compositions and methods according to this
invention are now described in the following examples. In these embodiments, specific products
identified by Arabic numerals (e.g., 1, 2, 3, etc.) refer to the specific structures so identified in
the following description, particularly in Table 1 below and the appended claims
III. EXAMPLES
The following examples are offered for illustrative purposes only and are not intended
to limit the scope of the present invention in any way. Indeed, various modifications of the
invention in addition to those shown and described herein will become apparent to those skilled
in the art from the foregoing description and the following examples and fall within the scope of
the appended claims.
Example 1: Synthesis of 33 EET Analogs
In this Example, the inventors report the synthesis of a library of EET analogs. The
chemical structures of these compounds, designated as compounds 1-33, are shown in Table 1
below.
General Procedures. Unless stated otherwise, yields refer to purified products and
are not optimized. Final compounds were judged ≥95% pure by HPLC using a Zorbax Eclipse
C18 (250 × 4.6 mm; Agilent) connected to an Agilent 1200 API/LC-MS with acetonitrile/water
combinations as solvent. All oxygen and/or moisture sensitive reactions were performed under
an argon atmosphere using oven-dried glassware and anhydrous solvents. Anhydrous solvents
were freshly distilled from sodium benzophenone ketyl, except for CH Cl , which was distilled
from CaH . Extracts were dried over anhydrous Na SO and filtered prior to removal of all
2 2 4
volatiles under reduced pressure. Unless otherwise noted, commercially available materials were
used without purification. Flash chromatography (FC) was performed using E Merck silica gel
60 (240–400 mesh). Thin layer chromatography (TLC) was performed using pre-coated plates
purchased from E. Merck (silica gel 60 PF254, 0.25 mm). Nuclear magnetic resonance (NMR)
spectra were recorded on Varian 300, 400 or 500 spectrometers at operating frequencies of
1 13
300/400/500 MHz ( H) or 75/100/125 MHz ( C) in CDCl , unless otherwise stated. Nuclear
magnetic resonance (NMR) splitting patterns are described as singlet (s), doublet (d), triplet (t),
quartet (q), and broad (br); the values of chemical shifts (δ) are given in ppm relative to residual
1 13
solvent (chloroform δ = 7.27 for H NMR or δ = 77.23 for proton decoupled C NMR), and
coupling constants (J) are given in Hertz (Hz). Melting points were determined using an
OptiMelt (Stanford Research Systems) and are uncorrected. The Notre Dame University Mass
Spectroscopy Facility or Prof. Kasem Nithipatikom (Medical College of Wisconsin) kindly
provided high-resolution mass spectral analyses.
Table 1: 33 EET analogs and measured vascular relaxation and sEH inhibition activity.
The synthesis of the EET-compounds of Table 1 are provided as follows:
Synthesis of Analog 25.
tert-Butyldiphenyl-[12-(tetrahydro-2H-pyranyloxy)dodecynyloxy)]silane.
N-Butyllithium (12.0 mL of 2.5 M solution in hexanes, 30.0 mmol) was added dropwise with
stirring to a –78 °C solution of 2-(hexynyloxy)tetrahydro-2H-pyran (5.0 g, 27.43 mmol, G. F.
Smith Chem. Co.) in THF/HMPA (4:1, 150 mL) under an argon atmosphere. After 30 min, the
reaction mixture was warmed to 0 °C and maintained at this temperature for 2 h. After re-cooling
to –78 °C, a solution of 1-tert-butyldiphenylsilyloxybromohexane (11.50 g, 27.43 mmol) in
THF (55 mL) was added and the temperature was raised over 3 h to 23 °C. After an additional 12
h, the reaction mixture was quenched with saturated aq. NH Cl solution (25 mL). The mixture
was extracted with EtOAc (2 × 100 mL) and the combined extracts were washed with water (2 ×
150 mL), brine (50 mL), dried, and concentrated under reduced pressure. The residue was
purified by SiO column chromatography to give the title compound (11.14 g, 78%), obtained as
a colorless oil, whose spectral data matched literature values. TLC: 15% EtOAc/hexanes, R ∼
0.60; H NMR (400 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 4.57 (t, J = 4.3 Hz, 1H), 3.78-
3.86 (m, 2H), 3.65 (t, J = 6.3 Hz, 2H), 3.32-3.54 (m, 2H), 2.10-2.22 (m, 4H), 1.24-1.84 (m,
18H), 1.04 (s, 9H); C NMR (100 MHz) δ 130.61, 129.17, 124.54, 122.62, 93.82, 75.48, 74.89,
72.41, 72.10, 71.78, 62.11, 58.93, 57.32, 27.51, 25.79, 24.18, 23.99, 23.68, 21.96, 21.87, 21.0,
.55, 20.40, 14.26, 13.77, 13.67.
12-(tert-Butyldiphenylsilyloxy)dodecynol. A mixture of tert-butyldiphenyl-
[12-(tetrahydro-2H-pyranyloxy)dodecynyloxy)]silane (11.0 g, 21.14 mmol) and p-
tolunesulfonic acid (165 mg) in MeOH (110 mL) was stirred at room temperature for 10 h. The
reaction mixture was quenched with sat. aq. NaHCO solution (10 mL). The methanol was
evaporated, then more water (50 mL), and the mixture extracted with EtOAc (3 × 75 mL). The
combined organic extracts were washed with water (2 × 50 mL), brine (40 mL), dried and
concentrated under reduced pressure. The residue was purified by SiO chromatography to give
the title compound (7.93 g, 86%), obtained as a colorless oil, whose spectral data matched
literature values. TLC: EtOAc/hexanes (3:7), R ∼ 0.44; H NMR (300 MHz) δ 7.64-7.68 (m,
4H), 7.34-7.42 (m, 6H), 3.62 (t, J = 6.3 Hz, 4H), 2.06-2.22 (m, 4H), 1.50-1.64 (m, 12H), 1.04 (s,
9H); C NMR (100 MHz) δ 135.81, 134.36, 129.74, 127.82, 80.89, 80.01, 64.14, 62.71, 32.71,
32.10, 29.34, 28.86, 27.11, 25.59, 25.57, 19.46, 18.93, 18.77.
12-(tert-Butyldiphenylsilyloxy)dodec-5(Z)-enol. NaBH (82 mg, 2.28 mmol)
was added in portions with vigorously stirring to a room temperature solution of Ni(OAc) ·4H O
(567 mg, 2.28 mmol) in absolute ethanol (20 mL) under a hydrogen atmosphere (1 atm). After
min, freshly distilled ethylenediamine (0.30 mL, 4.56 mmol) was added to the black
suspension, followed after a further 15 min by a solution of 12-(tert-
butyldiphenylsilyloxy)dodecynol (4.0 g, 9.16 mmol) in absolute EtOH (10 mL). After 1 h,
the reaction mixture was quenched with Et O (20 mL) and passed through a small bed of silica
gel. The bed was rinsed with another portion of Et O (5 mL). The combined ethereal filtrates
were concentrated under reduced pressure to afford the title compound (3.85 g, 96%) as a
colorless oil sufficiently pure to be used directly in the next step. TLC: EtOAc/hexanes (3:7), R
∼ 0.46. H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 5.42-5.28 (m, 2H), 3.65-
3.60 (t, J = 6.4 Hz, 4H), 2.08-1.96 (m, 4H), 1.50-1.60 (m, 4H), 1.40-1.24 (m, 10H), 1.04 (s, 9H);
C NMR (100 MHz) δ 135.81, 134.40, 130.61, 129.71, 129.60, 127.80, 64.21, 63.14, 32.78,
32.60, 29.98, 29.27, 27.42, 27.14, 27.10, 26.08, 25.92, 19.48. HRMS calcd for C H O Si
28 43 2
[M+1] 439.3032, found 439.3027.
1-tert-Butyldiphenylsilyloxyazidododec-7(Z)-ene. Diisopropyl
azodicarboxylate (DIAD; 1.46 mL, 7.35 mmol) was added dropwise to a –20 °C solution of PPh
(2.10 g, 8.0 mmol) in dry THF (45 mL) under an argon atmosphere. After 10 min, a solution of
12-(tert-butyldiphenylsilyloxy)dodec-5(Z)-enol (3.20 g, 7.35 mmol) from above in dry THF
(10 mL) was added dropwise. After 30 min, the mixture was warmed to 0 °C and
diphenylphosphoryl azide (1.58 mL, 7.35 mmol) was added dropwise. After stirring 4 h at rt, the
reaction mixture was quenched with water (150 mL) and extracted with EtOAc (2 × 100 mL).
The combined organic extracts were washed with brine (100 mL), dried (Na SO ), and
concentrated under reduced pressure. The residue was purified by SiO column chromatography
eluting with 4% EtOAc/hexane to afford the title compound (2.45 g, 72%). TLC: EtOAc/hexanes
(1:9), R ∼ 0.55; H NMR (400 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 5.28-5.42 (m, 2H),
3.70 (t, J = 5.8 Hz, 2H), 3.27 (t, J = 6.3 Hz, 2H), 1.96-2.10 (m, 4H), 1.24-1.64 (m, 12H), 1.04 (s,
9H); C NMR (100 MHz) δ 135.84, 134.41, 130.93, 129.75, 129.12, 127.83, 64.22, 51.62,
32.81, 29.93, 29.30, 28.68, 27.46, 27.14, 27.02, 26.90, 25.96, 19.49; IR (neat) 2930, 2783, 2331,
-1 +
2097, 1106 cm . HRMS calcd for C H N OSi [M+1] 464.3097, found 464,3099.
28 42 3
1-tert-Butyldiphenylsilyloxyaminododec-7(Z)-ene. Triphenylphosphine (1.18 g,
4.50 mmol) was added to a stirring solution of azide 1-tert-butyldiphenylsilyloxy
azidododec-7(Z)-ene (1.90 g, 4.10 mmol) in THF (12 mL) containing 4 drops of deionized water.
After 12 h, the reaction mixture was diluted with CH Cl (10 mL), dried, and concentrated in
vacuo to give the title compound (1.36 g, 76%) as a viscous, colorless oil that was used directly
in the next reaction without further purification. TLC: MeOH/CH Cl (1:4), R ∼ 0.25; H NMR
2 2 f
(400 MHz) δ 7.62-7.68 (m, 4H), 7.32-7.40 (m, 6H), 5.30-5.40 (m, 2H), 3.63 (t, J = 5.2 Hz, 2H),
2.62 (t, J = 4.8 Hz, 2H), 1.92-2.06 (m, 4H), 1.40-1.58 (m, 4H), 1.20-1.40 (m, 8H), 1.03 (s, 9H);
C NMR (100 MHz) δ 135.79, 134.37, 130.42, 129.70, 127.78, 64.19, 42.28, 33.44, 32.77,
29.93, 29.28, 27.40, 27.21, 27.10, 25.92, 19.44. HRMS calcd for C H NOSi [M + 1]
28 44
438.3192, found 438.3186.
1-(12-(tert-Butyldiphenylsilyloxy)dodec-5(Z)-enyl)n-pentylurea. A solution of
1-tert-butyldiphenylsilyloxyaminododec-7(Z)-ene (1.32 g, 3.0 mmol) in THF (5 mL) was
added dropwise to a stirring solution of n-pentyl isocyanate (0.386 mL, 3.0 mmol) in THF (10
mL). After 3 h stirring at room temperature, all volatiles were removed under reduced pressure
and the residue was purified by SiO column chromatography eluting with 20% EtOAc/hexane
to afford the title compound (1.26 g, 76%) as a viscous oil. TLC: EtOAc/hexanes (2:3), R ∼
0.40; H NMR (300 MHz) δ 7.60-7.70 (m, 4H), 7.35-7.42 (m, 6H), 5.28-5.42 (m, 2H), 5.16 (br s,
-NH, 2H), 3.65 (t, J = 6.5 Hz, 2H), 3.08-3.20 (m, 4H), 1.96-2.08 (m, 4H), 1.22-1.60 (m, 18H),
1.02 (s, 9H), 0.89 (t, J = 7.3 Hz, 3H); C NMR (100 MHz) δ 159.23, 135.80, 134.24, 130.52,
129.74, 129.49, 127.82, 64.22, 40.62, 40.54, 32.80, 30.33, 29.95, 29.37, 29.32, 27.46, 27.34,
27.18, 27.11, 25.97, 22.71, 19.46, 14.29. HRMS calcd for C H N O Si [M+1] 551.4033,
34 55 2 2
found 551.4032.
1-(12-Hydroxydodec-5(Z)-enyl)n-pentylurea. A mixture of 1-(12-(tert-
butyldiphenylsilyloxy)dodec-5(Z)-enyl)n-pentylurea (1.12 g, 2.0 mmol) and tetra-n-
butylammonium fluoride (2.20 mL of 1 M soln in THF, 2.2 mmol) in dry THF (10 mL) was
stirred at room temperature under an argon atmosphere for 12 h, and then evaporated to dryness
in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water (30 mL), brine
(30 mL), dried and evaporated in vacuo. Purification of the residue via SiO column
chromatography gave the title compound (0.56 g, 89%) as a colorless solid, mp 63.7-63.8 °C.
TLC: EtOAc/hexanes (7:3), R ∼ 0.30; H NMR (300 MHz) δ 5.25-5.42 (m, 2H), 4.40-4.56 (br s,
-NH, 2H), 3.60-3.68 (d, J = 6.5 Hz, 2H), 3.08-3.20 (m, 4H), 1.96-2.14 (m, 4H), 1.22-1.60 (m,
18H), 0.88 (t, J = 7.0 Hz, 3H); C NMR (125 MHz) δ 159.26, 130.23, 129.62, 63.72, 40.33,
40.29, 32.92, 30.30, 30.26, 29.74, 29.35, 29.13, 27.26, 27.20, 27.13, 25.82, 22.69, 14.27. HRMS
calcd for C H N O [M+1] 313.2855, found 313.2857.
18 37 2 2
1-(12-Bromododec-5(Z)-enyl)n-pentylurea. CBr (0.55 g, 1.66 mmol) and PPh
(0.43 g, 1.66 mmol) were added to a 0 °C solution of 1-(12-hydroxydodec-5(Z)-enyl)n-
pentylurea (0.43 g, 1.38 mmol) in CH Cl (20 mL). After 2 h at room temperature, the reaction
mixture was concentrated in vacuo and the residue was purified via SiO column
chromatography to give 1-(12-bromododec-5(Z)-enyl)n-pentylurea (0.43 g, 83%) as a viscous
oil, mp 46.7-46.8 °C. TLC: EtOAc/hexanes (2:3), R ∼ 0.60; H NMR (300 MHz) δ 5.22-5.42 (m,
2H), 4.40 (br s, 2H), 3.42 (t, J = 9.3 Hz, 2H), 3.10-3.20 (m, 4H), 1.98-2.10 (m, 4H), 1.80-1.90
(m, 2H), 1.25-1.55 (m, 16H), 0.92 (t, J = 7.2 Hz, 3H); C NMR (100 MHz) δ 159.51, 130.14,
129.69, 40.48, 40.39, 34.20, 32.96, 30.34, 29.67, 29.36, 28.58, 28.25, 27.31, 27.27, 27.17, 22.68,
14.26. HRMS calcd for C H BrN O [M+1] 375.2011, found 375.2014.
18 36 2
1-(12-Cyanododec-5(Z)-enyl)n-pentylurea. A mixture of potassium cyanide
(0.23 g, 3.54 mmol) and 1-(12-bromododec-5(Z)-enyl)n-pentylurea (0.90 g, 2.40 mmol) was
stirred in DMSO (5 mL) at room temperature. After 12 h, the reaction mixture was diluted with
water (20 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were
washed with water (2 × 25 mL), brine (25 mL), dried (Na SO ) and was passed through a silica
gel column to give the title compound (0.62 g, 81%) as a colorless solid, mp 56-57 °C. TLC:
EtOAc/hexanes (2:3), R ∼ 0.45. H NMR (300 MHz) δ 5.29-5.40 (m, 2H), 4.27 (br s, -NH, 2H),
3.10-3.20 (m, 4H), 2.34 (t, J = 7.0 Hz, 2H), 1.98-2.08 (m, 4H) 1.24-1.70 (m, 18H), 0.89 (t, J =
7.0 Hz, 3H); C NMR (125 MHz) δ 159.41, 129.94, 129.86, 120.14, 40.45, 40.35, 30.30, 29.50,
29.33, 28.70, 28.51, 27.26, 27.16, 25.47, 22.66, 17.28,14.24; IR (neat) 2930, 2281, 2184, 2042,
-1 +
1936, 1613, 1197, 1042 cm . HRMS calcd for C H N O [M+1] 322.2858, found 322.2867.
19 36 3
N'-Hydroxy(3-n-pentylureido)tridec-8(Z)-enimidamide. To a suspension of 1-
(12-cyanododec-5(Z)-enyl)n-pentylurea (350 mg, 1.09 mmol) in MeOH/H O (4:1; 12 mL)
was added H NOH⋅HCl (228 mg, 3.28 mmol) and Na CO (344 mg, 3.25 mmol). The reaction
2 2 3
mixture was heated at 60 °C for 18 h, then cooled to room temperature and all volatiles were
removed in vacuo. The residue was diluted with water (30 mL) and extracted into ethyl acetate
(2 × 25 mL). The combined organic extracts were washed with water (2 × 10 mL), brine (10
mL), dried and purified via flash silica gel column chromatography using 5% MeOH/CH Cl to
give the title compound (239 mg, 62%) as a colorless solid, mp 94.6-94.7 °C. TLC:
MeOH/CH Cl (1:4), R ∼ 0.20; H NMR (CD OD, 300 MHz) δ 5.34-5.42 (m, 2H), 3.33 (s, 2H),
2 2 f 3
3.08-3.16 (m, 3H), 2.02-2.10 (m, 6H), 1.52-1.60 (m, 2H), 1.44-1.52 (m, 5H), 1.30-1.44 (m, 10H),
0.92 (t, J = 7.2 Hz, 3H); C NMR (CD OD, 125 MHz) δ 160.14, 155.23, 129.95, 129.42, 39.86,
39.76, 30.70, 29.95, 29.89, 29.59, 29.06, 28.91, 27.18, 26.97, 26.95, 26.78, 22.39, 13.34. HRMS
calcd for C H N O [M+1] 355.3073, found 355.3078.
19 39 4 2
Analog 25. To an ice cooled solution of N'-hydroxy(3-n-pentylureido)tridec-8(Z)-
enimidamide (100 mg, 0.28 mmol) and pyridine (45 μL, 0.56 mmol) in THF (100 mL) was
added dropwise a solution of thionyl chloride (20 μL, 0.28 mmol) in CH Cl (2 mL). After 1 h,
the reaction mixture was concentrated in vacuo, diluted with water (25 mL), and extracted with
CH Cl (2 × 10 mL). The combined organic extracts were washed with water and dried. The
solvent was evaporated in vacuo and the residue was purified by SiO column chromatography
using 10% MeOH/CH Cl to give 25 (80 mg, 72%) as a sticky solid. TLC: MeOH/CH Cl (1:9),
2 2 2 2
R ∼ 0.60; H NMR (CD OD, 300 MHz) δ 5.33-5.36 (m, 2H), 3.04-3.13 (m, 4H), 2.57 (t, J = 7.4
Hz, 2H), 2.00-2.10 (m, 4H), 1.62-1.74 (m, 2H), 1.25-1.54 (m, 16H), 0.92 (t, J = 7.2 Hz, 3H); C
NMR (CD OD, 125 MHz) δ 160.16, 153.94, 129.83, 129.47, 39.83, 39.71, 29.89, 29.82, 29.40,
29.01, 28.59, 28.52, 26.87, 26.85, 26.71, 26.30, 23.37, 22.33, 13.25. HRMS calcd for
C H N O S [M+1] 398.2716, found 398.2720.
38 4 2
Synthesis of Analog 20.
Analog 20. A mixture of 1-(12-cyanododec-5(Z)-enyl)n-pentylurea (500 mg, 1.55
mmol), sodium azide (100 mg, 1.55 mmol) and zinc bromide (335 mg, 1.48 mmol) was heated at
110 °C in isopropanol/H O (1:3, 8 mL) while stirring vigorously in a sealed tube. After 18 h, the
mixture was cooled to room temperature and the pH was adjusted to 1 using aq. HCl (3 N, 4
mL). Ethyl acetate (10 mL) was added and the stirring was continued until no solid was present.
The organic layer was isolated and the aqueous layer extracted with EtOAc (2 × 25 mL). The
combined organic fractions were washed with water (3 × 25 mL), dried and concentrated in
vacuo. The residue was purified by flash silica gel column chromatography to give the analog 20
(431 mg, 76%) as a colorless solid, mp 205.6-205.8 °C. TLC: 10% MeOH/CH Cl , R ∼ 0.30; H
2 2 f
NMR (CD OD, 300 MHz) δ 5.40-5.30 (m, 2H), 3.06-3.11 (m, 4H), 2.93 (t, J = 8.0 Hz, 2H),
1.98-2.10 (m, 4H), 1.70-1.82 (m, 2H), 1.24-1.50 (m, 16H), 0.90 (t, J = 7.6 Hz, 3H); C NMR
(CD OD, 75 MHz) δ 160.16, 156.81, 129.77, 129.47, 39.81, 39.68, 29.88, 29.80, 29.35, 28.99,
28.69, 28.55, 27.48, 26.85, 26.81, 26.68, 22.96, 22.31, 13.22. HRMS calcd for C H N O
19 37 6
[M+1] 365.3029, found 365.3030.
Synthesis of Analog 29.
Analog 29. A mixture of N'-hydroxy(3-n-pentylureido)tridec-8(Z)-enimidamide
(150 mg 0.42 mmol) and 1,1'-thiocarbonyl diimidazole (90%; 91 mg, 0.51 mmol) in THF (5 mL)
was stirred at room temperature. After 45 min, the mixture was diluted with water (10 mL) and
extracted with ethyl acetate (3 × 5 mL). The combined extracts were washed with water, dried,
and concentrated in vacuo. The residue was dissolved in dry THF (5 mL) and boron trifluoride
diethyl etherate (103 μL, 0.84 mmol) was added. After another 1 h, the reaction mixture was
diluted with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). The combined extracts
were washed with water, dried (Na SO ), and the solvent was evaporated in vacuo. The residue
was purified by column chromatography to give 29 (104 mg, 63%) as a colorless solid, mp
124.2-125.1 °C. TLC: MeOH/CH Cl (1:9), R ∼ 0.60; H NMR (CD OD, 300 MHz) δ 5.30-5.40
2 2 f 3
(m, 2H), 3.02-3.12 (m, 4H), 2.54 (t, J = 8.0 Hz, 2H), 1.98-2.10 (m, 4H), 1.62-1.74 (m, 2H), 1.24-
1.52 (m, 16H), 0.90 (t, J = 7.0 Hz, 3H); C NMR (CD OD, 75 MHz) δ 181.12, 160.13, 159.12,
129.48, 128.84, 39.85, 39.73, 30.90, 29.91, 29.83, 29.41, 29.03, 28.69, 28.65, 26.89, 26.86,
26.73, 26.23, 22.35, 13.29; IR (neat) 2924, 1724, 1603, 1464, 1375 cm . HRMS calcd for
C H N O S [M+1] 397.2637, found 397.2638.
37 4 2
Synthesis of Analog 28.
Analog 28. A mixture of N'-hydroxy(3-n-pentylureido)tridec-8(Z)-enimidamide
(150 mg 0.42 mmol) and 1,1'-thiocarbonyl diimidazole (90%; 91 mg, 0.51 mmol) in THF (5 mL)
was stirred at room temperature for 45 min. The mixture was diluted with water (20 mL) and
extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with
water, dried, and the solvent was evaporated in vacuo. The residue was dissolved in acetonitrile
(5 mL) to which was then added DBU (147 mg, 0.96 mmol). After stirring at room temperature
for 1 h, the mixture was diluted with water 10 mL), adjusted pH~4 with 1N HCl, and extracted
with ethyl acetate (3 × 10 mL). The combined extracts were washed with water, dried over
Na SO , and the solvent was evaporated in vacuo. The residue was purified by silica gel column
chromatography to give 28 (101 mg, 61%) as a colorless syrup. TLC: MeOH/CH Cl (1:9), R ∼
2 2 f
0.55; H NMR (CD OD, 300 MHz) δ 5.30-5.40 (m, 2H), 3.04-3.14 (m, 4H), 2.62 (t, J = 7.7 Hz,
2H), 2.00-2.10 (m, 4H), 1.62-1.74 (m, 2H), 1.22-1.54 (m, 16H), 0.91 (t, J = 6.7 Hz, 3H); C
NMR (CD OD, 125 MHz) δ 188.49, 161.91, 160.15, 129.82, 129.53, 39.88, 39.75, 29.92, 29.85,
29.37, 29.05, 28.63, 28.55, 26.90, 26.86, 26.75, 25.91, 23.67, 22.37, 13.31. HRMS calcd for
C H N O S [M+1] 397.2637, found 397.2645.
37 4 2
Synthesis of Analog 11.
Analog 11. A solution of 1-(12-bromododec-5(Z)-enyl)n-pentylurea (300 mg, 0.79
mmol), sodium sulfite (352 mg, 2.8 mmol) and cyclohexene (649 mg, 7.9 mmol) in ethanol (5
mL) was refluxed overnight. The volatiles were removed under reduced pressure and the residue
was dissolved in de-ionized water. BioRad SM-2 Bio-beads (5 g; pre-washed with 0.1 N NH OH
and H O) were added, gently stirred for 30 min, and then collected on a sintered glass funnel.
The beads were washed with deionized water (2 × 10 mL) and then EtOH (3 × 10 mL).
Concentration of the ethanolic washes afforded 11 (235 mg, 75%) as a colorless solid, mp 133.6-
133.8 °C. H NMR (CD OD, 300 MHz) δ 5.30-5.40 (m, 2H), 3.02-3.14 (m, 4H), 2.78 (t, J = 8.0
Hz, 2H), 1.98-2.12 (m, 4H), 1.72-1.84 (m, 2H), 1.22-1.50 (m, 16H), 0.91 (t, J = 7.0 Hz, 3H); C
NMR (CD OD, 75 MHz) δ 160.12, 129.86, 129.49, 51.46, 39.01, 38.92, 29.92, 29.32, 29.02,
28.69, 28.42, 26.93, 26.62, 25.78, 24.78, 22.34, 12.02. HRMS calcd for C H N NaO S [M]
18 35 2 4
398.2215, found 398.2220.
Synthesis of Analog 10.
Dimethyl (12-(3-n-pentylureido)dodec-7(Z)-enyl)phosphonate. A solution of 1-
(12-bromododec-5(Z)-enyl)n-pentylurea (250 mg, 0.67 mmol) and trimethyl phosphite (10
mL) in THF (10 mL) was heated under reflux. After for 48 h, all volatiles were removed in
vacuo and the residue was purified by silica gel column chromatography using 60%
EtOAc/CH Cl to give dimethyl (12-(3-n-pentylureido)dodec-7(Z)-enyl)phosphonate (160 mg,
59%) as a viscous oil. TLC: EtOAc, R ∼ 0.55; H NMR (400 MHz) δ 5.30-5.40 (m, 2H), 5.10 (br
s, -NH, 1H), 5.02 (br s, -NH, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.06-3.14 (m, 4H), 1.97-2.20 (m,
4H), 1.63-1.78 (m, 2H), 1.20-1.60 (m, 18H), 0.88 (t, J = 7.2 Hz, 3H); C NMR (100 MHz) δ
159.11, 130.17, 129.93, 52.59, 52.56, 40.49, 30.49, 30.32, 30.28, 29.34, 29.33, 28.58, 27.21,
27.15, 27.11, 25.32, 23.93, 22.66, 22.35, 22.30, 14.24. HRMS calcd for C H N O P [M+1]
42 2 4
405.2882, found 405.2883.
Analog 10. Trimethylsilyl bromide (37 µL) was added to a solution of the above
phosphonate diester (100 mg, 0.25 mmol) in dry CHCl (4 mL). After 2 h at rt, the solution was
concentrated and the residue was suspended in ethyl acetate (5 mL). The resultant precipitate
was collected and dissolved in de-ionized water. BioRad SM-2 Bio-beads (5 g; pre-washed with
0.1 N NH OH and H O) were added, gently stirred for 1 h, and then collected on a sintered glass
funnel. The beads were washed with deionized water (2 × 10 mL) and then EtOH (3 × 10 mL).
Concentration of the ethanolic washes afforded disodium phosphonate 10 (68 mg, 65%). H
NMR (CD OD, 300 MHz) δ 5.30-5.42 (m, 2H), 3.18-3.24 (m, 4H), 1.97-2.20 (m, 4H), 1.50-1.78
(m, 8H), 1.20-1.60 (m, 12H), 0.92 (t, J = 7.2 Hz, 3H); C NMR (CD OD, 75 MHz) δ 159.48,
130.10, 129.25, 40.85, 40.76, 30.48, 30.25, 29.38, 29.13, 29.06, 28.81, 28.67, 27.62, 26.92,
26.70, 26.64, 25.80, 22.65, 22.58, 22.25, 13.02. HRMS calcd for C H N Na O P [M]
18 35 2 2 4
420.2130, found 420.2122.
Synthesis of Analog 16.
Analog 16. Sodium methoxide (180 µL, 30% methanolic solution) was added to a
solution of 1,2,4-triazolethiol (101 mg, 0.99 mmol) in dry DMF (5 mL). After stirring for 10
min, 1-(12-bromododec-5(Z)-enyl)n-pentylurea (250 mg, 0.66 mmol) was added. After
stirring overnight, the reaction mixture was poured into ice water (100 mL) and the resultant
precipitate was collected by filtration and dried in vacuo. The crude solid was suspended in
dichloromethane (100 mL), stirred for 1 h and filtered to give 16 (222 mg, 85%) as a colorless
solid, mp 76.1-76.2 °C. TLC: EtOAc, R ∼ 0.30; H NMR (CD OD, 300 MHz) δ 8.26 (br s, 1H),
.29-5.40 (m, 2H), 3.04-3.14 (m, 6H), 1.98-2.10 (m, 4H), 1.62-1.72 (m, 2H), 1.22-1.50 (m, 16H),
0.90 (t, J = 7.2 Hz, 3H); C NMR (CD OD, 75 MHz) δ 160.15, 157.16, 146.90, 129.86, 129.44,
39.84, 39.73, 32.10, 29.91, 29.84, 29.65, 29.49, 29.02, 28.60, 28.30, 26.88, 26.73, 22.34, 13.28.
HRMS calcd for C H N OS [M+1] 396.2797, found 396.2805.
38 5
Synthesis of Analog 17.
Analog 17. Ammonium molybdate (160 mg, 0.13 mmol) and hydrogen peroxide (0.6
mL, 30% aq. soln) were combined at 0 °C and stirred for 15 min. An aliquot of the resultant
bright yellow solution (0.15 mL) was added dropwise to a stirring, 0 °C solution of sulfide 16
(77 mg, 0.2 mmol) in ethanol (1.0 mL) resulting in a light yellow precipitate. Over the next 15
min, aliquots (0.15 mL) of the oxidizing solution were added every 5 min. After another 10 min,
the reaction mixture was partitioned between H O and dichloromethane (10 mL). The aqueous
phase was extracted with dichloromethane (10 mL) and the combined organic extracts were
washed with brine and dried (Na SO ). The residue was purified by flash SiO chromatography
2 4 2
(70% EtOAc/hexanes) to provide sulfoxide 17 (43 mg, 52%) as a colorless solid, mp 88.2-88.4
°C. TLC: MeOH/EtOAc (1:9), R ∼ 0.30; H NMR (CD OD, 300 MHz) δ 8.38 (br s, 1H), 5.26-
.36 (m, 2H), 5.18 (br s, 2H), 3.04-3.26 (m, 6H), 1.92-2.08 (m, 2H), 1.70-1.84 (m, 2H), 1.20-
1.50 (m, 18H), 0.86 (t, J = 7.2 Hz, 3H); C NMR (CD OD, 75 MHz) δ 163.82, 160.15, 146.98,
129.73, 129.54, 52.62, 39.81, 39.71, 29.90, 29.84, 29.25, 29.01, 28.57, 28.22, 26.88, 26.77,
26.73, 22.33, 21.92, 13.24. HRMS calcd for C H N O S [M+1] 412.2746, found 412.2741.
38 5 2
Synthesis of Analog 18.
Analog 18. Ammonium molybdate (960 mg, 0.77 mmol) and hydrogen peroxide (3.6
mL, 30% aq. soln) were combined at 0 °C and stirred for 15 min. An aliquot of the bright yellow
solution (0.45 mL) was added dropwise to a 0 °C solution of sulfide 16 (154 mg, 0.39 mmol) in
ethanol (3.6 mL) resulting in a light yellow precipitate. Over the next 90 min, aliquots (0.5 mL)
of the oxidizing solution were added every 15 min. After another 15 min, the reaction mixture
was partitioned between H O and dichloromethane (10 mL). The aqueous phase was extracted
with dichloromethane (10 mL) and the combined organic phases were washed with brine and
dried (Na SO ). The residue was purified by flash SiO chromatography (70% EtOAc/hexanes)
2 4 2
to provide sulfone 18 (129 mg, 78%) as a white solid, mp 90.6-90.8 °C. TLC: MeOH/EtOAc
(1:9), R ∼ 0.50; H NMR (CD OD, 300 MHz) δ 8.44 (br s, 1H), 5.25-5.30 (m, 2H), 5.02 (br s,
1H), 4.90 (br s, 1H), 3.35 (t, J = 7.9 Hz, 2H), 3.22-3.10 (m, 4H), 1.90-2.60 (m, 4H), 1.66-1.80
(m, 2H), 1.20-1.54 (m, 16H), 0.87 (t, J = 7.3 Hz, 3H); C NMR (CD OD, 75 MHz) δ 161.15,
160.13, 145.87, 129.73, 129.56, 54.26, 39.85, 39.74, 29.90, 29.83, 29.21, 29.02, 28.46, 27.80,
26.89, 26.79, 26.73, 22.34, 22.19, 13.30. HRMS calcd for C H N O S [M+1] 428.2695, found
38 5 3
428.2701.
Synthesis of Analog 23.
Analog 23. To a solution of N'-hydroxy(3-n-pentylureido)tridec-8(Z)-
enimidamide (50 mg, 0.14 mmol) in dry dioxane (3 mL) was added 1,1-carbonyldiimidazole
(CDI; 27 mg, 0.16 mmol) followed by 1,8-diazabicycloundecene (DBU; 23 mg, 0.15 mmol).
After stirring for 15 min, the reaction mixture was warmed to 110 °C for 15 min, then returned to
room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl
acetate (3 × 5 mL). The combined organic extracts were washed with water, brine, dried
(Na SO ), and concentrated in vacuo. The residue was purified by SiO column chromatography
2 4 2
to give 23 (36 mg, 67%) as a sticky solid. TLC: EtOAc/hexanes (4:1), R ∼ 0.40; H NMR
(CD OD, 300 MHz) δ 5.30-5.40 (m, 2H), 3.02-3.14 (m, 4H), 2.52 (t, J = 7.7 Hz, 2H), 2.00-2.10
(m, 4H), 1.60-1.70 (m, 2H), 1.24-1.50 (m, 16H), 0.90 (t, J = 6.7 Hz, 3H); C NMR (CD OD, 75
MHz) δ 158.30, 157.33, 126.98, 126.68, 37.02, 36.90, 26.97, 26.53, 26.19, 25.76, 25.72, 24.02,
23.89, 22.68, 21.84, 19.52, 10.43; IR (neat) 2929, 2854, 1809, 1776, 1738, 1620, 1580, 1467,
1257, 981 cm . HRMS (ESI-neg) calcd for C H N O [M-1] 379.2715, found 379.2731.
35 4 3
Synthesis of Analog 27.
N -n-Butyl-N -(12-(tert-butyldiphenylsilyloxy)dodec-5(Z)-enyl)oxalamide. A
mixture of 2-(n-butylamino)oxoacetic acid (0.40 g, 2.70 mmol), the above 1-tert-
butyldiphenylsilyloxyaminododec-7(Z)-ene (1.20 g, 2.70 mmol), 1-hydroxybenzotriazole
(HOBt; 0.44 g, 3.30 mmol) and [1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride]
(0.63 g, 3.30 mmol) in dry DMF (5 mL) was stirred at room temperature overnight. The reaction
mixture was quenched with water (30 mL) and extracted into ethyl acetate (3 × 20 mL). The
combined organic extracts were washed with water (2 × 10 mL), brine (10 mL), dried and
concentrated in vacuo. The residue was purified by SiO column chromatography to give N -n-
butyl-N -(12-(tert-butyldiphenylsilyloxy)dodec-5(Z)-enyl)oxalamide (1.10 g, 73%). TLC:
EtOAc/hexanes (2:3), R ∼ 0.55; H NMR (400 MHz) δ 8.05 (br s, -NH, 2H), 7.66-7.74 (m, 4H),
7.32-7.42 (m, 6H), 5.30-5.42 (m, 2H), 3.67 (t, J = 3.9 Hz, 2H), 3.31 (q, J = 5.2 Hz, 4H), 1.96-
2.10 (m, 4H), 1.50-1.64 (m, 6H), 1.22-1.44 (m, 10H), 1.06 (s, 9H), 0.92 (t, J = 7.8 Hz, 3H); C
NMR (100 MHz) δ 160.33, 135.80, 134.35, 130.73, 129.74, 129.20, 127.83, 64.17, 39.89, 39.69,
32.79, 31.48, 29.94, 29.29, 29.07, 27.46, 27.23, 27.14, 27.0, 25.96, 20.29, 19.46, 13.96. HRMS
calcd for C H N O Si [M+1] 565.3826, found 565.3824.
34 53 2 3
1 2 1 2
N -n-Butyl-N -(12-hydroxydodec-5(Z)-enyl)oxalamide. N -n-Butyl-N -(12-(tert-
butyldiphenylsilyloxy)dodec-5(Z)-enyl)oxalamide (1.20 g, 2.12 mmol) was de-silylated as
described above to give N -n-butyl-N -(12-hydroxydodec-5(Z)-enyl)oxalamide (0.568 g, 82%) as
a colorless solid, mp 102.8-102.9 °C. TLC: EtOAc/hexanes (7:3), R ∼ 0.55; H NMR (400 MHz)
δ 7.69 (br s, 2H), 5.20-5.35 (m, 2H), 3.56 (t, J = 4.2 Hz, 2H), 3.26 (q, J = 5.6 Hz, 4H), 2.17 (br s,
–OH), 1.95-2.02 (m, 4H), 1.44-1.56 (m, 6H), 1.20-1.40 (m, 10H), 0.87 (t, J = 7.2 Hz, 3H); C
NMR (100 MHz) δ 160.15, 130.66, 129.21, 62.98, 39.80, 39.63, 32.93, 31.39, 29.77, 29.18,
28.95, 27.26, 27.0, 26.88, 25.80, 20.18, 13.85. HRMS calcd for C H N O [M+1] 327.2648,
18 35 2 3
found 327.2648.
1 2 1 2
N -(12-Bromododec-5(Z)-enyl)-N -n-butyloxalamide. N -n-Butyl-N -(12-
hydroxydodec-5(Z)-enyl)oxalamide (330 mg, 1.0 mmol) was brominated as described above to
give N -(12-bromododec-5(Z)-enyl)-N -n-butyloxalamide (330 mg, 84%) as a white solid, mp
46.0-46.3 °C. TLC: EtOAc/hexanes (3:2), R ∼ 0.55; H NMR (400 MHz) δ 7.79 (br s, -NH,
1H), 7.77 (br s, -NH, 1H), 5.20-5.32 (m, 2H), 3.32 (t, J = 6.4 Hz, 2H), 3.22 (q, J = 7.2 Hz, 4H),
1.90-2.00 (m, 4H), 1.72-1.82 (m, 2H), 1.42-1.56 (m, 4H), 1.20-1.40 (m, 10H), 0.85 (t, J = 7.3
Hz, 3H); C NMR (100 MHz) δ 160.17, 160.15, 130.40, 129.34, 39.77, 39.59, 34.12, 32.93,
31.40, 29.62, 29.0, 28.54, 27.25, 27.24, 27.0, 26.91, 20.18, 13.85. HRMS calcd for
C H BrN O [M + 1] 389.1804, found 389.1809.
18 34 2 2
1 2 1
N -n-Butyl-N -(12-cyanododec-5(Z)-enyl)oxalamide. N -(12-bromododec-5(Z)-
enyl)-N -n-butyloxalamide (250 mg, 0.642 mmol) was treated as described above with potassium
cyanide to give N -n-butyl-N -(12-cyanododec-5(Z)-enyl)oxalamide (168 mg, 78%) as a
colorless solid, mp 83.0-83.3 °C. TLC: EtOAc/hexanes (3:2), R ∼ 035; H NMR (400 MHz) δ
7.45 (br s, -NH, 2H), 5.30-5.40 (m, 2H), 3.34 (q, J = 8.6 Hz, 4H), 2.32 (t, J = 7.6 Hz, 2H), 1.98-
2.08 (m, 4H), 1.30-1.68 (m, 16H), 0.92 (t, J = 7.2 Hz, 3H); C NMR (100 MHz) δ 160.03 (2C),
130.03, 129.08, 120.10, 39.88, 39.42, 31.22, 29.40, 28.82, 28.60, 28.42, 27.07, 27.06, 26.82,
.54, 20.06, 17.01, 13.80. HRMS calcd for C H N O [M+1] 336.2651, found 336.2650.
19 34 3 2
N -(13-Amino(hydroxyimino)tridec-5(Z)-enyl)-N -n-butyloxalamide.
Following the procedure described above, a mixture of N -n-butyl-N -(12-cyanododec-5(Z)-
enyl)oxalamide, H NOH⋅HCl, and Na CO was converted to N -(13-amino
2 2 3
(hydroxyimino)tridec-5(Z)-enyl)-N -n-butyloxalamide (102 mg, 62%) as a colorless solid, 116.3-
116.4 °C. TLC: MeOH/CH Cl (1:4), R ∼ 0.20; H NMR (CD OD, 400 MHz) δ 5.28-5.40 (m,
2 2 f 3
2H), 3.24 (t, J = 6.4 Hz, 4H), 1.98-2.00 (m, 6H), 1.50-1.60 (m, 6H), 1.26-1.40 (m, 10H), 0.92 (t,
J = 7.3 Hz, 3H); C NMR (CD OD, 100 MHz) δ 160.55 (2C), 156.31, 130.05, 129.18, 39.23,
39.09, 31.18, 30.63, 29.51, 28.83, 28.69, 27.10, 26.87, 26.59,19.88, 12.88. HRMS calcd for
C H N O [M+1] 369.2866, found 369.2864.
19 37 4 3
Analog 27. Treatment of N -(13-amino(hydroxyimino)tridec-5(Z)-enyl)-N -n-
butyloxalamide (100 mg, 0.27 mmol) with 1,1'-thiocarbonyl diimidazole gave 27 (71 mg, 63%)
as a white solid, mp 110.6-110.8 °C. TLC: MeOH/CH Cl (1:9), R ∼ 0.55; H NMR (400 MHz)
2 2 f
δ 8.90 (br s, NH, 1H), 7.52 (br s, NH, 2H), 5.28-5.40 (m, 2H), 3.20-3.40 (m, 4H), 2.59 (t, J = 7.5
Hz, 2H), 1.98-2.10 (m, 4H), 1.21-1.70 (m, 16H), 0.92 (t, J = 7.3 Hz, 3H); C NMR (100 MHz) δ
160.12, 160.08, 153.31, 130.62, 129.46, 39.93, 39.85, 31.35, 29.33, 28.94, 28.89, 28.68, 27.02,
26.84, 26.69, 23.96, 20.23, 13.90. HRMS calcd for C H N O S [M+1] 415.2379, found
19 35 4 4
415.2372.
Synthesis of Analog 21.
Analog 21. Following the procedure used to prepare 22, a mixture of N -n-butyl-N -
(12-cyanododec-5(Z)-enyl)oxalamide (30 mg, 0.10 mmol), sodium azide (11 mg, 0.20 mmol)
and zinc bromide (40 mg, 0.20 mmol) was heated in isopropanol/methanol/H O (1:1:3, 4 mL) to
give tetrazole 21 (25 mg, 74%) as a colorless solid, mp 113-114 °C. TLC: 10% MeOH/CH Cl ,
R ∼ 0.26; H NMR (CD OD, 400 MHz) δ 5.40-5.35 (m, 2H), 3.26 (t, J = 7.0 Hz, 4H), 2.44 (t, J =
7.0 Hz, 2H), 2.05-2.15 (m, 4H), 1.65-1.60 (m, 6H), 1.40-1.30 (m, 10H), 0.94 (t, J = 7.3 Hz, 3H);
C NMR (CD OD, 100 MHz) δ 160.12, 160.05, 156.80, 130.35, 129.50, 39.20, 39.08, 31.15,
29.33, 28.66, 28.65, 28.53, 27.38, 26.83, 26.79, 26.55, 22.86, 19.85, 12.84. HRMS calcd for
C H N O [M+1] 379.2822, found 379.2814.
19 35 6 2
Synthesis of Analog 26.
1-(tert-ButyldiphenylsilyloxyIodododec-7(Z)-ene. Triphenylphosphine (504
mg, 1.14 mmol) and imidazole (156 mg, 2.30 mmol) were added to a 0 °C solution of the above
12-(tert-butyldiphenylsilyloxy)dodec-5(Z)-enol (500 mg, 1.14 mmol) in dry THF (25 mL)
under an argon atmosphere. After 10 min, solid iodine (252 mg, 1.2 equiv) was added in
portions. After stirring at room temperature for 3 h, the reaction mixture was quenched with sat.
aq. sodium bisulfite solution (10 mL). After an additional 1 h, the solution was washed with
water (2 × 30 mL) and concentrated under reduced pressure. The residue was purified by flash
SiO column chromatography using 10% EtOAc/hexanes as eluent to give the title compound
(474 mg, 76%) as a colorless oil. TLC: 20% EtOAc/hexanes, R ~ 0.65; H NMR (300 MHz) δ
7.65-7.70 (m, 4H), 7.35-7.45 (m, 6H), 5.30-5.40 (m, 2H), 3.64 (t, J = 6.4 Hz, 2H), 3.18 (t, J = 5.5
Hz, 2H), 1.95-2.10 (m, 4H), 1.85-1.90 (m, 2H), 1.22-1.50 (m, 10H), 1.20 (s, 9H); C NMR (75
MHz) δ 135.87, 130.42, 130.22, 130.20, 129.95, 127.89, 64.15, 38.35, 36.20, 32.50, 29.90,
28.62, 28.32, 27.25, 27.20, 27.18, 26.22, 19.12. HRMS calcd for C H IOSi [M+1] 549.2050,
28 42
found 549.2044.
1-(tert-ButyldiphenylsilyloxyN-isopropylamino-dodec-7(Z)-ene.
Isopropylamine (464 μL, 5.45 mmol) and K CO (373 mg, 2.73 mmol) were added sequentially
to a room temperature solution of 1-(tert-butyldiphenylsilyloxyiodododec-7(Z)-ene (500 mg,
0.91 mmol) in dry tetrahydrofuran (8 mL). The mixture was heated in a sealed tube at 90 °C for
12 h, then cooled to rt, diluted with water (5 mL), filtered and the filtrate was extracted with
ethyl acetate (3 × 10 mL). The combined organic extracts were dried, concentrated under
reduced pressure, and the residue was purified by SiO column chromatography using a gradient
from 2% to 5% MeOH/ CH Cl as eluent to give the title amine (335 mg, 77%) as a colorless oil.
TLC: 5% MeOH/CH Cl , R ∼ 0.3; H NMR (300 MHz) δ 7.62-7.70 (m, 4H), 7.34-7.44 (m, 6H),
2 2 f
.30-5.40 (m, 2H), 3.64 (t, J = 6.4 Hz, 2H), 2.72-2.84 (m, 1H), 2.58 (t, J = 7.0 Hz, 2H), 1.94-
2.08 (m, 4H), 1.20-1.60 (m, 12H), 1.05 (d, J = 7.2 Hz, 6H), 1.04 (s, 9H); C NMR (75 MHz) δ
135.81, 134.40, 132.0, 129.72, 127.81, 64.21, 48.96, 47.75, 32.80, 30.33, 29.97, 29.31, 27.85,
27.44, 27.33, 27.11, 25.95, 23.27, 19.46. HRMS calcd for C H NOSi [M+1] 480.3662, found
31 50
480.3666.
N-(12-(tert-Butyldiphenylsilyloxy)dodec-5(Z)-enyl)-N-isopropyl n-heptanamide.
Solid [1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride] (EDCI; 131 mg, 0.69
mmol) was added in portions to a room temperature solution of 1-(tert-butyldiphenylsilyloxy
N-isopropylamino-dodec-7(Z)-ene (300 mg, 0.63 mmol), DMAP (84 mg, 0.69 mmol), N-
hydroxybenzotriazole (HOBt; 93 mg, 0.69 mmol), and n-heptanoic acid (90 mg, 0.68 mmol) in
dry DMF (5 mL). After 12 h, the reaction mixture was diluted with water (10 mL) and extracted
with ether (3 × 5 mL). The combined ethereal extracts were washed with brine, dried, and
evaporated in vacuo. The residue was purified via SiO column chromatography to give the title
compound (281 mg, 76%) as a colorless oil. TLC: EtOAc/hexanes (1:4), R ∼ 0.65; H NMR
(300 MHz, 1:1 mixture of rotamers) δ 7.62-7.70 (m, 4H), 7.34-7.44 (m, 6H), 5.30-5.40 (m, 2H),
4.60-4.70 and 4.00-4.05 (m, 1H for two rotamers), 3.05 (t, J = 5.2 Hz, 2H), 3.02-3.19 (m, 2H),
2.20-2.40 (m, 2H), 1.95-2.10 (m, 4H), 1.20-1.60 (m, 20 H), 1.18 and 1.08 (d, J = 7.0 Hz, 6H for
two rotamers), 1.02 (s, 9H), 0.88 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ 177.24, 173.35,
172.25, 136.16, 135.80, 135.14, 134.37, 134.34, 130.97, 130.31, 129.74, 129.73, 129.54, 129.04,
127.82, 127.75, 64.21, 64.18, 48.42, 45.68, 43.62, 41.19, 34.46, 34.02, 32.81, 32.79, 31.95,
31.94, 31.75, 31.28, 30.0, 29.92, 29.55, 29.46, 29.31, 29.09, 27.87, 27.52, 27.49, 27.45, 27.21,
27.13, 26.94, 26.88, 25.97, 25.95, 25.79, 25.15, 22.81, 22.75, 21.63, 20.77, 19.46, 19.33, 14.34,
14.30. HRMS calcd for C H NO Si [M+1] 592.4550, found 592.4552.
38 62 2
N-(12-Hydroxydodec-5(Z)-enyl)-N-isopropyl n-heptanamide. Following the
desilylation procedure above, N-(12-(tert-butyldiphenylsilyloxy)dodec-5(Z)-enyl)-N-isopropyl n-
heptanamide (275 mg, 0.464 mmol) was converted to the title alcohol (155 mg, 94%) as a syrup.
TLC: 40% EtOAc/hexanes, R ∼ 0.45; H NMR (300 MHz, 45/55 mixture of rotamers) δ 5.30-
.46 (m, 2H), 4.62-4.72 and 4.00-4.08 (m, 1H for two rotamers), 3.63 (t, J = 5.4 Hz, 2H), 3.06-
3.14 (m, 2H), 2.22-2.36 (m, 2H), 1.98-2.10 (m, 4H), 1.24-1.70 (m, 20 H), 1.17 and 1.10 (d, J =
6.8 Hz, 6H for two rotamers), 0.88 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ 173.23, 172.67,
130.83, 130.12, 129.71, 128.96, 62.69, 62.64, 48.34, 45.56, 43.52, 41.07, 34.0, 33.91, 32.91,
32.88, 31.84, 31.81, 31.18, 29.82, 29.74, 29.46, 29.33, 29.11, 27.78, 27.37, 27.35, 27.16, 27.13,
26.84, 25.89, 25.81, 25.66, 22.69, 21.51, 20.65, 14.21. HRMS calcd for C H NO [M+1]
22 44 2
354.3372, found 354.3380.
N-(12-Bromododec-5(Z)-enyl)-N-isopropyl-n-hexanamide. Following the
procedure above, N-(12-hydroxydodec-5(Z)-enyl)-N-isopropyl n-heptanamide (150 mg, 0.43
mmol) was transformed as described above into the corresponding bromide (144 mg, 82%) as a
syrup. TLC: 30% EtOAc/hexanes, R ∼ 0.65; H NMR (300 MHz, 45/55 ratio of rotamers) δ
.30-5.42 (m, 2H), 4.60-4.70 and 4.00-4.10 (m, 1H for two rotamers), 3.42 (t, J = 5.3 Hz, 2H),
3.02-3.20 (m, 2H), 2.20-2.38 (m, 2H), 1.80-2.10 (m, 4H), 1.20-1.70 (m, 20H), 1.16 and 1.12 (d, J
= 7.2 Hz, 6H for two rotamers), 0.87 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ 173.20, 172.64,
130.61, 130.46, 129.96, 129.94, 129.24, 48.34, 45.56, 43.54, 41.09, 34.20, 34.16, 34.05, 33.97,
32.98, 32.93, 32.60, 31.90, 31.88, 31.26, 29.78, 29.68, 29.62, 29.51, 29.40, 28.94, 28.55, 28.25,
28.20, 27.81, 27.69, 27.45, 27.30, 27.25, 27.18, 26.92, 25.87, 25.20, 22.75, 21.59, 20.72, 14.72.
HRMS calcd for C H BrNO [M+1] 416.2528, found 416.2523.
22 43
N-(12-Cyanododec-5(Z)-enyl)-N-isopropyl-n-hexanamide. Following the cyanide
displacement procedure above, N-(12-bromododec-5(Z)-enyl)-N-isopropyl-n-hexanamide (500
mg, 1.20 mmol) gave the title nitrile (339 mg, 78%) as a syrup. TLC: EtOAc/hexanes (3:7), R ∼
0.40; H NMR (500 MHz, 45/55 ratio of rotamers) δ 5.20-5.34 (m, 2H), 4.52-4.62 and 3.90-4.02
(m, 1H for two rotamers), 3.00-3.10 (m, 2H), 2.16-2.30 (m, 4H), 1.90-2.05 (m, 4H), 1.60-1.70
(m, 8H), 1.22-1.50 (m, 12H), 1.18 and 1.11, (d, J = 6.8 Hz, 6H for two rotamers), 0.88 (t, J = 7.2
Hz, 3H); C NMR (75 MHz) δ 173.22, 172.66, 130.42, 130.04, 129.78, 129.35, 120.04, 119.99,
48.34, 45.58, 43.54, 41.07, 34.02, 33.95, 31.89, 31.86, 31.22, 29.53, 29.49, 29.37, 28.73, 28.70,
28.57, 28.53, 27.78, 27.39, 27.26, 27.18, 27.17, 26.91, 25.85, 25.70, 25.52, 25.49, 22.73, 21.56,
.70, 17.26, 14.27. HRMS calcd for C H N O [M+1] 363.3375, found 363.3375.
23 43 2
N-(13-Amino(hydroxyimino)tridec-5(Z)-enyl)-N-isopropyl-n-heptanamide.
Following the procedure above, a mixture of N-(12-cyanododec-5(Z)-enyl)-N-isopropyl-n-
hexanamide, H NOH⋅HCl, and Na CO was converted into the title compound (64%). TLC:
2 2 3
MeOH/CH Cl (3:7), R ∼ 0.30; H NMR (500 MHz, 1:1 ratio of rotamers) δ 5.24-5.40 (m, 2H),
2 2 f
4.62-4.68 (m, 0.5H), 4.50-4.60 (-NH, 2H), 3.96-4.40 (m, 0.5H), 3.02-3.14 (m, 2H), 2.18-2.28 (m,
2H), 1.90-2.16 (m, 6H), 1.46-1.64 (m, 8H), 1.20-1.36 (m, 12 H), 1.15 and1.08 (d, J = 7.3 Hz, 6H
for two rotamers), 0.85 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ 173.22, 172.58, 154.26,
154.21, 130.82, 130.13, 129.79, 129.08, 48.32, 45.50, 43.52, 41.09, 36.03, 34.05, 33.97, 31.89,
31.86, 31.459, 31.25, 29.72, 29.67, 29.53, 29.39, 29.21, 29.19, 29.11, 29.03, 27.83, 27.41, 27.24,
27.17, 26.90, 26.84, 25.87, 25.70, 22.74, 21.58, 20.73, 14.26. HRMS calcd for C H N O
23 46 3 2
[M+1] 396.3590, found 396.3698.
Analog 26. N-(13-Amino(hydroxyimino)tridec-5(Z)-enyl)-N-isopropyl-n-
heptanamide (150 mg, 0.38 mmol) was treated with thionyl chloride at 0 °C as described above
to give 26 (133 mg, 68%) as a syrup. TLC: EtOAc/hexanes (1:1), R ∼ 0.30; H NMR (400 MHz,
/65 ratio of rotamers) δ 5.22-5.40 (m, 2H), 4.48-4.70 and 4.00-4.12 (m, 1H for two rotamers),
3.04-3.20 (m, 2H), 2.50 and 2.64 (t, J = 6.9 Hz, 2H for two rotamers), 2.22,2.38 (t, J = 8.0 Hz,
2H for two rotamers), 1.90-2.10 (m, 4H), 1.50-1.78 (m, 8H), 1.20-1.40 (m, 12H), 1.22 and 1.12
(d, J= 6.7 Hz 6H for two rotamers), 0.88 (t, J = 7.2 Hz, 3H); C NMR (100 MHz) δ 173.82,
173.40, 153.39, 153.26, 131.03, 130.02, 129.97, 129.10, 48.85, 46.04, 43.82, 41.50, 34.13, 34.02,
31.85, 31.80, 31.23, 29.58, 29.32, 29.11, 29.09, 29.02, 28.80, 28.17, 27.96, 27.32, 27.24, 27.19,
26.03, 26.75, 26.64, 26.10, 24.02, 29.96, 22.75, 21.56, 21.53, 20.74, 20.72, 14.27, 14.25. HRMS
calcd for C H N O S [M+1] 442.3103, found 442.3106.
24 44 3 3
Synthesis of Analog 19.
Analog 19. N-(12-Cyanododec-5(Z)-enyl)-N-isopropyl-n-hexanamide (350 mg, 0.97
mmol) was treated with sodium azide as described above to give tetrazole 19 (250 mg, 64%) as a
sticky solid. TLC: EtOAc, R ∼ 0.40; H NMR (300 MHz, 35/65 ratio of rotamers) δ 5.22-5.40
(m, 2H), 4.58-4.68 and 4.02-4.18 (m, 1H for two rotamers), 3.10-3.24 (m, 2H), 2.98 (t, J = 7.6
Hz, 2H), 2.44 and 2.30 (t, J = 7.3 Hz, 2H for two rotamers), 1.94-2.10 (m, 4H), 1.72-1.84 (m,
2H), 1.50-1.70 (m, 4H), 1.18-1.40 (m, 14H), 1.21 and 1.10 (d, J = 7.2 Hz, 6H for two rotamers),
0.82-0.87 (m, 3H); C NMR (75 MHz) δ 174.06, 173.80, 130.85, 130.04, 129.79, 129.08, 48.94,
46.32, 43.97, 41.55, 34.11, 34.05, 31.79, 31.72, 31.12, 29.61, 29.61, 29.51, 29.25, 29.05, 28.85,
28.22, 27.98, 27.89, 27.32, 27.19, 26.92, 25.97, 23.70, 22.67, 21.51, 20.67, 14.02. HRMS calcd
for C H N O [M+1] 406.3546, found 406.3547.
23 44 5
Synthesis of Analog 22.
1-tert-Butyldiphenylsilyloxy(tetrahydro-2H-pyranyloxy)tridecyne.
Following the procedure applied in the synthesis of analog 25, 2-(hexynyloxy)tetrahydro-2H-
pyran (5.0 g, 27.40 mmol) was coupled with 1-tert-butyldiphenylsilyloxybromoheptane
(11.90 g, 27.40 mmol) to give 1-tert-butyldiphenylsilyloxy(tetrahydro-2H-pyran
yloxy)tridecyne (10.50 g, 72%) as a colorless syrup whose spectral data matched literature
values. TLC: EtOAc/hexanes (1:4), R ∼ 0.60; H NMR (400 MHz) δ 7.64-7.68 (m, 4H), 7.34-
7.42 (m, 6H), 4.57 (t, J = 4.3 Hz, 1H), 3.78-3.86 (m, 2H), 3.65 (t, J = 6.3 Hz, 2H), 3.32-3.54 (m,
2H), 2.10-2.22 (m, 4H), 1.24-1.84 (m, 20H), 1.04 (s, 9H); C NMR (100 MHz) δ 135.80,
134.38, 129.72, 127.81, 99.0, 80.72, 80.10, 67.30, 64.17, 62.49, 32.77, 30.99, 29.34, 29.18,
29.13, 29.0, 27.11, 26.19, 25.91, 25.74, 19.87, 19.45, 19.0, 18.86.
13-(tert-Butyldiphenylsilyloxy)tridecynol. Following the procedure applied in
the synthesis of analog 25, 1-tert-butyldiphenylsilyloxy(tetrahydro-2H-pyranyloxy)tridec-
8-yne (10.0 g, 18.70 mmol) was deprotected with PPTS to give 13-(tert-
butyldiphenylsilyloxy)tridecynol (7.70 g, 91%) as a colorless syrup. TLC: EtOAc/hexanes
(3:7), R ∼ 0.43; H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.62 (t, J = 5.6 Hz,
4H), 2.06-2.22 (m, 4H), 1.50-1.64 (m, 14H), 1.04 (s, 9H); C NMR (100 MHz) δ 135.82,
134.37, 129.76, 127.85, 80.93, 80.04, 64.21, 62.63, 32.77, 32.09, 29.33, 29.13, 29.10, 27.14,
.92, 25.63, 19.47, 19.0, 18.81. HRMS calcd for C H O Si [M+1] 451.3032, found
29 43 2
451.3032.
(Z)(tert-Butyldiphenylsilyloxy)tridecenol. Following the procedure
applied in the synthesis of analog 25, 13-(tert-butyldiphenylsilyloxy)tridecynol (7.50 g,
16.60 mmol) was subjected to semi-hydrogenation to give 13-(tert-butyldiphenylsilyloxy)tridec-
(Z)-enol (6.90 g, 92%) as a syrup whose spectral values matched literature data. TLC:
EtOAc/hexanes (3:7), R ∼ 0.45; H NMR (400 MHz) δ 7.64-7.68 (m, 4H), 7.42-7.34 (m, 6H),
.28-5.42 (m, 2H), 3.68-3.67 (t, J = 6.4 Hz, 4H), 1.98-2.12 (m, 4H), 1.50-1.60 (m, 4H), 1.40-
1.24 (m, 10H), 1.04 (s, 9H); C NMR (100 MHz) δ 135.83, 134.40, 130.61, 129.74, 129.60,
127.83, 64.21, 63.08, 32.83, 32.60, 29.94, 29.54, 27.50, 27.18, 27.14, 26.12, 26.01, 19.48.
1-tert-Butyldiphenylsilyloxyazidotridec-8(Z)-ene. Following the procedure
applied in the synthesis of analog 25, 13-(tert-butyldiphenylsilyloxy)tridec-5(Z)-enol (7.0 g,
.48 mmol) was converted to 1-tert-butyldiphenylsilyloxyazidotridec-8(Z)-ene (5.30 g,
72%) obtained as a syrup. TLC: EtOAc/hexanes (1:9), R ∼ 0.55; H NMR (400 MHz) δ 7.68-
7.64 (m, 4H), 7.42-7.34 (m, 6H), 5.28-5.42 (m, 2H), 3.64 (t, J = 6.4 Hz, 2H), 3.26 (t, J = 5.6 Hz,
2H), 1.96-2.10 (m, 4H), 1.64-1.24 (m, 14H), 1.04 (s, 9H); C NMR (100 MHz) δ 135.86,
134.44, 131.0, 129.77, 129.12, 127.85, 64.27, 51.63, 32.87, 29.95, 29.56, 28.70, 27.54, 27.17,
27.05, 26.93, 26.05, 19.51. IR (neat) 2930, 2783, 2361, 2331, 2094, 1109 cm . HRMS calcd for
C H N OSi [M+1] 478.3254, found 478.3250.
29 44 3
1-tert-Butyldiphenylsilyloxyaminotridec-8(Z)-ene. Following the procedure
applied in the synthesis of analog 25, 1-tert-butyldiphenylsilyloxyazidotridec-8(Z)-ene (3.50
g, 7.32 mmol) was reduced with triphenylphosphine to give 1-tert-butyldiphenylsilyloxy
aminotridec-8(Z)-ene (2.44 g, 74%) as a colorless oil. TLC: MeOH/CH Cl (1:4), R ∼ 0.25; H
2 2 f
NMR (400 MHz) δ 7.62-7.68 (m, 4H), 7.32-7.40 (m, 6H), 5.30-5.40 (m, 2H), 3.63 (t, J = 5.2 Hz,
2H), 2.62 (br s, 2H), 1.92-2.06 (m, 4H), 1.40-1.58 (m, 4H), 1.20-1.40 (m, 10H), 1.03 (s, 9H); C
NMR (100 MHz) δ 135.79, 134.39, 130.46, 129.70, 127.78, 64.22, 42.02, 32.80, 29.92, 29.52,
27.46, 27.23, 27.10, 25.98, 19.44. HRMS calcd for C H NOSi [M+1] 452.3349, found
29 46
452.3357.
1-(13-(tert-Butyldiphenylsilyloxy)tridec-5(Z)-enyl)n-pentylurea. Following the
procedure applied in the synthesis of analog 25, 1-tert-butyldiphenylsilyloxyaminotridec-
8(Z)-ene (2.35 g, 5.20 mmol) was reacted with n-pentyl isocyanate to give 1-(13-(tert-
butyldiphenylsilyloxy)tridec-5(Z)-enyl)n-pentylurea (2.23 g, 76%) as a syrup. TLC:
EtOAc/hexanes (1:4), R ∼ 0.65; H NMR (500 MHz) δ 7.62-7.70 (m, 4H), 7.32-7.44 (m, 6H),
.28-5.44 (m, 2H), 4.37 (br s, 2H), 3.66 (t, J = 4.2 Hz, 2H), 3.08-3.20 (m, 4H), 1.98-2.08 (m,
4H), 1.20-1.60 (m, 20H), 1.05 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H); C NMR (125 MHz) δ 159.22,
135.80, 134.12, 130.24, 129.88, 129.76, 127.81, 64.21, 40.62, 40.54, 32.82, 30.31, 29.95, 29.56,
29.39, 27.51, 27.35, 27.20, 27.13, 26.01, 22.72, 19.43, 14.30. HRMS calcd for C H N O Si
57 2 2
[M+1] 565.4189, found 565.4186.
1-(13-Hydroxytridec-5(Z)-enyl)n-pentylurea. Following the procedure applied
in the synthesis of analog 25, 1-(13-(tert-butyldiphenylsilyloxy)tridec-5(Z)-enyl)n-pentylurea
(2.30 g, 4.07 mmol) was desilylated using TBAF to give 1-(13-hydroxytridec-5(Z)-enyl)n-
pentylurea (1.22 g, 92%) as a white solid, mp 63.1-63.3 °C. TLC: EtOAc/hexanes (7:3), R ∼
0.55; H NMR (400 MHz) δ 5.24-5.38 (m, 2H), 4.74 (br s, -NH, 2H), 3.62 (t, J = 5.6 Hz, 2H),
3.06-3.18 (m, 4H), 1.98-2.06 (m, 4H), 1.20-1.60 (m, 20H), 0.86 (t, J = 7.3 Hz, 3H); C NMR
(100 MHz) δ 159.31, 130.38, 129.63, 62.90, 40.51, 40.46, 32.93, 30.30, 30.29, 29.79, 29.41,
29.34, 29.23, 27.30, 27.24, 27.15, 25.98, 22.67, 14.25. HRMS calcd for C H N O [M+1]
19 39 2 2
327.3012, found 327.3011.
1-(13-Bromotridec-5(Z)-enyl)n-pentylurea. Following the procedure applied in
the synthesis of analog 25, 1-(13-hydroxytridec-5(Z)-enyl)n-pentylurea (1.20 g, 3.68 mmol)
was transformed into 1-(13-bromotridec-5(Z)-enyl)n-pentylurea (1.17 g, 82%), obtained as a
sticky solid. TLC: EtOAc/hexanes (2:3), R ∼ 0.60; H NMR (500 MHz) δ 5.28-5.40 (m, 2H),
4.71 (br s, -NH, 2H), 3.40 (t, J = 4.2 Hz, 2H), 3.10-3.20 (m, 4H), 1.98-2.06 (m, 4H), 1.82-1.88
(m, 2H), 1.26-1.50 (m, 18H), 0.87 (t, J = 7.2 Hz, 3H); C NMR (125 MHz) δ 159.38, 130.34,
129.59, 40.55, 40.46, 34.29, 33.02, 30.34, 29.81, 29.38, 29.30, 28.89, 28.35, 27.39, 27.33, 27.18,
22.71, 14.29. HRMS calcd for C H BrN O [M] 388.2089, found 388.2090.
19 37 2
1-(13-Cyanotridec-5(Z)-enyl)n-pentylurea. 1-(13-Bromotridec-5(Z)-enyl)n-
pentylurea (1.10 g, 2.82 mmol) was reacted with potassium cyanide as described above in the
synthesis of analog 25 to give 1-(13-cyanotridec-5(Z)-enyl)n-pentylurea (0.69 g, 73%) as a
colorless solid, mp 44.3-44.4 °C. TLC: EtOAc/hexanes (1:1), R ∼ 0.32; H NMR (500 MHz) δ
.30-5.42 (m, 2H), 4.35 (br s, 2H), 3.04-3.20 (m, 4H), 2.34 (t, J = 7.6 Hz, 2H), 1.98-2.10 (m,
4H), 1.60-1.72 (m, 2H), 1.24-1.56 (m, 18H), 0.89 (t, J = 7.2 Hz, 3H); C NMR (125 MHz) δ
159.24, 130.23, 129.68, 120.02, 40.24, 40.13, 30.27, 29.69, 29.32, 29.07, 28.82, 28.78, 27.29,
27.26, 27.13, 25.49, 22.64, 17.30, 14.24. HRMS calcd for C H N O [M+1] 336.3015, found
38 3
336.3019.
1-(13-(1H-Tetrazolyl)tridec-5(Z)-enyl)n-pentylurea (22). Following the
procedure described above in the synthesis of analog 20, a mixture of 1-(13-cyanotridec-5(Z)-
enyl)n-pentylurea, sodium azide, and zinc bromide was heated at 110 °C to give analog 22
(66%) as a colorless solid, mp 86.0-86.2 °C. TLC: MeOH/CH Cl (1:9), R ∼ 0.30; H NMR
2 2 f
(CD OD, 300 MHz) δ 5.30-5.40 (m, 2H), 3.06-3.11 (m, 4H), 2.93 (t, J = 8.0 Hz, 2H), 1.98-2.10
(m, 4H), 1.70-1.82 (m, 2H), 1.24-1.50 (m, 18H), 0.90 (t, J = 7.6 Hz, 3H); C NMR (CD OD, 100
MHz) δ 160.15, 156.21, 129.89, 129.39, 39.84, 39.71, 29.89, 29.82, 29.53, 29.01, 29.00, 28.81,
27.45, 26.90, 26.70, 22.89, 22.33, 13.25. HRMS calcd for C H N O [M] 378.3107, found
38 6
378.3111.
Synthesis of Analog 13.
1-(tert-Butyldiphenylsilyloxy)(tetrahydro-2H-pyranyloxy)undecyne.
Following the procedure applied in the synthesis of analog 25, 2-(hexynyloxy)tetrahydro-2H-
pyran was treated with n-BuLi and 1-(tert-butyldiphenylsilyloxybromopentane to give the
title compound (73%) as a colorless liquid. TLC: EtOAc/hexanes (1:4), R ~ 0.60; H NMR (400
MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 4.57 (t, J = 4.3 Hz, 1H), 3.78-3.86 (m, 2H), 3.65
(t, J = 6.3 Hz, 2H), 3.32-3.54 (m, 2H), 2.10-2.22 (m, 4H), 1.24-1.84 (m, 16H), 1.04 (s, 9H); C
NMR (125 MHz) δ 135.80, 134.32, 129.74, 127.84, 99.01, 80.54, 80.16, 67.30, 64.02, 62.50,
32.34, 30.98, 29.18, 29.12, 27.32, 27.10, 26.17, 25.73, 25.32, 19.87, 18.99, 18.86. HRMS calcd
for C H O Si [M+1] 493.3138, found 493.3144.
31 45 3
11-(tert-Butyldiphenylsilyloxy)undecynol. Following the procedure reported
to prepare analog 25, 1-(tert-butyldiphenylsilyloxy)(tetrahydro-2H-pyranyloxy)undec
yne was cleaved with a catalytic amount of PPTS to give the title compound (72%) as a colorless
liquid. TLC: EtOAc/hexanes (3:7), R ~ 0.43; H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-
7.42 (m, 6H), 3.62 (t, J = 5.6 Hz, 4H), 2.06-2.22 (m, 4H), 1.64-1.50 (m, 10H), 1.04 (s, 9H); C
NMR (100 MHz) δ 135.82, 134.33, 129.77, 127.84, 80.77, 80.11, 64.06, 62.69, 32.35, 32.10,
29.10, 27.12, 25.60, 25.33, 18.97, 18.78. HRMS calcd for C H O Si [M+1] 423.2719, found
27 39 2
423.2718.
11-(tert-Butyldiphenylsilyloxy)undec-5(Z)-enol. 11-(tert-
Butyldiphenylsilyloxy)undecynol (6.50 g, 15.40 mmol) was subjected to semi-
hydrogenation as described above to give the title olefin (6.07 g, 93%) as a colorless oil. TLC:
EtOAc/hexanes (3:7), R ~ 0.45; H NMR (300 MHz) δ 7.68-7.64 (m, 4H), 7.34-7.32 (m, 6H),
.28-5.42 (m, 2H), 3.68-3.60 (t, J = 6.4 Hz, 4H), 2.08-1.96 (m, 4H), 1.60-1.50 (m, 4H), 1.40-
1.24 (m, 6H), 1.04 (s, 9H); C NMR (100 MHz) δ 135.79, 134.36, 130.45, 129.71, 129.63,
127.79, 64.16, 63.15, 32.69, 32.59, 29.94, 29.67, 27.43, 27.13, 27.08, 26.06, 25.68, 19.45.
HRMS calcd for C H O Si [M+1] 425.2876, found 425.2874.
27 41 2
1-(tert-Butyldiphenylsilyloxyazidoundec-6(Z)-ene. Following the protocol
described above, 11-(tert-butyldiphenylsilyloxy)undec-5(Z)-enol (6.0 g, 14.24 mmol) was
converted into the title azide (4.60 g, 72%), a colorless liquid. TLC: EtOAc/hexanes (1:9), R ~
0.55; H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 5.28-5.42 (m, 2H), 3.65 (t, J
= 6.4 Hz, 2H), 3.25 (t, J = 7.1 Hz, 2H), 1.96-2.10 (m, 4H), 1.24-1.64 (m, 10H), 1.04 (s, 9H); C
NMR (100 MHz) δ 136.63, 135.85, 134.41, 130.83, 129.79, 129.22, 127.88, 64.20, 51.62, 32.77,
29.73, 28.70, 27.53, 27.18, 27.05, 26.94, 25.77, 19.52; IR (neat) 2931, 2857, 2094, 1589, 1110
-1 +
cm . HRMS calcd for C H N OSi [M + 1] 450.2940, found 450.2941.
27 40 3
1-Amino(tert-butyldiphenylsilyloxy)undec-5(Z)-ene. 1-(tert-
Butyldiphenylsilyloxyazidoundec-6(Z)-ene (4.30 g, 9.57 mmol) was reduced with
triphenylphosphine as described above to give the title amine (2.96 g, 74%) as a colorless oil.
TLC: MeOH/CH Cl (1:4), R ~ 0.25; H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m,
2 2 f
6H), 5.28-5.42 (m, 2H), 3.64 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 4.8 Hz, 2H), 1.96-2.10 (m, 4H),
1.52-1.64 (m, 4H), 1.30-1.42 (m, 6H), 1.04 (s, 9H); C NMR (100 MHz) δ 135.82, 134.37,
132.37, 132.27, 130.70, 129.78, 129.21, 128.93, 128.81, 127.86, 64.19, 40.88, 32.77, 29.89,
29.73, 27.52, 27.37, 27.17, 27.12, 27.03, 25.76, 19.47. HRMS calcd for C H NOSi [M + 1]
27 42
420.3046, found 420.3050.
1-(11-(tert-Butyldiphenylsilyloxy)undec-5(Z)-enyl)n-pentylurea. 76% as a
colorless oil. TLC: EtOAc/hexanes (2:3), R ~ 0.45; H NMR (300 MHz) δ 7.64-7.68 (m, 4H),
7.34-7.42 (m, 6H), 5.28-5.42 (m, 2H), 4.13 (br s, 2H), 3.65 (t, J = 6.4 Hz, 2H), 3.02-3.20 (m,
4H), 1.96-2.08 (m, 4H), 1.20-1.60 (m, 16H), 1.04 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H); C NMR
(100 MHz) δ 158.02, 135.79, 134.36, 130.06, 129.74, 127.90, 127.82, 64.17, 40.42, 40.32, 32.52,
.28, 29.71, 29.35, 27.62, 27.54, 27.16, 27.11, 25.71, 22.69, 19.45, 14.28. HRMS calcd for
C H N O Si [M + 1] 537.3876, found 537.3876.
33 53 2 2
1-(11-Hydroxyundec-5(Z)-enyl)n-pentylurea. 94%, mp 62.2-62.5 °C. TLC:
EtOAc/hexanes (7:3), R ~ 0.55; H NMR (300 MHz) δ 5.28-5.42 (m, 2H), 4.37 (br s, 2H), 3.64
(t, J = 6.4 Hz, 2H), 3.02-3.20 (m, 4H), 1.96-2.10 (m, 4H), 1.20-1.60 (m, 16H), 0.89 (t, J = 7.2
Hz, 3H); C NMR (75 MHz) δ 159.41, 130.30, 129.73, 62.77, 40.50, 40.34, 32.75, 30.27, 30.10,
29.56, 29.33, 27.23, 27.15, 27.04, 25.56, 22.66, 14.24. HRMS calcd for C H N O [M + 1]
17 35 2 2
299.2699, found 299.2705.
1-(11-Bromoundec-5(Z)-enyl)n-pentylurea. 84%, colorless oil. TLC:
EtOAc/hexanes (2:3), R ~ 0.60; H NMR (300 MHz) δ 5.28-5.42 (m, 2H), 4.36 (br s, 2H), 3.32
(t, J = 6.4 Hz, 2H), 3.02-3.20 (m, 4H), 1.96-2.10 (m, 4H), 1.20-1.60 (m, 16H), 0.89 (t, J = 7.2
Hz, 3H); C NMR (75 MHz) δ 159.20, 129.94, 40.60, 40.49, 34.19, 32.91, 30.29, 29.35, 29.02,
28.01, 27.26, 27.16, 22.67, 14.26. HRMS calcd for C H BrN O [M] 360.1776, found
17 33 2
360.1773.
1-(11-(2-Hydroxyphenylthio)undec-5(Z)-enyl)n-pentylurea (13). To a solution
of 2-mercaptophenol (100 mg, 0.79 mmol) in DMF (3 mL) was added K CO (161 mg, 1.18
mmol) and 1-(11-bromoundec-5(Z)-enyl)n-pentylurea (0.29 g, 0.79 mmol). After 12 h at rt,
the solution was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The
combined organic extracts were washed with water, brine and dried (Na SO ). The residue was
purified by SiO column chromatography to give the analog 13 (230 mg, 69%) as a sticky solid.
TLC: EtOAc/hexanes (1:1), R ∼ 0.32; H NMR (300 MHz) δ 7.45 (dd, J = 1.9, 7.6 Hz, 1H),
7.22-7.28 (m, 1H), 6.99 (dd, J = 1.2, 8.2 Hz, 1H), 6.88 (dt, J = 1.2, 7.6 Hz, 1H ), 5.28-5.42 (m,
2H), 4.26 (br s, 2H), 3.02-3.20 (m, 4H), 2.69 (t, J = 7.7 Hz, 2H), 1.94-2.08 (m, 4H), 1.20-1.60
(m, 16H), 0.89 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ 159.05, 157.10, 135.60, 130.76,
130.11, 129.82, 120.78, 119.74, 115.02, 40.70, 40.60, 36.50, 30.23, 29.68, 29.32, 28.38, 27.21,
27.11, 22.66, 14.27. HRMS (ESI-neg) calcd for C H N O S [M-1] 405.2576, found 405.2575.
23 37 2 2
Synthesis of Analog 14.
1-(11-(2-Hydroxyphenylsulfonyl)undec-5(Z)-enyl)n-pentylurea (14). Following
the procedure utilized to prepare analog 18, analog 13 was oxidized to give 14 (60 mg, 75%) as a
colorless liquid. TLC: EtOAc/hexanes (2:3), R ∼ 0.32; H NMR (300 MHz) δ 9.08 (br s, -OH),
7.72 (dd, J = 1.9, 7.4 Hz, 1H), 7.44 (dt, J = 1.2, 7.3 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.12 (t, J =
6.4 Hz, 1H), 5.28-5.42 (m, 2H), 4.70-4.85 (m, 2H), 3.40-3.60 (t, J = 6.2 Hz, 2H), 3.20-3.40 (m,
4H), 1.90-2.10 (m, 4H), 1.70-1.80 (m, 2H), 1.20-1.50 (m, 14H), 0.85 (t, J = 7.2 Hz, 3H); C
NMR (75 MHz) δ 159.25, 156.66, 136.23, 130.22, 129.78, 129.52, 122.78, 120.22, 118.55,
55.97, 40.08, 40.62, 30.07, 30.02, 29.25, 28.82, 27.62, 27.15, 27.05, 26.62, 22.61, 22.20, 14.24.
HRMS (ESI-neg) calcd for C H N O S [M-1] 437.2474, found 437.2454.
23 37 2 4
Synthesis of Analog 15.
1-n-Pentyl(11-thiocyanatoundec-5(Z)-enyl)urea. A mixture of 1-(11-
bromoundec-5(Z)-enyl)n-pentylurea (191 mg, 0.53 mmol) and potassium thiocyanate (154
mg, 1.58 mmol) in dry DMSO (4 mL) were stirred at rt. After 24 h, the reaction mixture was
diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic
extracts were washed with water, brine and dried (Na SO ) and concentrated in vacuo. The
residue was purified by SiO column chromatography to give the title urea (116 mg, 65%) as a
colorless syrup. TLC: EtOAc/hexanes (2:3), R ∼ 0.32; H NMR (300 MHz) δ 5.28-5.42 (m, 2H),
4.42 (br s, 2H), 3.10-3.20 (m, 4H), 2.94 (t, J = 7.0 Hz, 2H), 2.00-2.10 (m, 4H), 1.70-1.80 (m,
2H), 1.20-1.56 (m, 14H), 0.88 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ 158.92, 130.20, 129.68,
112.84, 40.67, 40.54, 34.23, 30.22, 30.03, 29.31, 29.08, 27.66, 27.19, 27.15, 27.04, 22.66, 14.27;
-1 +
IR (neat) 2929, 2856, 2153, 1630, 1573, 1456, 1256 cm . HRMS calcd for C H N OS [M+1]
18 34 3
340.2423, found 340.2421.
1-(11-(1H-Tetrazolylthio)undec-5(Z)-enyl)pentylurea (15). Following the
procedure utilized to prepare analog 19, 1-n-pentyl(11-thiocyanatoundec-5(Z)-enyl)urea (150
mg, 0.44 mmol) was treated with sodium azide to give analog 15 (104 mg, 62%) as a sticky
solid. TLC: 5% MeOH/CH Cl , R ∼ 0.40; H NMR (300 MHz) δ 5.28-5.42 (m, 2H), 4.63 (br s,
2 2 f
2H), 3.30 (t, J = 6.7 Hz, 2H), 3.17-3.23 (m, 4H), 1.95-2.04 (m, 4H), 1.44-1.80 (m, 6H), 1.24-1.42
(m, 10H), 0.89 (t, J = 7.2 Hz, 3H); C NMR (CD OD, 75 MHz) δ 160.17, 155.38, 129.65,
129.58, 39.81, 39.69, 32.38, 29.87, 29.79, 29.36, 28.99, 28.96, 27.84, 26.84, 26.72, 26.69, 22.31,
13.21. HRMS (ESI-neg) calcd for C H N OS [M-1] 381.2442, found 381.2348.
18 33 6
Synthesis of Analog 12.
N-(11-(3-n-Pentylureido)undec-6(Z)-enyl)benzenesulfonamide (12). To a solution
of benzenesulfonamide (50 mg, 0.31 mmol) in THF/HMPA (4:1; 5 mL) was added n-
butyllithium (2.5 M soln in hexane, 125 μL, 0.31 mmol) at -78 °C under an argon atmosphere. A
solution of 1-(11-bromoundec-5(Z)-enyl)n-pentylurea (115 mg, 0.32 mmol) in THF (2 mL)
was added dropwise. After 2 h at the same temperature, the reaction was quenched with saturated
aq. NH Cl (5 mL). The mixture was extracted with EtOAc (3 × 5 mL) and the combined extracts
were washed with water, brine, dried, and concentrated under reduced pressure. The residue was
purified by SiO column chromatography to give analog 12 (44 mg, 32%) as a colorless solid,
mp 73.5-73.6 °C. TLC: 5% MeOH/CH Cl , R ∼ 0.40; H NMR (300 MHz) δ 7.84-7.90 (m, 2H),
2 2 f
7.46-7.60 (m, 3H), 5.48 (br s, -NH, 1H), 5.24-5.38 (m, 2H), 4.70 (br s, -NH, 1H), 4.60 (br s, -
NH, 1H), 3.08-3.20 (m, 4H), 2.88-2.94 (q, J = 6.4 Hz, 2H), 1.94-2.40 (m, 4H), 1.20-1.58 (m, 16
H), 0.88 (t, J = 6.8 Hz, 3H); C NMR (75 MHz) δ 159.90, 140.06, 132.69, 130.03, 129.98,
129.27, 127.19, 43.26, 40.80, 40.52, 30.09, 29.99, 29.61, 29.28, 29.16, 27.02, 26.99, 26.96,
26.13, 22.63, 14.25. HRMS calcd for C H N O S [M + 1] 438.2790, found 438.2782.
23 40 3 3
Synthesis of Analog 24.
1-(11-(2,4-Dioxothiazolidinyl)undec-5(Z)-enyl)n-pentylurea (24). n-
Butyllithium (1.10 mL, 2.76 mmol, 2.5 M solution in hexanes) was added dropwise to a -78 ºC
solution of thiazolidine-2,4-dione (0.16 g, 1.38 mmol) in dry THF/HMPA (50 mL, 4:1) under an
argon atmosphere. After 30 min, the reaction mixture was warmed to 0 ºC over 1h, kept at that
temperature for 2h, and then re-cooled to -78 ºC. Following the addition of a solution of 1-(11-
bromoundec-5(Z)-enyl)n-pentylurea (0.50 g, 1.38 mmol) in THF (15 mL), the reaction
temperature was slowly increased to rt over 3h and stirred further for 12 h. The reaction mixture
was quenched with sat. aq. NH Cl (5 mL), the pH was adjusted to 4 using 1 M oxalic acid, and
the reaction mixture was extracted with EtOAc (3 × 125 mL). The combined extracts were
washed with water (2 × 100 mL), brine (100 mL), dried (Na SO ) and concentrated in vacuo.
The residue was purified by SiO column chromatography using 5% MeOH/CH Cl to afford
2 2 2
analog 24 (169 mg, 31%) as a colorless solid, mp 92.8-93 ºC. TLC: 10% MeOH/CH Cl , R ∼
2 2 f
0.20; H NMR (CD OD, 300 MHz) δ 5.30-5.40 (m, 2H), 4.42 (dd, J = 3.4, 4.2 Hz, 1H), 3.04-
3.13 (m, 4H), 2.00-2.16 (m, 4H), 1.80-1.96 (m, 2H), 1.24-1.58 (m, 16H), 0.91 (t, J = 6.7 Hz,
3H); C NMR (75 MHz) δ 177.09, 172.56, 160.15, 129.68, 129.60, 51.89, 39.69, 32.57, 29.90,
29.83, 29.23, 29.02, 28.43, 26.88, 26.73, 26.47, 22.35, 13.27. HRMS calcd for C H N O S
36 3 3
[M+1] 398.2477, found 398.2477.
Synthesis of Analog 7.
(S)-Dimethyl 2-(13-(3-n-pentylureido)tridec-8(Z)-enamido)succinate. L-Aspartic
acid dimethyl ester hydrochloride (38 mg, 0.19 mmol) and HATU (67 mg, 0.18 mmol) were
added to a stirring solution of 13-(3-n-pentylureido)tridec-8(Z)-enoic acid (50 mg, 0.15 mmol)
in anhydrous DMF (20 mL) under an argon atmosphere. After 5 min, 1-ethyl(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDCI; 33 mg, 0.17 mmol) was added
followed by diisopropylethylamine (33 µL, 0.19 mmol). After 12 h, the reaction mixture was
diluted with EtOAc (30 mL), washed with water (30 mL), and brine (20 mL). The combined
aqueous layers were back-extracted with EtOAc (3 × 30 mL). The combined organic extracts
were dried over Na SO , concentrated under reduced pressure, and the residue was purified by
SiO column chromatography using 50% EtOAc/hexanes as eluent to give the title diester (60
mg, 84%) as a viscous oil. TLC: EtOAc/hexanes (3:2), R ∼ 0.30; H NMR (300 MHz) δ 6.62 (d,
J =7.0 Hz, 1H), 5.22-5.40 (m, 2H), 4.85-5.04 (m, 1H), 4.80-4.88 (m, 2H), 3.75 (s, 3H), 3.66 (s,
3H), 3.10-3.20 (m, 4H), 3.01 (dd, J = 4.3, 10 Hz, 1H), 2.82 (dd, J = 4.6, 10 Hz, 1H), 2.25 (t, J =
8.3 Hz, 2H), 1.98-2.07 (m, 4H), 1.60-1.68 (m, 4H), 1.20-1.50 (m, 14H), 0.88 (t, J = 6.7 Hz, 3H);
C NMR (75 MHz) δ 173.51, 171.81, 171.52, 159.02, 130.33, 129.76, 53.05, 52.30, 48.57,
40.61, 40.55, 36.61, 36.28, 30.24, 30.20, 29.51, 29.31, 29.10, 28.88, 27.20, 27.12, 25.72, 22.66,
14.26.
(S)(13-(3-n-Pentylureido)tridec-8(Z)-enamido)succinic acid (7). LiOH (2 mL, 2
M aqueous solution) was added to a 0 ºC solution of the above (S)-dimethyl 2-(13-(3-n-
pentylureido)tridec-8(Z)-enamido)succinate (60 mg, 0.12 mmol) in THF (25 mL) and deionized
H O (4 mL). After stirring at room temperature overnight, the reaction mixture was cooled to 0
ºC, the pH was adjusted to 4 with 1 M aq. oxalic acid, and the mixture was extracted with EtOAc
(3 × 15 mL). The combined extracts were washed with water (30 mL), brine (25 mL), dried over
anhydrous Na SO , and concentrated in vacuo. The residue was purified by SiO column
2 4 2
chromatography using 25% EtOAc/hexanes as eluent to give analog 7 (48 mg, 85%) as a
colorless oil. TLC: 5% MeOH/EtOAc (3:2), R ∼ 0.30; H NMR (CD OD, 300 MHz) δ 5.30-5.38
(m, 2H), 4.72 (t, J = 4.2 Hz, 1H), 3.26-3.32 (m, 4H), 2.86 (dd, J = 4.3, 10 Hz, 1H), 2.77 (dd, J =
4.6, 10 Hz, 1H), 2.22 (t, J = 7.7 Hz, 2H), 1.98-2.10 (m, 4H), 1.54-1.64 (m, 4H), 1.20-1.52 (m,
14H), 0.89 (t, J = 6.7 Hz, 3H); C NMR (CD OD, 75 MHz) δ 174.93, 173.01, 172.83, 160.17,
129.94, 129.39, 49.0, 39.81, 39.73, 35.78, 35.60, 29.90, 29.82, 29.49, 29.02, 28.87, 26.90, 26.73,
.70, 22.35, 13.29. HRMS calcd for C H N O [M+1] 456.3074, found 456.3071.
23 42 3 6
Synthesis of Analog 3.
2-(2-(2-Hydroxyethoxy)ethoxy)ethyl13-(2-(n-butylamino)-2 oxoacetamido)tridec-
8(Z)-enoate (3). Triethylene glycol (0.12 g, 0.8 mmol; dried over molecular sieves) was added to
a solution of 13-(2-(n-butylamino)oxoacetamido)tridec-8(Z)-enoic acid (30 mg, 0.08 mmol)
and N,N-dimethylaminopyridine (DMAP, 11mg, 0.09 mmol) in anhydrous dichloromethane (10
mL) under an argon atmosphere at room temperature. After 3 min, solid EDCI (18 mg, 0.09
mmol) was added. After 12 h, the reaction mixture was diluted with EtOAc (10 mL), washed
with water (5 mL), and concentrated in vacuo. The residue was purified by SiO column
chromatography using EtOAc to give analog 3 (33 mg, 82%) as a colorless solid, mp 71.7-71.9
ºC. TLC: EtOAc/hexanes (4:1), R ∼ 0.30; H NMR (300 MHz) δ 7.46 (br s, 2H), 5.24-5.40 (m,
2H), 4.23 (t, J = 4.6 Hz, 2H), 3.58-3.78 (m, 10H), 3.27 (apparent q, J = 6.7 Hz, 4H), 2.32 (t, J =
7.6 Hz, 2H), 1.50-1.66 (m, 6H), 1.24-1.44 (m, 14H), 0.92 (t, J = 6.7 Hz, 3H); C NMR (100
MHz) δ 174.10, 160.09, 130.66, 129.24, 72.70, 70.76, 70.55, 69.42, 39.80, 39.61, 34.35, 31.45,
29.69, 29.21, 29.12, 29.02, 27.36, 27.07, 26.92, 25.04, 20.21, 13.90. HRMS calcd for
C H N O [M+1] 487.3383, found 487.3379.
47 2 7
Synthesis of Analog 2.
2-(2-(2-Hydroxyethoxy)ethoxy)ethyl 13-(3-n-pentylureido)tridec-8(Z)-enoate (2).
13-(3-n-Pentylureido)tridec-8(Z)-enoic acid (80 mg, 0.20 mmol) was condensed with triethylene
glycol as described above to give analog 2 (86 mg, 78%) as a colorless solid, mp 42.4-42.6 °C.
TLC: EtOAc, R ∼ 0.20; H NMR (300 MHz) δ 5.24-5.40 (m, 2H), 4.28 (br s, 2H), 4.23 (dd, J =
4.9, 1.0 Hz, 2H), 3.58-3.68 (m, 10H), 3.10-3.20 (m, 4H), 2.52 (br s, -OH, 1H), 2.33 (t, J = 7.6
Hz, 2H), 1.90-2.10 (m, 4H), 1.44-1.64 (m, 4H), 1.22-1.40 (m, 14), 0.88 (t, J = 7.3 Hz, 3H); C
NMR (75 MHz) δ 174.22, 158.50, 130.41, 129.62, 72.76, 70.75, 70.51, 69.38, 63.47, 61.94,
40.78, 40.71, 34.33, 30.13, 30.08, 29.57, 29.25, 29.09, 28.94, 27.23, 27.15, 27.06, 25.03, 22.61,
14.24. HRMS calcd for C H N O [M+1] 473.3591, found 473.3588.
49 2 6
Synthesis of Analog 1.
2-(2-(2-Hydroxyethoxy)ethoxy)ethyl 13-(N-isopropylheptanamido)tridec-8(Z)-
enoate (1). 13-(N-Isopropylheptanamido)tridec-8(Z)-enoic acid (60 mg, 0.16 mmol) was
condensed with triethylene glycol as described above to give analog 1 (58 mg, 73%) as a
viscous, colorless oil. TLC: EtOAc (4:1), R ∼ 0.40; H NMR (300 MHz, 65/35 mixture of
rotamers) δ 5.26-5.40 (m, 2H), 4.62-4.70 (m, 0.5H), 4.20-4.26 (m, 2H), 3.98-4.08 (m, 0.5H),
3.58-3.76 (m, 10H), 3.04-3.16 (m, 2H), 2.20-2.36 (m, 4H for the two rotamers), 1.98-2.10 (m,
4H), 1.46-1.66 (m, 6H), 1.24-1.38 (m, 14H), 1.18 and 1.10 (d, J = 7.3 Hz, 6H for two rotamers),
0.87 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ 174.05, 174.01, 173.10, 172.55, 130.75, 130.11,
129.85, 129.15, 72.70, 70.76, 70.55, 69.40, 63.43, 61.94, 48.30, 45.52, 43.53, 41.09, 34.36,
34.32, 34.10, 34.0, 31.93, 31.89, 31.28, 29.90, 29.75, 29.69, 29.56, 29.43, 29.23, 29.12, 27.84,
27.48, 27.42, 27.35, 27.18, 26.93, 25.88, 25.70, 25.05, 25.02, 22.76, 21.60, 20.75, 14.28. HRMS
calcd for C H NO [M+1] 514.4108, found 514. 4111.
29 56 6
Synthesis of Analog 8.
N-Hydroxysuccinimidyl 13-(3-n-pentylureido)tridec-8(Z)-enoate. A mixture of
13-(3-n-pentylureido)tridec-8(Z)-enoic acid (100 mg, 0.29 mmol) and N-hydroxysuccinimide
(37 mg, 0.31 mmol) were azeotropically dried using anhydrous benzene (2 × 5 mL), then
dissolved in dry CH Cl (5 mL). To this was added EDCI (67 mg, 0.35 mmol) and DMAP (38
mg, 0.31 mmol) under an argon atmosphere. After 12 h at rt, the reaction mixture was diluted
with more CH Cl (20 mL), washed with water, brine, dried (Na SO ) and concentrated in vacuo.
2 2 2 4
The residue was purified by SiO column chromatography to give the title NHS ester (110 mg,
86%) as a sticky solid that was used immediately without further purification. TLC:
EtOAc/hexanes (7:3), R ∼ 0.40; H NMR (400 MHz) δ 5.27-5.36 (m, 2H), 4.48 (br s, 2H), 3.09-
3.15 (m, 4H), 2.81 (br s, 4H), 2.58 (t, J = 7.8 Hz, 2H), 1.94-2.06 (m, 4H), 1.68-1.74 (m, 2H),
1.20-1.50 (m, 16 H), 0.86 (t, J = 7.2 Hz, 3H); C NMR (100 MHz) δ 169.40, 168.96, 158.62,
130.29, 129.71, 40.75, 40.68, 31.12, 30.18, 30.14, 29.51, 29.28, 28.80, 27.21, 27.19, 27.10,
.81, 24.72, 22.62, 14.24.
13-(3-n-Pentylureido)-N-(phenylsulfonyl)tridec-8(Z)-enamide (8). A mixture of N-
hydroxysuccinimidyl 13-(3-n-pentylureido)tridec-8(Z)-enoate (150 mg, 0.34 mmol) from above,
benzenesulfonamide (78 mg, 0.49 mmol) and 4-dimethylaminopyridine (DMAP; 50 mg, 0.40
mmol) were heated in dry hexamethylphosphoramide (HMPA; 3 mL) at 80 ºC for 24 h. After
cooling to rt, the reaction mixture was diluted with water and extracted into EtOAc (3 × 10 mL).
The combined extracts were washed with water, brine, dried (Na SO ) and concentrated in
vacuo. The residue was purified by SiO column chromatography to give analog 8 (105 mg,
65%) as a colorless solid, mp 91.4-91.6 ºC. TLC: EtOAc/hexanes (3:2), R ∼ 0.30; H NMR (300
MHz) δ 8.00-8.10 (dd, J = 0.9, 7.3 Hz, 2H), 7.44-7.60 (m, 3H), 5.28-5.42 (m, 2H), 5.03 (br s, -
NH, 1H), 4.57 (br s, -NH, 1H), 3.21 (t, J = 6.8 Hz, 2H), 3.12 (t, J = 6.5 Hz, 2H), 2.29 (t, J = 7.9
Hz, 2H), 1.98-2.10 (m, 4H), 1.18-1.60 (m, 18H), 0.90 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ
172.66, 159.28, 139.67, 133.57, 130.69, 129.65, 128.93, 128.40, 41.41, 40.53, 36.22, 29.89,
29.61, 29.24, 28.87, 28.33, 27.69, 26.91, 26.69, 26.47, 24.70, 22.588, 14.22. HRMS calcd for
C H N O S [M+1] 480.2896, found 480.2899.
42 3 4
Synthesis of Analog 9.
N-(Methylsulfonyl)(3-n-pentylureido)tridec-8(Z)-enamide (9). N-
Hydroxysuccinimidyl 13-(3-n-pentylureido)tridec-8(Z)-enoate from above (150 mg, 0.34 mmol)
was reacted with methanesulfonamide (48 mg, 0.50 mmol) as described above to give analog 8
(102 mg, 72%) as a colorless solid, mp 113.5-113.6 ºC. TLC: EtOAc/hexanes (1:1), R ∼ 0.30; H
NMR (300 MHz) δ 5.30-5.40 (m, 2H), 3.21 (s, 3H), 3.04-3.12 (m, 4H), 2.29 (t, J = 7.3 Hz, 2H),
2.00-2.10 (m, 4H), 1.22-1.66 (m, 18H), 0.90 (t, J = 7.0 Hz, 3H); C NMR (75 MHz) δ 175.14,
161.50, 131.17, 130.78, 41.44, 41.10, 41.02, 37.13, 31.22, 31.15, 30.73, 30.34, 30.07, 30.05,
28.19, 28.17, 28.03, 25.80, 23.66, 14.56. HRMS calcd for C H N O S [M+1] 418.2740, found
40 3 4
418.2739.
Synthesis of Analog 6.
Methyl 2-(13-(1,3-dimethyln-pentylureido)tridec-8(Z)-enamido)acetate.
Glycine hydrochloride (32 mg, 0.29 mmol) and 1-hydroxybenzotriazole (32 mg, 0.23 mmol;
HOBt) were added to a solution of 13-(1,3-dimethyln-pentylureido)tridec-8(Z)-enoic acid (70
mg, 0.19 mmol) and diisopropylethylamine (50 µL, 0.29 mmol) in anhydrous DMF (20 mL)
under an argon atmosphere. After 5 min, 1-ethyl(3-dimethylaminopropyl)carbodiimide
hydrochloride (45 mg, 0.23 mmol; EDCI) was added as a solid. After stirring for 12 h at room
temperature, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 ×
mL). The combined organic extracts were dried over Na SO , concentrated under reduced
pressure, and the residue was purified by SiO column chromatography using 30%
EtOAc/hexanes as eluent to give the title methyl ester (65 mg, 79%) as a viscous oil. TLC:
EtOAc/hexanes (7:3), R ∼ 0.40; H NMR (300 MHz) δ 6.18 (br s, -NH, 1H), 5.26-5.40 (m, 2H),
4.04 (d, J = 5.2 Hz, 2H), 3.75 (s, 3H), 3.11 (apparent q, J = 7.6 Hz, 4H), 2.77 (s, 3H), 2.76 (s,
3H), 2.24 (t, J = 7.6 Hz, 2H), 1.96-2.08 (m, 4H), 1.46-1.70 (m, 6H), 1.20-1.38 (m, 12H), 0.88 (t,
J = 7.2 Hz, 3H); C NMR (100 MHz) δ 170.69, 170.07, 165.65, 130.36, 129.38, 52.45, 50.43,
50.42, 41.23, 35.86, 30.09, 29.62, 29.26, 29.22, 29.05, 27.32, 27.15, 26.67, 25.74, 25.38, 21.65,
14.48. HRMS Calcd for C H N O [M+1] 440.3488, found 440.3485.
24 46 3 4
2-(13-(1,3-Dimethyln-pentylureido)tridec-8(Z)-enamido)acetic acid (6).
Following the ester hydrolysis conditions described above, methyl 2-(13-(1,3-dimethyln-
pentylureido)tridec-8(Z)-enamido)acetate was converted into analog 6 (87%), obtained as a
colorless liquid. TLC: EtOAc/hexanes (4:1), R ∼ 0.40; H NMR (300 MHz) δ 6.39 (br s, -NH,
1H), 5.24-5.40 (m, 2H), 4.03 (d, J = 4.5 Hz, 2H), 3.16 (apparent q, J = 5.8 Hz, 4H), 2.79 (s, 3H),
2.77 (s, 3H), 2.25 (t, J = 7.0 Hz, 2H), 1.90-2.10 (m, 4H), 1.48-1.70 (m, 6H), 1.20-1.40 (m, 12H),
0.88 (t, J = 7.2 Hz, 3H); C NMR (100 MHz) δ 174.31, 171.97, 166.01, 130.44, 129.51, 50.79,
50.61, 41.72, 36.86, 36.72, 36.42, 29.64, 29.18, 29.05, 27.36, 27.26, 27.09, 27.04, 25.76, 22.63,
14.24. HRMS Calcd for C H N O [M+1] 426.3332, found 426.3315.
23 44 3 4
Synthesis of Analog 5.
Methyl 2-(13-(N-Isopropylheptanamido)tridec-8(Z)-enamido)acetate. 13-(N-
Isopropyl heptanamido)tridec-8(Z)-enoic acid (100 mg, 0.26 mmol) was condensed with glycine
methyl ester as described above to give the corresponding amide (97 mg, 82%) as a colorless
syrup that was used directly in the next step. TLC: EtOAc (2:1), R ∼ 0.45; H NMR (300 MHz,
1:1 mixture of rotamers) δ 6.25 (br s, -NH, 0.5 H), 6.08 (br s, -NH, 0.5 H), 5.24-5.42 (m, 2H),
4.60-4.72 (m, 1H), 4.05 (d, J = 2.4 Hz, 2H), 3.76 (s, 1.5 H), 3.75 (s, 1.5 H), 3.06-3.15 (m, 2H),
2.20-2.38 (m, 4H), 1.90-2.10 (m, 4H), 1.40-1.68 (m, 6 H), 1.24-1.38 (m, 14 H), 1.19 (d, J = 6.7
Hz, 3 H), 1.10 (d, J = 6.7 Hz, 3 H), 0.88 (t, J = 7.1 Hz, 3H); C NMR (100 MHz) δ 173.60,
173.46, 173.16, 172.60, 170.82, 130.84, 130.12, 129.88, 129.16, 53.66, 52.58, 52.53, 48.35,
45.52, 43.55, 41.38, 41.15, 36.57, 34.11, 34.02, 31.95, 31.92, 31.32, 29.92, 29.72, 29.63, 29.60,
29.45, 29.40, 29.26, 29.21, 28.97, 27.94, 27.45, 27.41, 27.26, 27.16, 26.96, 25.91, 25.80, 25.75,
22.79, 21.62, 20.78, 14.31.
2-(13-(N-Isopropylheptanamido)tridec-8(Z)-enamido)acetic acid (5). Following
the ester hydrolysis conditions described above, methyl 2-(13-(N-isopropylheptanamido)tridec-
8(Z)-enamido)acetate (50 mg, 0.10 mmol) was hydrolyzed to give analog 5 (44 mg, 91%)
obtained as a colorless liquid. TLC: EtOAc (4:1), R ∼ 0.20; H NMR (300 MHz, 65/35 mixture
of rotamers) δ 6.47 and 6.35 (br s, -NH, 1H for the two rotamers), 5.24-5.42 (m, 2H), 4.60-4.70
(m, 1H), 4.05 and 4.06 (d, J = 2.8 Hz, 2H for the two rotamers), 3.06-3.18 (m, 2H), 2.20-2.38
(m, 4H), 1.90-2.10 (m, 4H), 1.50-1.68 (m, 6H), 1.24-1.38 (m, 14H), 1.20 and 1.10 (d, J= 7.3 Hz,
6H for the two rotamers), 0.87 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ 174.35, 174.23, 174.18,
173.64, 172.0, 171.93, 130.98, 130.25, 129.75, 129.0, 48.86, 45.99, 43.77, 41.79, 41.62, 41.48,
34.05, 33.95, 31.85, 31.79, 31.13, 29.62, 29.51, 29.35, 29.31, 29.23, 28.85, 28.81, 27.83, 27.44,
27.34, 27.21, 27.02, 26.90, 26.03, 25.87, 25.80, 25.75, 22.75, 21.54, 20.70, 14.29. HRMS calcd
for C H N O [M+1] 439.3536, found 439.3531.
47 2 4
Synthesis of Analog 31.
1-(5-(tert-Butyldiphenylsilyloxy)pentyl)n-pentylurea. 5-(tert-
Butyldiphenylsilyloxy)pentanamine (3.0 g, 8.78 mmol) was reacted with n-pentyl isocyanate
(995 mg, 8.78 mmol) as described above to give the title urea (85%) as a colorless oil. TLC:
EtOAc/hexanes (2:3), R ∼ 0.40; H NMR (300 MHz) δ 7.60-7.70 (m, 4H), 7.30-7.40 (m, 6H),
4.24 (br s, -NH, 2H), 3.64 (t, J = 7.9 Hz, 2H), 3.06-3.20 (m, 4H), 1.20-1.60 (m, 12 H), 1.03 (s,
9H), 0.89 (t, J = 7.2 Hz, 3H); C NMR (75 MHz) δ 159.7, 134.90, 132.47, 132.40, 129.70,
128.81, 128.71, 127.92, 63.2, 40.91, 40.81, 32.42, 29.60, 29.28, 27.11, 23.30, 22.35, 19.38.
HRMS calcd for C H N O Si [M+1] 455.3094, found 455.3093.
27 43 2 2
1-(5-Hydroxypentyl)n-pentylurea. 1-(5-(tert-Butyldiphenylsilyloxy)pentyl)n-
pentylurea (3.0 g, 6.60 mmol) was de-silylated as described above to give the title alcohol (1.31
g, 92%) as a colorless solid, mp 81.4-81.8 ºC. TLC: EtOAc/hexanes (7:3), R ∼ 0.40; H NMR
(CD OD, 300 MHz) δ 3.54 (t, J = 5.8 Hz, 2H), 3.06 (q, J = 6.4 Hz, 4H), 1.22-1.60 (m, 12H),
0.89 (t, J = 7.3 Hz, 3H); C NMR (CD OD, 100 MHz) δ 160.17, 61.67, 39.82, 39.77, 32.17,
.02, 29.91, 29.03, 23.04, 22.34, 13.25. HRMS calcd for C H N O [M+1] 217.1916, found
11 25 2 2
217.1916.
1-(5-Bromopentyl)n-pentylurea. Following the protocol described above, 1-(5-
hydroxypentyl)n-pentylurea (1.30 g, 6.02 mmol) was converted into the corresponding
bromide (1.45 g, 87%), obtained as a colorless oil. TLC: EtOAc/hexanes (2:3), R ∼ 0.40; H
NMR (300 MHz) δ 4.44 (br s, -NH, 2H), 3.40 (t, J = 6.7 Hz, 2H), 3.10-3.20 (m, 4H), 1.82-1.92
(m, 2H), 1.40-1.58 (m, 6H), 1.24-1.38 (m, 4H), 0.89 (t, J = 7.3 Hz, 3H); C NMR (100 MHz) δ
159.46, 40.02, 33.88, 33.02, 30.29, 29.92, 29.36, 25.83, 22.12, 14.02. HRMS calcd for
C H BrN O [M+1] 279.1072, found 279.1073.
11 24 2
N-(4-(5-(3-n-Pentylureido)pentyloxy)benzo[d]thiazolyl)acetamide (31). A
mixture of 1-(5-bromopentyl)n-pentylurea (100 mg, 0.37 mmol), commercial N-(4-
hydroxybenzo[d]thiazolyl)acetamide (100 mg, 0.48 mmol), and K CO (67 mg, 0.48 mmol) in
DMF (5 mL) was heated at 60 ºC. After 6 h, the reaction mixture was cooled to rt, diluted with
water (25 mL), and extracted into EtOAc (3 × 10 mL). The combined organic extracts were
washed with water (2 × 5 mL), brine (10 mL), dried (Na SO ) and concentrated in vacuo. The
residue thus obtained was purified by silica gel column chromatography to give 31 (61 mg,
40%), mp 61.6-61.8 ºC. TLC: EtOAc/hexane (3:2), R ∼ 0.40; H NMR (300 MHz) δ 7.39 (dd, J
= 0.9, 7.3 Hz, 1H), 7.20 (dd, J = 7.8, 7.3 Hz, 1H), 6.86 (dd, J = 0.9, 7.8 Hz, 1H), 4.42 (br s, -NH,
2H), 4.17 (t, J = 5.4 Hz, 2H), 3.19-3.30 (m, 4H), 2.33 (s, 3H), 1.82-1.98 (m, 2H), 1.64-1.80 (m,
4H), 1.42-1.60 (m, 2H), 1.24-1.40 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H); C NMR (75 MHz) δ
170.16, 159.91, 158.94, 151.37, 139.10, 133.67, 124.40, 113.94, 108.68, 68.21, 40.64, 39.98,
.27, 29.30, 28.33, 26.54, 23.25, 22.64, 22.33, 14.26. HRMS (ESI-neg) calcd for C H N O S
29 4 3
[M-1] 405.1960, found 405.1938.
Synthesis of Analog 32.
N -n-Butyl-N -(5-(tert-butyldiphenylsilyloxy)pentyl)oxalamide. A mixture of 2-(n-
butylamino)oxoacetic acid (22 mg, 0.15), 5-(tert-butyldiphenylsilyloxy)pentanamine (50
mg, 0.15 mmol), N,N-diisopropylethylamine (40 mg, 0.30 mmol), and 2-(1Hazabenzotriazol-
1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 72 mg, 0.19
mmol) in dry DMF (5 mL) was stirred at rt overnight under an argon atmosphere, then quenched
with water (2 mL). The reaction mixture was extracted with EtOAc (3 × 5 mL). The combined
organic extracts were washed with water, dried and concentrated in vacuo. The residue was
purified by flash SiO column chromatography using EtOAc/hexanes (1:3) as eluent to give the
title oxamide (65 mg, 91%) as a colorless oil. TLC: 50% EtOAc/hexane, R ∼ 0.56; H NMR
(400 MHz) δ 7.55-7.70 (m, 4H), 7.60 (br s, -NH, 2H), 7.35-7.40 (m, 6H), 3.65 (t, J = 6.0 Hz,
2H), 3.35-3.25 (m, 4H), 1.55-1.35 (m, 10H), 1.05 (s, 9H), 0.92 (t, J = 7.3 Hz, 3H); C NMR
(100 MHz) δ 160.28, 160.25, 135.80, 134.20, 129.85, 127.90, 63.80, 40.0, 39.70, 32.40, 31.50,
29.20, 27.10, 27.05, 23.40, 20.30, 19.45, 14.0. HRMS calcd for C H N O Si [M+1] 469.2886,
27 41 2 3
found 469.2892.
1 2 1 2
N -n-Butyl-N -(5-hydroxypentyl)oxalamide. A mixture of N -n-butyl-N -(5-(tert-
butyldiphenylsilyloxy)pentyl)oxalamide (65 mg, 0.14 mmol) and n-tetrabutylammonium fluoride
(0.41 mL, 1 M soln, 0.42 mmol) in dry THF solution was stirred at room temperature under an
argon atmosphere for 12 h. All volatiles were evaporated in vacuo, the residue was dissolved in
EtOAc (30 mL) and the organic layer was washed with water (10 mL), brine (15 mL), dried and
evaporated. Purification of the residue via SiO column chromatography using EtOAc/hexanes
(1:2) as eluent gave the title compound (30 mg, 92%) as a colorless solid, mp 136-137 ºC. TLC:
50% EtOAc/hexane, R ∼ 0.28; H NMR (300 MHz) δ 7.65 (br s, NH, 1H), 7.60 (br s, -NH, 1H),
3.65 (t, J = 6.0 Hz, 2H), 3.35-3.25 (m, 4H), 1.90 (br s -OH, 1H), 1.60-1.50 (m, 6H), 1.40-1.35
(m, 4H), 0.92 (t, J = 7.3 Hz, 3H); C NMR (100 MHz) δ 160.25, 160.10, 62.70, 39.80, 39.65,
32.40, 31.45, 29.20, 23.25, 20.20, 13.85. HRMS calcd for C H N O [M+1] 231.1709, found
11 23 2 3
231.1701.
N -(5-Bromopentyl)-N -n-butyloxalamide. A solution of carbon tetrabromide (51
mg, 0.15 mmol) in CH Cl (5 mL) was stirred into a 0 ºC solution of triphenylphosphine (48 mg,
0.18 mmol) and N -n-butyl-N -(5-hydroxypentyl)oxalamide (30 mg, 0.130 mmol) in dry CH Cl
(5 mL) under an argon atmosphere. After 2 h, the reaction mixture was washed with water (5
mL), brine (10 mL), dried over anhydrous Na SO , and all volatiles were removed under reduced
pressure. The residue was purified by SiO column chromatography using EtOAc/hexane (1:4) to
give compound the title compound (32 mg, 84%) as a colorless solid, mp 109-110 ºC. TLC: 50%
EtOAc/hexanes, R ∼ 0.50; H NMR (300 MHz) δ 7.55 (br s, NH, 1H), 7.50 (br s, -NH, 1H), 3.40
(t, J = 6.0 Hz, 2H), 3.25-3.35 (m, 4H), 1.80-1.85 (m, 2H), 1.40-1.60 (m, 6H), 1.25-1.35 (m, 2H),
0.92 (t, J = 7.3 Hz, 3H); C NMR (100 MHz) δ 160.30, 160.15, 39.65, 33.65, 32.45, 31.40,
28.60, 25.60, 20.20, 13.90. HRMS calcd for C H BrN O [M+1] 293.0865, found 293.0870.
11 22 2 2
N -(5-(2-Acetamidobenzo[d]thiazolyloxy)pentyl)-N -n-butyloxalamide. A
mixture of N -(5-bromopentyl)-N -n-butyloxalamide (32 mg, 0.11 mmol), commercial N-(4-
hydroxybenzo[d]thiazolyl)acetamide (22 mg, 0.11 mmol), and K CO (45 mg, 0.32 mmol) in
DMF (3 mL) was heated at 80 ºC for 3h, then cooled to room temperature, diluted with water (15
mL) and extracted into EtOAc (3 × 10 mL). The combined organic extracts were washed with
water (2 × 5 mL), brine (10 mL), dried (Na SO ) and concentrated in vacuo. The residue was
purified by silica gel column chromatography using EtOAc/hexanes (1:2) as eluent to give
analog 32 (35 mg, 76%) as a colorless solid, mp 154-155 ºC. TLC: 70% EtOAc/hexanes, R ∼
0.35; H NMR (300 MHz) δ 11.05 (br s, NH, 1H), 8.30 (br s, NH, 1H), 7.70 (br s, NH, 1H), 7.40
(d, J = 7.4 Hz, 1H), 7.25 (dd, J = 7.4, 7.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 4.20 (t, J = 6.0 Hz,
2H), 3.50 (q, J = 7.2 Hz, 2H), 3.35 (q, J = 7.0 Hz, 2H), 2.35 (s, 3H), 1.95-1.90 (m, 2H), 1.85-
1.80 (m, 2H), 1.70-1.65 (m, 2H), 160-1.55 (m, 2H), 1.40-1.35 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H);
C NMR (75 MHz) δ 169.40, 160.55, 159.90, 157.85, 151.50, 139.10, 134.00, 124.75, 113.75,
108.10, 68.90, 39.80, 39.30, 31.35, 28.20, 27.40, 23.70, 23.45, 20.25, 13.90. HRMS calcd for
C H N O S [M+1] 421.1910, found 421.1906.
29 4 4
Synthesis of Analog 30.
5-(tert-Butyldiphenylsilyloxy)-N-isopropylpentanamine. Following literature
precedent, a mixture of 1-(tert-butyldiphenylsilyloxy)iodopentane (1.50 g, 3.32 mmol),
isopropylamine (1.70 mL, 19.92 mmol) and K CO (1.37 g, 10.03 mmol) was reacted to give the
title amine (0.92 g, 72%) as a colorless liquid. TLC: MeOH/CH Cl (1:4), R ∼ 0.30; H NMR
2 2 f
(300 MHz) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 3.65 (t, J = 6.4 Hz, 2H), 2.70-2.82 (m, 1H),
2.55 (t, J = 7.3 Hz, 2H), 1.50-1.64 (m, 2H), 1.32-1.48 (m, 4H), 1.05 (d, J = 5.8 Hz, 3H), 1.04 (s,
9H); C NMR (100 MHz) δ 135.68, 134.21, 129.63, 127.70, 63.95, 48.81, 47.64, 32.60, 30.27,
27.0, 23.76, 23.15, 19.34. HRMS calcd for C H NOSi [M+1] 384.2723, found 384.2724.
24 38
N-(5-(tert-Butyldiphenylsilyloxy)pentyl)-N-isopropylheptanamide. Following
literature precedent, 5-(tert-butyldiphenylsilyloxy)-N-isopropylpentanamine (0.90 g, 2.30
mmol) was condensed with heptanoic acid (0.26 g, 2.0 mmol) to give the title amide (0.90 g,
79%) as a viscous oil. TLC: EtOAc/hexanes (3:8), R ∼ 0.60; H NMR (300 MHz, 1:1 mixture of
rotamers) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 4.62-4.72 (m, 0.5 H), 4.00-4.80 (m, 0.5H),
3.62 (t, J = 4.8 Hz, 1H), 3.68 (t, J = 4.8 Hz, 1H), 3.02 (t, J = 5.2 Hz, 1H), 3.16 (t, J = 5.2 Hz,
1H), 2.38 (t, J = 5.3 Hz, 1H), 2.24 (t, J = 5.3 Hz, 1H), 1.50-1.68 (m, 6H), 1.26-1.44 (m, 8H), 1.18
(d, J = 7.3 Hz 3H), 1,12, (d, J = 7.3 Hz 3H), 1.03 (s, 4.5 H), 1.04 (s, 4.5H ), 0.88 (t, J = 7.3 Hz,
3H); C NMR (125 MHz) δ 173.38, 172.76, 135.80, 135.78, 134.36, 134.12, 129.85, 129.73,
127.88, 127.82, 64.22, 63.68, 48.43, 45.62, 43.64, 41.27, 34.13, 34.05, 32.61, 32.36, 31.96,
31.93, 31.51, 29.63, 29.47, 27.10, 27.03, 25.94, 25.78, 24.03, 23.77, 22.81, 21.63, 20.78, 19.47,
14.33, 14.28. HRMS calcd for C H NO Si [M+1] 496.3611, found 496.3615.
31 50 2
N-(5-Hydroxypentyl)-N-isopropylheptanamide. N-(5-(tert-
Butyldiphenylsilyloxy)pentyl)-N-isopropylheptanamide (0.70 g, 1.37 mmol) was de-silylated as
described above to give the title alcohol (0.34 g, 96%) as a colorless solid. TLC: EtOAc/hexanes
(2:3), R ∼ 0.30; H NMR (300 MHz, 53/47 mixture of rotamers) δ 4.58-4.66 and 3.96-4.08 (m,
1H for the two rotamers), 3.56 and 3.70 (t, J = 5.4 Hz, 2H for the two rotamers), 3.02-3.16 (m,
2H), 2.30 and 2.26 (t, J = 6.3 Hz, 2H for the two rotamers), 1.50-1.64 (m, 6H), 1.22-1.40 (m,
8H), 1.13 and 1.09 (d, J = 7.5 Hz, 6H for the two rotamers), 0.84 (t, J = 7.3 Hz, 3H); C NMR
(100 MHz) δ 172.81 62.66, 62.60, 48.41, 45.55, 43.56, 41.04, 34.08, 34.0, 32.46, 32.43, 31.86,
31.57, 29.40, 25.87, 25.70, 23.77, 23.73, 22.75, 21.57, 20.72, 14.26. HRMS calcd for C H NO
32 2
[M+1] 258.2433, found 258.2436.
N-(5-Bromopentyl)-N-isopropylheptanamide. N-(5-Hydroxypentyl)-N-
isopropylheptanamide (0.25 g, 0.97 mmol) was converted to the corresponding bromide as
described above to give the title compound (0.25 g. 82%) as a colorless oil. TLC:
EtOAc/hexanes (3:7), R ∼ 0.40; H NMR (300 MHz, 55/45 mixture of rotamers) δ 4.60-4.70 and
3.96-4.10 (m, 1H for two rotamers), 3.46 and 3.36 (t, J = 5.8 Hz 2H for two rotamers), 3.02-3.10
(m, 2H), 2.30 and 2.22 (t, J = 7.9 Hz, 2H for two rotamers), 1.80-1.97 (m, 2H), 1.40-1.70 (m,
6H), 1.20-1.40 (m, 6H), 1.16 and 1.10, (d, J = 7.3 Hz, 6H for two rotamers), 0.86 (t, J =7.3 Hz,
3H); C NMR (75 MHz) δ 172.79, 172.39, 48.17, 45.47, 43.32, 40.70, 33.89, 33.87, 33.49,
32.48, 32.30, 31.81, 31.78, 30.78, 29.27, 28.74, 26.05, 25.84, 25.69, 25.54, 22.64, 21.47, 20.62,
14.17. HRMS calcd for C H BrNO [M+1] 320.1589, found 320.1588.
31
N-(5-(2-Acetamidobenzo[d]thiazolyloxy)pentyl)-N-isopropylheptanamide (30).
N-(5-Bromopentyl)-N-isopropylheptanamide (75 mg, 0.23 mmol) was alkylated with commercial
N-(4-hydroxybenzo[d]thiazolyl)acetamide (54 mg, 0.26 mmol) as described above to give
analog 30 (43 mg, 42%) as a sticky solid. TLC: EtOAc/hexanes (1:4), R ∼ 0.30; H NMR (300
MHz, 45/55 mixture of rotamers) δ 11.50 (br s, -NH, 1H), 7.37-7.42 (m, 1H), 7.18-7.26 (m, 1H),
6.84-6.88 (m, 1H), 4.58-4.78 and 4.00-4.10 (m, 1H for two rotamers), 4.02 (t, J = 6.3 Hz, 2H),
3.12 (t, J = 7.3 Hz, 2H), 2.22-2.45 (m, 5H), 1.82-1.92 (m, 2H), 1.44-1.70 (m, 4H), 1.20-1.40 (m,
8H), 1.11-1.19 (m, 6H), 0.82-0.95 (m, 3H); C NMR (75 MHz) δ 173.94, 172.78, 169.40,
169.36, 157.89, 151.62, 138.43, 138.32, 133.91, 133.87, 124.92, 124.85, 114.02, 113.87, 109.66,
108.35, 69.46, 69.08, 48.53, 48.33, 45.94, 43.61, 41.20, 34.26, 34.09, 31.91, 31.88, 31.39, 29.55,
29.45, 29.37, 29.30, 25.88, 25.77, 25.71, 24.43, 24.16, 23.55, 22.77, 21.59, 20.80, 14.28. HRMS
(ESI-neg) calcd for C H N O S [M-1] 446.2477, found 446.2434.
24 36 3 3
Synthesis of Analog 33.
1-(tert-Butyldiphenylsilyloxy)(tetrahydro-2H-pyranyloxy)octyne. 4-(tert-
Butyldiphenylsilyloxy)butyne (5.0 g, 16.23 mmol) was coupled with 2-(4-
bromobutoxy)tetrahydro-2H-pyran (4.59 g, 19.48 mmol) as described above to give the title
acetylene (5.57 g, 74%) as a colorless oil. TLC: EtOAc/hexanes (1:9), R ∼ 0.40; H NMR (300
MHz) δ 7.66-7.69 (m, 4H), 7.34-7.42 (m, 6H), 4.57 (t, J = 4.3 Hz, 1H), 3.78-3.86 (m, 2H), 3.73-
3.90 (m, 3H), 3.32-3.40 (m, 3H), 2.40-2.45 (m, 2H), 2.06-2.10 (m, 2H), 1.93-2.02 (m, 2H), 1.40-
1.80 (m, 6H), 1.02 (s, 9H); C NMR (100 MHz) δ 137.87, 133.96, 129.70, 128.0, 99.0, 81.0,
77.41, 67.32, 63.15, 62.51, 30.97, 29.20, 27.0, 26.98, 26.0, 25.74, 23.18, 19.83, 19.44, 18.88.
HRMS calcd for C H O Si [M+1] 465.2825, found 465.2829.
29 41 3
8-(tert-Butyldiphenylsilyloxy)octynol. 1-(tert-Butyldiphenylsilyloxy
(tetrahydro-2H-pyranyloxy)octyne (5.50 g, 11.84 mmol) was de-silylated as described
above to give the title compound (3.87 g, 86%) as a colorless oil. TLC: EtOAc/hexanes (2:3), R
∼ 0.40; H NMR (300 MHz) δ 7.60-7.68 (m, 4H), 7.30-7.40 (m, 6H), 3.77 (t, J = 7.4 Hz, 2H),
3.60-3.72 (m, 2H), 2.40-2.48 (m, 2H), 2.22-2.40 (m, 2H), 1.50-1.70 (m, 4H), 1.03 (s, 9H); C
NMR (100 MHz) δ 135.83, 133.96, 129.90, 127.92, 81.31, 63.16, 62.60, 32.0, 27.0, 25.43, 23.17,
19.43, 18.78. HRMS calcd for C H O Si [M+1] 381.2250, found 381.2256.
24 33 2
8-(tert-Butyldiphenylsilyloxy)oct-5(Z)-enol. 8-(tert-Butyldiphenylsilyloxy)oct
ynol (5.32 g, 14.0 mmol) was semi-hydrogenated as described above to give 8-(tert-
butyldiphenylsilyloxy)oct-5(Z)-enol (5.18 g, 97%) as a colorless oil whose spectral values
were in agreement with literature data. TLC: EtOAc/hexanes (2:3), R ∼ 0.45; H NMR (300
MHz) δ 7.60-7.70 (m, 4H), 7.30-7.40 (m, 6H), 5.34-5.44 (m, 2H), 3.65 (t, J = 7.0 Hz, 2H), 3.58-
3.64 (m, 2H), 2.23 (q, J = 4.2 Hz, 2H), 1.98-2.20 (m, 2H), 1.30-1.60 (m, 4H), 1.03 (s, 9H); C
NMR (100 MHz) δ 135.84, 134.21, 131.64, 129.82, 127.87, 126.28, 63.94, 63.12, 32.54, 31.12,
27.23, 27.11, 26.02.
1-(tert-Butyldiphenylsilyloxyazido-oct-3(Z)-en. Following the procedure
described above, 8-(tert-butyldiphenylsilyloxy)-oct-5(Z)-enol (5.20 g, 13.61 mmol) was
transformed into the title azide (3.98 g, 72%), obtained as a colorless oil. TLC: EtOAc/hexanes
(1:9), R ∼ 0.60; H NMR (300 MHz) δ 7.60-7.70 (m, 4H), 7.30-7.40 (m, 6H), 5.34-5.44 (m, 2H),
3.63 (t, J = 7.0 Hz, 2H), 3.22 (t, J = 6.4 Hz, 2H), 2.31 (q, J = 3.6 Hz, 2H), 1.95-2.05 (m, 2H),
1.50-1.60 (m, 2H), 1.30-1.40 (m, 2H), 1.03 (s, 9H); C NMR (100 MHz) δ 135.98, 135.90,
134.28, 131.24, 130.05, 129.79, 128.10, 127.87, 126.76, 63.98, 51.64, 31.24, 28.74, 27.29, 27.16,
-1 +
27.07, 27.0, 19.55; IR (neat) 2931, 2858, 2095, 1111 cm . HRMS calcd for C H N OSi [M+1]
24 34 3
408.2471, found 408.2470.
1-(8-(tert-Butyldiphenylsilyloxy)oct-5(Z)-enyl)n-pentylurea. 1-(tert-
Butyldiphenylsilyloxyazido-oct-3(Z)-en was reduced to the corresponding amine using
triphenylphosphine as described above. The crude amine was reacted with n-pentyl isocyanate in
THF as noted above and the product was purified by SiO column chromatography eluting with
% EtOAc/hexane to afford the title compound (1.94 g, 84%) as a viscous oil. TLC:
EtOAc/hexanes (2:3), R ∼ 0.45; H NMR (300 MHz) δ 7.60-7.70 (m, 4H), 7.30-7.40 (m, 6H),
.35-5.42 (m, 2H), 4.65 ( br s, -NH, 2H), 3.64 (t, J = 5.5 Hz, 2H), 3.06-3.18 (m, 4H), 2.24-2.34
(q, J = 3.9 Hz, 2H), 1.94-2.02 (q, J = 3.6 Hz, 2H), 1.20-1.50 (m, 10H), 1.03 (s, 9H), 0.83 (t, J =
7.3 Hz, 3H); C NMR (100 MHz) δ 159.52, 135.85, 134.21, 131.53, 129.85, 127.90, 126.28,
63.93, 40.58, 40.50, 31.13, 30.43, 30.41, 29.45, 27.35, 22.77, 19.47, 14.36. HRMS calcd for
C H N O Si [M+1] 495.3407, found 495.3406.
47 2 2
1-(8-Hydroxyoct-5(Z)-enyl)n-pentylurea. 1-(8-(tert-Butyldiphenylsilyloxy)oct-
(Z)-enyl)n-pentylurea (3.0 g, 6.07 mmol) was de-silylated as described above to give the title
alcohol (1.44 g, 93%) as a colorless solid, mp 57.8-57.9 ºC. TLC: EtOAc/hexanes (1:4), R ∼
0.30; H NMR (300 MHz) δ 5.30-5.60 (m, 2H), 4.40 (br s, -NH, 2H), 3.63 (t, J = 6.4 Hz, 2H),
3.08-3.22 (m, 4H), 2.29 (q, J = 5.3 Hz, 2H), 2.09 (q, J = 5.2 Hz, 2H), 1.20-1.58 (m, 10H), 0.88 (t,
J = 7.3 Hz, 3H); C NMR (100 MHz) δ 159.48, 132.35, 126.21, 62.28, 40.54, 40.15, 31.12,
.28, 29.96, 29.35, 27.02, 26.98, 22.68, 14.27. HRMS calcd for C H N O [M+1] 257.2229,
14 29 2 2
found 257.2236.
1-(8-Bromooct-5(Z)-enyl)n-pentylurea. Obtained in 82% yield as a colorless oil.
TLC: EtOAc/hexanes (2:3), R ∼ 0.60; H NMR (300 MHz) δ 5.30-5.58 (m, 2H), 4.70 (br s, 2H),
3.35 (t, J = 6.8 Hz, 2H), 3.08-3.19 (m, 4H), 2.60 (q, J = 5.6 Hz, 2H), 2.05 (q, J = 5.4 Hz, 2H),
1.24-1.54 (m, 10H), 0.88 (t, J = 7.3 Hz, 3H); C NMR (100 MHz) δ 159.54, 132.73, 126.45,
40.53, 40.33, 32.85, 30.98, 30.33, 30.30, 29.36, 27.36, 27.0, 22.69, 14.28. HRMS calcd for
C H BrN O [M+1] 319.1385, found 319.1392.
14 28 2
N-(4-(8-(3-n-Pentylureido)oct-3(Z)-enyloxy)benzo[d]thiazolyl)acetamide (33).
Obtained in 40% yield as a colorless solid, mp 113.7-113.8 ºC. TLC: EtOAc/hexane (3:2), R ∼
0.40; H NMR (300 MHz) δ 12.10 (br s, -NH, 1H), 7.40 (dd, J = 0.8, 7.8 Hz, 1H), 7.22 (dt, J =
0.6, 8.9 Hz, 1H), 6.90 (dd, J = 0.5, 6.9 Hz, 1H), 5.40-5.50 (m, 2H), 4.60 (br s, -NH, 2H), 4.20 (t,
J = 5.3 Hz, 2H), 3.05-3.20 (m, 4H), 2.65 (q, J = 3.9 Hz, 2H), 2.29 (s, 3H), 2.15 (q, J = 3.9 Hz,
2H), 1.40-1.70 (m, 10 H), 0.87 (t, J = 7.3 Hz, 3H); C NMR (100 MHz) δ 170.07, 159.21,
158.52, 151.46, 138.41, 133.84, 132.26, 126.13, 124.81, 113.81, 108.29, 68.46, 40.75, 40.64,
.20, 29.30, 27.78, 26.84, 26.47, 23.42, 22.62, 14.24. HRMS calcd for C H N O S [M+1]
23 35 4 3
447.2430, found 447.2431.
Synthesis of Analog 4.
1-(Tetrahydro-2H-pyranyloxy)(tert-butyldiphenylsilyloxy)decyne.
Obtained in 73% yield as a colorless oil. TLC: 15% EtOAc/hexanes, R ∼ 0.50; H NMR (500
MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 4.62 (t, J = 4.3 Hz, 1H), 3.78-3.92 (m, 2H), 3.68
(t, J = 6.3 Hz, 2H), 3.40-3.56 (m, 2H), 2.14-2.26 (m, 4H), 1.42-1.90 (m, 14H), 1.04 (s, 9H); C
NMR (75 MHz) δ 135.83, 132.02, 129.80, 127,88, 99.0, 80.52, 80.30, 67.31, 63.74, 62.49, 32.0,
31.06, 29.21, 27.14, 26.21, 25.82, 25.78, 19.89, 18.90, 18.81. HRMS calcd for C H O Si [M +
31 45 3
1] 493.3138, found 493.3140.
10-(tert-Butyldiphenylsilyloxy)decynol. Obtained in 88% yield as a colorless
oil whose spectral values were in agreement with literature data. TLC: EtOAc/hexanes (3:7), R
∼ 0.40; H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.67 (t, J = 5.3 Hz, 4H),
2.06-2.22 (m, 4H), 1.50-1.64 (m, 8H), 1.04 (s, 9H); C NMR (75 MHz) δ 135.82, 135.08,
134.27, 129.80, 127.87, 80.74, 80.60, 63.67, 62.69, 32.09, 31.99, 27.12, 26.83, 25.78, 25.58,
.48, 19.49, 18.79, 18.76.
10-(tert-Butyldiphenylsilyloxy)dec-5(Z)-enol. Obtained in 92% yield as a
colorless oil whose spectral values were in agreement with literature data. TLC:
EtOAc/hexanes (3:7), R ∼ 0.45; H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.42-7.25 (m, 6H),
.30-5.40 (m, 2H), 3.67 (t, J = 5.3 Hz, 4H), 2.06-2.22 (m, 4H), 1.40-1.64 (m, 8H), 1.04 (s, 9H);
C NMR (75 MHz) δ 135.90, 135.81, 134.37, 129.92, 129.87, 129.84, 127.98, 127.80, 64.09,
63.05, 32.47, 27.24, 27.22, 27.13, 26.21, 26.14, 19.51.
1-(10-Azidodec-5(Z)-enyloxy)(tert-butyldiphenylsilane. Obtained in 71% yield as a
colorless oil. TLC: EtOAc/hexanes (1:9), R ∼ 0.60; H NMR (300 MHz) δ 7.64-7.68 (m, 4H),
7.25-7.42 (m, 6H), 5.30-5.40 (m, 2H), 3.65 (t, J = 5.3 Hz, 2H), 3.24 (t, J = 4.9 Hz, 2H), 2.06-
2.22 (m, 4H), 1.40-1.64 (m, 8H), 1.04 (s, 9H); C NMR (75 MHz) δ 137.87, 134.35, 130.69,
129.74, 127.91, 64.02, 51.62, 32.44, 28.67, 27.21, 27.16, 27.08, 26.91, 26.16, 19.48; IR (neat)
-1 +
2930, 2861, 2331, 2324, 2096, 1106 cm . HRMS calcd for C H N OSi [M+1] 436.2784,
26 38 3
found 436.2784.
1-(10-(tert-Butyldiphenylsilyloxy)dec-5(Z)-enyl)n-pentylurea. Obtained in 78%
yield as a colorless oil. TLC: EtOAc/hexanes (2:3), R ∼ 0.60; H NMR (300 MHz) δ 7.64-7.68
(m, 4H), 7.34-7.42 (m, 6H), 5.22-5.43 (m, 2H), 4.50 (br s, -NH, 2H), 3.65 (t, J = 6.2 Hz, 2H),
3.10-3.40 (m, 4H), 1.96-2.06 (m, 4H), 1.20-1.60 (m, 14H), 1.03 (s, 9H), 0.88 (t, J = 7.3 Hz, 3H);
C NMR (75 MHz) δ 159.08, 136.03, 134.02, 130.03, 128.26, 126.82, 63.28, 40.67, 40.47,
32.91, 30.48, 29.28, 27.26, 27.22, 26.93, 26.02, 22.64, 19.39, 14.26. HRMS calcd for
C H N O Si [M+1] 523.3720, found 523.3724.
32 51 2 2
1-(10-Hydroxydec-5(Z)-enyl)n-pentylurea. Obtained in 94% yield as a colorless
oil. TLC: EtOAc/hexanes (7:3), R ∼ 0.30; H NMR (400 MHz) δ 5.30-5.43 (m, 2H), 4.28 (br s,
2H), 3.63 (q, J = 4.6 Hz, 2H), 3.10-3.20 (m, 4H), 2.00-2.10 (m, 4H), 1.24-1.64 (m, 14H), 0.88 (t,
J =7.3 Hz, 3H); C NMR (75 MHz) δ 158.67, 130.17, 129.88, 62.71, 40.59, 40.34, 32.52, 30.23,
.0, 29.32, 27.09, 26.96, 25.99, 22.52, 14.25. HRMS calcd for C H N O [M+1] 285.2542,
16 33 2 2
found 285.2545.
2-(10-(3-n-Pentylureido)dec-5(Z)-enyloxy)acetic acid (4). A solution of 1-(10-
hydroxydec-5(Z)-enyl)n-pentylurea (66 mg, 0.23 mmol) and tetra-n-butylammonium sulfate
(39 mg, 0.12 mmol) in benzene/50% aq. KOH (4 mL, 1:1) was stirred at 10 ºC. After 15 min,
tert-butyl 2-bromoacetate (136 mg, 0.70 mmol) was added to the reaction mixture and stirred at
the same temperature for an additional 1 h. The reaction mixture was then diluted with water (10
mL) and extracted into EtOAc (2 × 10 mL). The combined organic extracts were washed with
water, brine and dried (Na SO ) and concentrated in vacuo. The residue was dissolved in CH Cl
2 4 2 2
(4 mL), cooled to 0 ºC, and trifluoroacetic acid (1 mL) was added dropwise. The reaction
mixture was diluted with more CH Cl (5 mL), washed with water, brine and dried (Na SO ).
2 2 2 4
The residue was purified by SiO column chromatography to give analog 4 (37 mg, 47%) as a
sticky solid. TLC: EtOAc, R ∼ 0.30; H NMR (400 MHz) δ 5.30-5.42 (m, 2H), 4.06 (s, 2H),
3.54 (t, J = 6.6 Hz, 2H), 3.07-3.15 (m, 4H), 2.00-2.12 (m, 4H), 1.21-1.66 (m, 14H), 0.88 (t, J
=7.3 Hz, 3H); C NMR (75 MHz) δ 174.32, 160.08, 130.33, 129.71, 71.60, 68.12, 41.11, 41.02,
29.68, 29.40, 29.17, 28.96, 27.20, 27.07, 26.64, 25.96, 22.55, 14.20. HRMS calcd for
C H N O [M+1] 343.2597, found 343.2594.
18 35 2 4
Example 2: Synthesis of Sodiuem (S)(13-(3-pentylureido)tridec-8(Z)-enamido)succinate
(NIH-F=EET A or JLJ)
As set forth in Figures 16A and 16B, the synthesis of EET A is as follows:
7- bromoheptaneol (2): Heptane-1,7-diol (36.0 g, 272 mmol; Alfa Aesar) and aq.
48% HBr (38 mL, 0.9 equiv.) were heated under reflux in benzene (400 mL) with water removal
using a Dean-Stark apparatus. After 16 h, all volatiles were removed in vacuo and the residue
was purified by SiO column chromatography using a gradient of 10-30% EtOAc/hexanes as
eluent to give 7-bromoheptanol (26.22 g, 62%) as a colorless oil. TLC: 50% EtOAc/hexanes,
R ≈ 0.40; H NMR (400 MHz, CDCl ) δ 3.61 (t, 2H, J = 7.1 Hz), 3.39 (t, 2H, J = 6.8 Hz), 1.80-
1.88 (m, 2H), 1.52-1.58 (m, 2H), 1.30-1.46 (m, 6H).
2-(7-Bromoheptyloxy)tetrahydro-2H-pyran (3): Dihydropyran (5.20 g, 6.11
mmol) was added to a stirring 0°C solution of 7-bromoheptaneol (2) (11.0 g, 56.7 mmol) and
a catalytic amount of PTSA in CH Cl . After stirring at rt for 12 h, the reaction mixture was
diluted with CH Cl (200 mL), washed with water (100 mL × 2), brine (100 mL × 3), dried over
anhydrous sodium sulphate, and evaporated. The residue was purified by silica gel column
chromatography using a gradient of 10-20% ethyl acetate/hexane as eluent to give 2-(7-
bromoheptyloxy)tetrahydro-2H-pyran (3) (14.50 g, 92%) as a colorless oil. TLC: 10%
EtOAc/hexanes, R ≈ 0.55; H NMR (400 MHz, CDCl ) δ 4.58-4.56 (m, 1H), 3.84-3.88 (m, 1H),
3.68-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.43 (m, 3H), 1.80-1.81 (m, 2H), 1.30-1.62 (m, 14
tert-Butyl(hexynyloxy)diphenylsilane (5): tert-Butyldiphenylchlorosilane
(3.2 mL, 12.4 mmol) was added dropwise to a stirring, 0°C solution of 5-hexynol (4, 1.07 g,
.9 mmol) and anhydrous imidazole (1.84 g, 27.1 mmol) in anhydrous CH Cl (20 mL) under
an argon atmosphere. After complete addition, the reaction mixture was stirred at room
temperature for 12 hours, then quenched with saturated aq. NH Cl solution (50 mL) and
extracted with Et O (3 × 50 mL). The combined ethereal extracts were washed with saturated aq.
NaCl solution (25 mL), dried over NaSO , and the solvent was removed in vacuo. The residue
was purified by flash chromatography (5% ethyl acetate/hexane) to yield 1-tert-
butyldiphenylsilyloxy-hexyne (5) (3.54 g, 10.5 mmol, 96%) as a colorless oil. TLC: 5%
EtOAc/hexanes, R ≈ 0.65; H NMR (400 MHz, CDCl ) δ 7.77-7.65 (m, 4H), 7.40-7.30 (m, 6H),
3.70 (t, 2H, J = 5.6 Hz), 2.40-2.25 (m, 2H), 2.05 (t, 1H, J = 2.8 Hz), 1.90-1.70 (m, 4H), 1.18 (s,
9H).
tert-Butyldiphenyl((tetrahydro-2H-pyranyloxy)tridecynyl)oxy)silane (6):
n-Butyllithium (14.3 mL, 35.9 mmol, 2.5 M solution in hexanes) was added dropwise to a -78°C
solution of tert-butyl(hexynyloxy)diphenylsilane (10 g, 29.76 mmol) in THF and dry HMPA
(4:1, 200 mL) under an argon atmosphere. After 30 min, the reaction mixture was warmed to
0°C over a period of 1 h and held there for 2 h. The reaction mixture was re-cooled -78°C and a
THF solution (50 mL) of bromide 3 (8.20 g, 29.3 mmol) was added. The reaction temperature
was allowed to warm to rt over 3h and was held at this temperature for 12 h before being
quenched by adding saturated aq. NH Cl solution (5 mL). The pH of the reaction mixture was
adjusted to ~ 4 using 1 M oxalic acid and extracted with EtOAc (2 × 250 mL). The combined
organic extracts were washed sequentially with water (2 ×100 mL) and brine (100 mL), the
organic layer was dried using anhydrous Na SO and concentrated under vacuo. Residue was
purified by silica gel column chromatography using 10% EtOAc/hexanes to afford 6 (12.4 g,
78%) as a colorless thick oil. H NMR (CDCl , 400 MHz) δ 7.68-7.64 (m, 4H), 7.42-7.34 (m,
6H), 4.57 (t, J = 4.3 Hz, 1H), 3.86-3.78 (m, 1H), 3.65 (t, J = 6.3 Hz, 3H), 3.54-3.32 (m, 4H),
2.22-2.10 (m, 4H), 1.84-1.24 (m, 18H), 1.04 (s, 9H) ; C NMR (CDCl , 100 MHz) δ 135.82,
135.77, 134.25, 129.72, 127.85, 127.80, 127.77, 99.09, 99.05, 80.59, 80.22, 67.84, 67.74, 63.70,
62.58, 62.54, 31.00, 25.73, 19.92, 19.44, 18.97, 18.77.
13-(tert-Butyldiphenylsilyloxy)tridecynol (7): A solution of 6 (15.0 g, 0.59
mmol) and a catalytic amount of PPTS (10 mg) in MeOH (20 mL) was stirred at 0°C for 10h,
then quenched with saturated aq. NaHCO solution. Most of the methanol was evaporated in
vacuo. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL ×
3). The combined organic extracts were concentrated under reduced pressure and the residue was
purified by silica gel column chromatography using 20-30 % ethyl acetate /hexane as eluent to
afford 7 as a colorless oil (8.80 g, 78.7%). TLC: 20% EtOAc/hexanes, R ≈ 0.36; H NMR
(CDCl , 400 MHz) δ 7.68-7.65 (m, 4H), 7.41-7.35 (m, 6H), 3.66-3.62 (m, 4H), 2.10-1.95 (m,
4H), 1.64-1.50 (m, 2H), 1.48-1.20 (m, 10H), 1.04 (s, 9H); C NMR (CDCl , 100 MHz) δ
135.79, 135.77, 134.26, 129.73, 127.84, 127.83, 127.80, 127.78, 80.56, 80.28, 63.72, 63.22,
32.96, 31.90, 29.01, 25.78, 19.45, 18.95, 18.77.
13-(tert-Butyldiphenylsilyloxy)tridec-8(Z)-enol (8): In a two neck round bottom
flask, NaBH (176 mg, 4.65 mmol) was added in small portions to a solution of Ni(OAc) ⋅4H O
4 2 2
(1.16 g, 9.3 mmol) in absolute ethanol (10 mL) under a hydrogen atmosphere (1 atm). After 15
min, dry ethylenediamine (0.56 g, 9.3 mmol) was added followed after an additional 15 min by a
solution of alcohol 7 (8.0 g, 18.7 mmol) in absolute ethanol (25 mL). The reduction was
monitored by TLC until complete and then diluted with ether (50 mL), passed through a small
pad of silica gel to remove inorganic impurities. The filtrate was concentrated under reduced
pressure to afford 8 as a viscous, colorless oil (7.60 g, 95%). TLC: 50% EtOAc/hexane, R ≈
0.42; H NMR (CDCl , 400 MHz) δ 7.68-7.65 (m, 4H), 7.41-7.35 (m, 6H), 5.40-5.30 (m, 2H),
3.58-3.65 m, 4H), 1.88-2.10 (m, 4H), 1.50-1.61 (m, 4H), 1.25-1.45 (m, 10H), 1.04 (s, 9H); C
NMR (CDCl , 100 MHz) δ 135.83, 134.36, 130.30, 129.98, 129.77, 127.85, 64.09, 63.17, 32.48,
29.96, 29.53, 27.49, 27.37, 27.21, 27.16, 26.23, 26.01, 19.50.
13-(tert-Butyldiphenylsilyloxy)tridec-8(Z)-enoic acid (9): Jones reagent (5.8 mL of
a 10 N solution in water) in acetone (25 mL) was added to a stirring, -40°C solution of alcohol 8
(5.0 g, 11.8 mmol) in acetone (75 mL). After 1 h, the reaction mixture was warmed to -10°C and
maintained for another 2 h, then quenched with an excess (5.0 equiv) of isopropanol. The green
chromium salts were removed by filtration and the filter cake was washed with acetone. The
combined filtrates and washings were concentrated in vacuo and the resultant residue was
dissolved in EtOAc (100 mL), washed with water (50 mL), dried over anhydrous sodium
sulphate, and concentrated in vacuo. The residue was purified by SiO column chromatography
using 15% EtOAc/hexanes as eluent to give 9 (3.84 g, 74.20%) as a liquid. TLC: 40%
EtOAc/hexanes, R ≈ 0.40. H NMR (CDCl , 400 MHz) δ 7.68-7.64 (m, 4H), 7.43-7.34 (m, 6H),
.40-5.26 (m, 2H), 3.66 (t, J = 6.6 Hz, 2H), 2.35 (t, J = 7.3 Hz, 2H), 2.10-1.90 (m, 4H) 1.64-1.50
(m, 2H), 1.48-1.20 (m, 10H), 1.04 (s, 9H); C NMR (CDCl , 100 MHz) δ 180.62, 135.81,
134.34, 130.10, 130.07, 129.73, 127.82, 127.80, 127.79, 64.06, 32.44, 29.12, 27.38, 27.18, 27.12,
26.19, 24.87, 19.47.
Methyl 13-hydroxytridec-8(Z)-enoate (10): A solution of 9 (7.60 g, 3.49 mmol)
and p-toluenesulphonic acid (50 mg; PTSA) in MeOH (50 mL) was stirred at room temperature
for 4 h, and then concentrated in vacuo. The residue was purified by SiO column
chromatography using 25% EtOAc/hexanes as eluent to give 10 (3.41 g, 87%) as a colorless oil.
TLC: 40% EtOAc/hexanes, R ≈ 0.35; H NMR (CDCl , 400 MHz) δ 5.40-5.36 (m, 2H), 3.60-
3.66 (m, 5H), 2.30 (t, J= 7.3 Hz, 2H), 2.10-1.90 (m, 4H) 1.64-1.50 (m, 2H), 1.48-1.20 (m, 10H).
Methyl 13-azidotridec-8(Z)-enoate (11): Diisopropyl azodicaboxylate (DIAD; 3.0
g, 14.8 mmol,) was added dropwise to a -20°C solution of triphenylphosphine (3.9 g, 14.8 mmol)
in dry THF (100 mL) under an argon atmosphere. After stirring for 10 min, a solution of 10 (3.0
g, 4.75 mmol) in anhydrous THF (5 mL) was added dropwise. After 30 min at -20°C, the
reaction mixture was warmed to 0°C and diphenylphosphorylazide (DPPA, 4.0 g, 14.5 mmol)
was added dropwise. After stirring at room temperature for 6 h, the reaction was quenched with
water (3 mL), diluted with ether (100 mL), and washed with brine (40 mL). The aqueous layer
was back-extracted with ether (2 × 150 mL). The combined organic extracts were dried over
Na SO and concentrated under reduced pressure. The residue was purified by SiO column
2 4 2
chromatography using 5% EtOAc/hexanes as eluent to afford 11 (2.72 g, 82%) as light yellow
oil. TLC: 10% EtOAc/hexanes, R ≈ 0.45; H NMR (CDCl , 400 MHz) δ 5.40-5.34 (m, 2H), 3.64
(s, 3H), 3.26 (t, J = 6.7 Hz, 2H), 2.30 (t, J = 7.7 Hz, 2H) 2.10-1.98 (m, 4 H) 1.66-1.54 (m, 2H),
1.48-1.24 (m, 10H).
Methyl 13-(3-pentylureido)tridec-8(Z)-enoate (12): Triphenylphosphine (2.7 g.,
11.0 mmol) was added to a room temperature solution of 11 (1.4 g, 5.24 mmol) in dry THF (25
mL). After 2 h, water (200 µL) was added and the stirring was continued for another 8 h. The
reaction mixture was then diluted with EtOAc (100 mL), washed with water (20 mL) and brine
(25 mL). Aqueous layers were back-extracted with EtOAc (2 × 30 mL). The combined organic
extracts were dried over Na SO , concentrated under reduced pressure and further dried under
high vacuum for 4 h. The crude amine was used in the next step without additional purification.
Procedure ref.: S. Chandrasekhar; S. S. Sultana; N. Kiranmai; Ch. Narsihmulu Tetrahedron Lett.
2007: 48, 2373.
n-Pentyl isocyanate (0.78 g, 6.9 mmol) was added to a room temperature solution of
the above crude amine (1.4 g, 5.8 mmol) in dry THF (25 mL). After 6 h, reaction mixture was
concentrated under reduced pressure and the residue was purified by SiO column
chromatography using 30% EtOAc/hexanes as eluent to give 12 (1.70 g, 85%) as a colorless,
viscous oil. TLC: 50% EtOAc/hexanes, R ≈ 0.40; H NMR (CDCl , 400 MHz) δ 5.40-5.26 (m,
2H), 4.46-4.32 (m, NH, 2H), 3.66 (s, 3H), 3.18-3.10 (m, 4H), 2.34 (t, J = 7.7 Hz 4H), 2.06-1.94
(m, 4H), 1.66-1.56 (m, 2H), 1.54-1.42 (m, 14 H), 0.88 (t, J = 7.0 Hz, 3H).
Methyl 13-(3-pentylureido)tridec-8(Z)-enoic acid (13): LiOH (6.2 mL, 2.0 M
aqueous solution, 3.0 equiv) was added to a 0°C solution of 12 (1.80 g, 5.8 mmol) in THF (25
mL) and deionized H O (4 mL). After stirring at room temperature overnight, the reaction
mixture was cooled to 0°C, the pH was adjusted to 4.0 with 1 M aq. oxalic acid, and extracted
with ethyl acetate (2 × 20 mL). The combined extracts were washed with water (30 mL), brine
(25 mL), dried over anhydrous Na SO , and concentrated in vacuo. The residue was purified by
SiO column chromatography using 25% EtOAc/hexanes as eluent to give 13 (1.48 g, 86%) as
white solid, m.p. = 67.1°C. TLC: 80% EtOAc/hexanes, R ≈ 0.30; H NMR (CDCl , 400 MHz)
δ 5.40-5.26 (m, 2H), 3.17-3.10 (m, 4H), 2.32 (t, J = 6.7 Hz, 2H), 2.09-1.95 (m, 4H), 1.65-1.48
(m, 6H), 1.44-1.22 (m, 12H), 0.89 (t, J = 7.1 Hz, 3H); C NMR (CDCl , 75 MHz) δ 178.5,
159.6, 130.5, 129.5, 40.9, 40.8, 34.4, 29.9, 29.8, 29.2, 28.7, 28.5, 27.2, 26.7, 24.9, 22.6, 14.2.
(S)(13-(3-Pentylureido)tridec-8(Z)-enamido)succinate (14): L-Aspartic acid
dimethyl ester (38 mg, 0.191 mmol) and HATU (67 mg, 0.176 mmol) were added to a stirring
solution of 13 (50 mg, 0.147 mmol) and DIPEA (74 mg, 0.573 mmol) in anhydrous DMF (2 mL)
under an argon atmosphere. After 5 min, 1-ethyl(3-dimethylaminopropyl)carbodiimide (33.8
mg, 0.176 mmol; EDCI) was added as a solid. After stirring for 12 h at room temperature, the
reaction mixture was diluted with EtOAc (15 mL), washed with water (5 mL), and brine (10
mL). The combined aqueous layers were back-extracted with EtOAc (3 × 10 mL). The combined
organic extracts were dried over Na SO , concentrated under reduced pressure, and the residue
was purified by SiO column chromatography using 50% EtOAc/hexanes as eluent to give 14
(60 mg, 84%) as viscous oil. TLC: 60% EtOAc/hexanes, R ≈ 0.35; H NMR (CDCl , 400 MHz)
δ 6.64 (d, J = 7.9 Hz, 1H), 5.38-5.30 (m, 2H), 4.90-4.82(m, 1H), 4.58-4.44 (m, 2H), 3.75 (s, 3H),
3.66 (s, 3H), 3.20-3.10 (m, 4H), 3.04 (dd, J = 4.3 Hz, J = 13.1 Hz, 1H), 2.84 (dd, J = 4.6 Hz, J
1 2 1 2
= 12.8 Hz, 1H), 2.22 (t, J = 6.3 Hz, 2H), 2.05-1.98 (m, 4H), 1.70-1.60 (m, 2H), 1.50-1.20 (m,
16H), 0.88 (t, J = 6.7 Hz, 3H).
(S)(13-(3-pentylureido)tridec-8(Z)-enamido)succinic acid (15): An aqueous
solution of LiOH (2 mL, 2 M solution, 6.0 equiv) was added to a 0°C solution of 14 (60 mg,
0.124 mmol) in THF (8 mL) and deionized H O (2 mL). After stirring at room temperature
overnight, the reaction mixture was cooled to 0°C, the pH was adjusted to 4.0 with 1 M aq.
oxalic acid, and extracted with ethyl acetate (2 × 10 mL). The combined extracts were washed
with water (5 mL), brine (5 mL), dried over anhydrous Na SO , and concentrated in vacuo. The
residue was purified by SiO column chromatography using 70-90% EtOAc/hexanes as eluent to
give 15 (48 mg, 85%) as a viscous, colorless oil. TLC: 5% MeOH/EtOAc, R ≈ 0.20; H NMR
(CD OD, 400 MHz) δ 5.38-5.30 (m, 2H), 4.72 (t, J = 4.3 Hz, 1H), 3.12-3.05 (m, 4H), 2.90-2.72
(m, 2H), 2.22 (t, J = 7.7 Hz, 2H), 2.10-1.98 (m, 4H), 1.60-1.22 (m, 18H), 1.20 (t, J = 7.1 Hz,
3H); C NMR (CDCl , 75 MHz) δ 174.9, 173.0, 172.8, 160.1, 129.9, 129.3, 51.8, 49.8, 39.8,
39.7, 35.7, 35.6, 29.9, 29.8, 29.5, 29.0, 28.8, 26.9, 26.7, 25.7, 22.3, 13.2.
Disodium (S)(13-(3-pentylureido)tridec-8(Z)-enamido)succinate (16): Sodium
bicarbonate (93 mg, 1.1 mmol) was added to a stirring solution of 15 (100 mg, 0.22 mmol) in
THF/H O (4:1, 5 mL) at rt. After 2 h, the THF was removed in vacuo and the remaining aqueous
phase was stirred with SM-2 Bio-Beads (Bio-Rad, 20-50 mesh; 2 g). After 1 h, the Bio-Beads
were collected by filtration on a sintered-glass funnel, washed with water (5 mL × 2) and finally
with 95% ethanol (20 mL × 3). Evaporation of the ethanol washes in vacuo gave 16 (72 mg,
84%) as a white solid, m.p. = 258.5°C. TLC: 10% MeOH/CH Cl , R ∼ 0.15; H NMR (CD OD,
2 2 f 3
500 MHz) δ 5.25-5.23 (m, 2H), 4.40 (t, 1H, J = 4.0), 3.01-2.97 (m, 4H), 2.58-2.56 (m, 2H), 2.13
(t, 2H, J = 7.0), 1.96-1.94 (m, 4H), 1.51-1.47 (m, 2H), 1.30-1.19 (m, 16H), 0.83 (t, 3H, J = 7.0);
C NMR (75 MHz, CDCl ) δ 178.52, 178.38, 173.99, 160.21, 129.93, 129.37, 52.66, 39.81,
39.74, 36.27, 29.50, 28.93, 26.76, 22.34, 13.26.
Example 3: Synthesis of N-Isopropyl-N-(5-(2-pivalamidobenzo[d]thiazol
yloxy)pentyl)heptanamide (MV=EET-B or SRD-2)
As set forth in Figure 15, the synthesis of EET B is as follows:
5-(tert-Butyldiphenylsilyloxy)pentanol (2): Imidazole (0.65 g, 9.60 mmol) was
added to a stirring solution of pentan-1,5-diol (1.00 g, 9.60 mmol) in dry dichloromethane (10
mL) at 0°C under an argon atmosphere followed by the dropwise addition of tert-
butylchlorodiphenylsilane (3.85 mL, 9.60 mmol) in CH Cl (2 mL). The reaction was allowed to
slowly reach room temperature. After 12 hours, the reaction mixture was washed with water (2 ×
mL), brine (20 mL), dried over Na SO , and concentrated under reduced pressure. The
residue which was purified by SiO flash chromatography using 30% ethyl acetate/hexane as
eluent to furnish 2 (1.35 g, 46%), recovered SM and di-protected compound. TLC: 30%
EtOAc/hexanes, R ∼ 0.38; H NMR (CDCl , 400 MHz) δ 7.67-7.62 (m, 4H), 7.45-7.35 (m, 6H),
3.67 (t, 2H, J = 6.0 Hz), 3.52 (t, 2H, J = 6.7 Hz), 2.03-1.93 (m, 2H), 1.72-1.64 (m, 4H), 1.04 (s,
9H).
tert-Butyl(5-iodopentyloxy)diphenylsilane (3): Imidazole (310 mg, 4.40 mmol),
iodine (440 mg, 3.5 mmol), and a solution of 2 (1 g, 2.98 mmol) in CH Cl (2 mL) were added
sequentially to a 0°C solution of PPh (450 mg, 3.5 mmol) in CH Cl (15 mL) and kept in the
3 2 2
dark. After 2 h, the reaction mixture was quenched by adding 20% aq. Na S O (5 mL). The
2 2 3
aqueous layer was extracted with CH Cl (2 × 50 mL). The combined organic extracts were
washed with brine (30 mL), dried over anhydrous Na SO , and the solvent was removed in
vacuo. The residue was purified by careful column chromatography using 5% EtOAC/hexane to
afford iodide 3 (1.25 mg, 92%). TLC: 10% EtOAc/hexane, R ~ 0.85; H NMR (CDCl , 400
MHz) δ 7.67-7.62 (m, 4H), 7.45-7.35 (m, 6H), 3.67 (t, 2H, J = 6.0 Hz), 3.41 (t, 2H, J = 6.7 Hz),
2.03-1.93 (m, 2H), 1.72-1.64 (m, 4H), 1.04 (s, 9H).
IPA,K CO
TBDPSO
I OTBDPS
5-(tert-Butyldiphenylsilyloxy)-N-isopropylpentanamine (4): K CO (1.50 g,
11.05 mmol), isopropylamine (0.65 mL, 11.05 mmol) and iodide 3 (2.50 g, 5.83 mmol) in dry
THF (15 mL) were heated at 66°C in a sealed tube under an argon atmosphere. After 12 h, water
(5 mL) was added to the reaction mixture which was then extracted with EtOAc (3 × 50 mL).
The combined organic extracts were dried over MgSO and concentrated under reduced pressure
to afford 4 as a colorless liquid (1.90 g, 92%) sufficiently pure it was used without further
purification. TLC: MeOH/CH Cl (1:4), R ∼ 0.30; H NMR (400 MHz) δ 7.65-7.67 (m, 4H),
2 2 f
7.30-7.40 (m, 6H), 3.65 (t, J = 6.4 Hz, 2H), 2.70-2.82 (m, 1H), 2.55 (t, J = 7.3 Hz, 2H), 1.50-
1.64 (m, 2H), 1.32-1.50 (m, 4H), 1.05 (d, J = 5.8 Hz, 3H), 1.04 (s, 9H); C NMR (100 MHz) δ
135.68, 134.21, 129.63, 127.70, 63.95, 48.81, 47.64, 32.60, 30.27, 27.0, 23.76, 23.15, 19.34.
OTBDPS
TBDPSO
EDCI/DIPEA/DMF
N-(5-(tert-Butyldiphenylsilyloxy)pentyl)-N-isopropylheptanamide (5): Heptanoic
acid (2.06 g, 15.86 mmol), and diisopropylethylamine (2.72 mL, 21.14 mmol; DIPEA) were
added to a stirring solution of the amine 4 (4.00 g, 10.57 mmol) in anhydrous DMF (20 mL)
under an argon atmosphere. After 5 min, 1-ethyl(3-dimethylaminopropyl)carbodiimide (3.04
g, 15.86 mmol; EDCI) was added as a solid. After stirring for 12 h at room temperature, the
reaction mixture was diluted with EtOAc (100 mL), washed with water (2 × 30 mL), and brine
(20 mL). The combined aqueous layers were back-extracted with EtOAc (3 × 30 mL). The
combined organic extracts were dried over Na SO , concentrated under reduced pressure, and the
residue was purified by SiO column chromatography using 30% EtOAc/hexanes as eluent to
give amide 5 (4.75 g, 91%) as a viscous oil. TLC: EtOAc/hexanes (3:7), R ∼ 0.60; H NMR (400
MHz, 1:1 mixture of rotamers) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 4.62-4.72 and 3.96-4.80
(m, 1H, rotamers), 3.62 and 3.68 (t, J = 4.8 Hz, 2H, rotamers), 3.02 and 3.16 (t, J = 5.2 Hz, 2H,
rotamers), 2.38 and 2.24 (t, J = 5.3 Hz, 2H, rotamers), 1.50-1.68 (m, 6H), 1.26-1.44 (m, 8H),
1.18 and 1,12, (d, J = 7.3 Hz, 6H, rotamers), 1.03 and 1.04 (s, 9H, rotamers), 0.88 (t, J = 7.3 Hz,
3H); C NMR (100 MHz, 1:1 mixture of rotamers) δ 173.38, 172.76, 135.80, 135.78, 134.36,
134.12, 129.85, 129.73, 127.88, 127.82, 64.22, 63.68, 48.43, 45.62, 43.64, 41.27, 34.13, 34.05,
32.61, 32.36, 31.96, 31.93, 31.51, 29.63, 29.47, 27.10, 27.03, 25.94, 25.78, 24.03, 23.77, 22.81,
21.63, 20.78, 19.47, 14.33, 14.28.
N-(5-hydroxypentyl)-N-isopropylheptanamide (6): A solution of 5 (4.75 g, 9.02
mmol) and p-toluenesulfonic acid in MeOH (50 mL) was stirred at rt for 12 h, then quenched
with solid NaHCO and filtered. The filtrate was evaporated under vacuum and the residue was
dissolved in ethyl acetate (50 mL). The ethyl acetate layer was washed with water (2 × 50 mL),
brine (50 mL), dried over anhydrous Na SO and concentrated under reduced pressure. The
residue was purified by silica gel flash column chromatography using 50-60% ethyl
acetate/hexane as eluent to afford alcohol 6 (2.35 g, 93%) as a colorless, viscous liquid. TLC:
EtOAc/hexanes (1:1), R ∼ 0.30; H NMR (400 MHz, 55/45 mixture of rotamers) δ 4.58-4.66 and
3.96-4.08 (m, 1H, rotamers), 3.56 and 3.70 (t, J = 5.4 Hz, 2H, rotamers), 3.02 and 3.16 (t, J = 5.2
Hz, 2H, rotamers), 2.38 and 2.26 (t, J = 6.3 Hz, 2H, rotamers), 1.50-1.64 (m, 6H), 1.22-1.40 (m,
8H), 1.13 and 1.09 (d, J = 7.5 Hz, 6H, rotamers), 0.84 (t, J = 7.3 Hz, 3H); C NMR (100 MHz,
55/45 mixture of rotamers) δ 172.81, 62.66, 62.60, 48.41, 45.55, 43.56, 41.04, 34.08, 34.0,
32.46, 32.43, 31.86, 31.57, 29.40, 25.87, 25.70, 23.77, 23.73, 22.75, 21.57, 20.72, 14.26.
N-(5-Bromopentyl)-N-isopropylheptanamide (7): TPP (4.45 g, 9.34 mmol) was
added to a 0°C solution of alcohol 6 (2.00 g, 7.78 mmol) in dry CH Cl (50 mL). After 10 min,
CBr (3.10 g, 9.34 mmol) was added and the stirring was continued at 0°C. After 2 h, water (20
mL) was added and the reaction mixture was extracted with EtOAc (3 × 50 mL). The combined
extracts were washed with water (2 × 20 mL), brine (20 mL), dried over Na SO , and
concentrated under reduced pressure. The residue was purified by SiO column chromatography
using 30-35% ethyl acetate/hexane to afford 7 (2.20 g, 91%). TLC: EtOAc/hexanes (3:7), R ∼
0.40; H NMR (400 MHz, 45/55 mixture of rotamers) δ 4.60-4.70 and 3.96-4.10 (m, 1H,
rotamers), 3.46 and 3.36 (t, J = 5.8 Hz, rotamers), 3.02-3.10 (m, 2H), 2.30 and 2.22 (t, J = 7.9
Hz, 2H), 1.80-1.97 (m, 2H), 1.40-1.70 (m, 6H), 1.20-1.40 (m, 6H), 1.16 and 1.10, (d, J = 7.3 Hz,
6H, rotamers), 0.86 (t, J = 7.3 Hz, 3H); C NMR (100 MHz, rotamers) δ 172.79, 172.39, 48.17,
45.47, 43.32, 40.70, 33.89, 33.87, 33.49, 32.48, 32.30, 31.81, 31.78, 30.78, 29.27, 28.74, 26.05,
.84, 25.69, 25.54, 22.64, 21.47, 20.62, 14.17.
Isopropyl-N-(5-(2-pivalamidobenzo[d]thiazolyloxy)pentyl)heptanamide (11):
A solution of bromide 7 (0.35 g, 1.09 mmol), N-(4-hydroxybenzo[d]thiazolyl)pivalamide (10)
(0.27 g, 1.09 mmol), and K CO (0.30 g, 2.18 mmol) in DMF (10 mL) was heated at 80°C. After
4 h, the reaction mixture was cooled to rt, water (5 mL) was added and the mixture was extracted
using ethyl acetate (3 × 30 mL). The combined organic extracts were washed with H O (2 × 20
mL), brine (20 mL), dried over Na SO , and filtered. The filtrate was evaporated under reduced
pressure and the residue was purified by silica gel column chromatography (50-70%
EtOAc/hexanes) to give 11 (0.39 g, 72%) as a viscous liquid. TLC: EtOAc/hexanes (7:3), R ∼
0.26; H NMR (400 MHz, 45/55 mixture of rotamers) δ 7.24 and 7.20 (d, J = 7.4 Hz, 1H,
rotamers), 7.16 and 7.14 (dd, J = 7.4 Hz, J = 7.4 Hz, 1H, rotamers), 6.90 and 6.80 (d, J = 7.4 Hz,
1H, rotamers), 4.58-4.78 and 3.96-4.10 (m, 1H, rotamers), 4.02 (t, J = 6.3 Hz, 2H), 3.12 (t, J =
7.3 Hz, 2H), 2.30 and 2.27 (t, J = 5.6 Hz, 2H, rotamers), 1.82-1.92 (m, 2H), 1.44-1.70 (m, 4H),
1.38-1.32 (m, 8H), 1.20 (d, J = 6.4 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H),
0.88-085 (m, 6H); C NMR (100 MHz, 45/55 mixture of rotamers) δ 189.64, 189.62, 173.04,
172.57, 172.55, 167.16, 167.09, 167.06, 146.85, 146.77, 146.67, 128.90, 128.87, 125.90, 125.79,
124.24, 124.13, 115.32, 115.06, 111.00, 110.09, 110.05, 68.97, 68.74, 58.50, 48.34, 45.62, 41.24,
41.10, 40.95, 34.10, 29.52, 29.15, 25.72, 24.28, 21.66, 20.76, 14.30.
N-(4-hydroxybenzo[d]thiazolyl)pivalamide (10) To a suspension of 2-
aminobenzo[d]thiazolol (0.50 g, 3.01 mmol) in toluene (10 mL) was added trimethyacetyl
chloride (3.60 mL, 30.10 mmol) at room temperature. The reaction mixture was stirred at 115 °C
for 22 h. The solvents were evaporated and the residue was azeotroped with EtOAc to give 9
(0.78 g, 78%) as a tan solid. The suspension of the above solid (0.78 g) in MeOH (15 mL) was
treated with K CO (0.20 g, 3.50 mmol) and stirred at room temperature for 6 h. MeOH was
evaporated and the residue was diluted with H O. The resulting mixture was neutralized with
concd HCl to pH = 7 and extracted with EtOAc (3 × 30 mL). The combined organic phases were
dried over sodium sulfate, filtered, and concentrated in vacuo to provide 10 (0.48 g, 82%) s a tan
solid. TLC: EtOAc/hexanes (7:3), R ∼ 0.32; H NMR (400 MHz, CDCl ) δ 10.25 (br s, 1 H),
9.66 (br s, 1 H), 7.33 (d, J = 7.4 Hz, 1H), 7.09 (dd, J = 7.4, 7.4, Hz, 1H), 6.82 (d, J = 7.4 Hz,
1H), 1.45 (s, 9H). C NMR (100 MHz, CDCl ) δ 177.15, 159.12, 148.10, 136.55, 133.00,
125.55, 113.40, 111.50, 39.70, 27.38.
Example 4: In Vitro Screening of EET Analog Library
In this Example, the inventors performed both vascular relaxation assays and a
soluble epoxide hydrolase inhibition assay using the newly synthesized compounds. The results
of these assays are recorded in the last three columns of Table 1 above and Figure 14. As a
result of these assays, four compounds, compounds 26, 20, 7 and 30 were selected for further in
vivo testing, as outlined in later Examples.
Soluble Epoxide Hydrolase Inhibition. Compounds were tested for their ability to
inhibit recombinant soluble epoxide hydrolase (sEH) protein. The assay utilizes (3-Phhenyl-
oxiranyl)-acetic acid cyano-(6-methoxy-naphthalenyl)-methyl ester (PHOME), a sensitive
substrate for sEH that can be used to monitor the activity of both human and murine enzymes.
Hydrolysis of the substrate epoxide yields a highly fluorescent product, 6-methoxy
Naphthaldehyde, which can be monitored at excitation and emission wavelengths of 330 and 465
nm, respectively. See Wolf et al., Anal Biochem 355:71-80, 2006 PMID: 16729954. Human
recombinant sEH was incubated with substrate and compounds ranging in concentration from
0.1 to 1000 nM. The percent activity remaining at each concentration was plotted and an IC50
(concentration at which there is 50% inhibition) determined utilizing statistical software.
Vasodilator Activity. Vasorelaxant activity was measured in bovine coronary artery.
Bovine hearts were obtained and the left anterior descending coronary artery was dissected and
cleaned of connective tissue. Vessels of 1 mm diameter were cut into rings of 3 mm width as
previously described (3, 27, 39). Vessels were stored in Krebs buffer consisting of (in mM) 119
NaCl, 4.8 KCl, 24 NaHCO , 1.2 KH PO , 1.2 MgSO , 11 glucose, 0.02 EDTA, and 3.2 CaCl .
3 2 4 4 2
The vessels were suspended from a pair of stainless steel hooks in a 6-ml water-jacketed organ
chamber. The organ chamber was filled with Krebs buffer and bubbled with 95% O -5% CO at
37°C. One hook was anchored to a steel rod and the other hook to a force transducer (model FT-
03C; Grass Instruments, West Warwick, RI). Tension of the vessel was measured by an ETH-
400 bridge amplifier, and the data were acquired with a MacLab 8e analog-to-digital converter
and MacLab software version 3.5.6 (AD Instruments, Milford, MA) and stored on a Macintosh
computer for subsequent data analysis.
Basal tension was set at the length-tension maximum of 3.5 g and equilibrated for 1.5
h. KCl (40 mM) was added to the chamber until reproducible maximal contractions were
maintained. U-46619 (10–20 nM), a thromboxane receptor agonist, was used to precontract the
vessels from basal tension to between 50% and 90% of the maximal KCl contraction.
Cumulative additions of compounds were added to the chamber. Between concentration-
response curves, the chambers were rinsed with fresh Krebs buffer, 40 mM KCl was
administered to determine the maximum contraction, and the vessels were rinsed. Consecutive
concentration-response curves were performed with 14,15-EET followed by a concentration-
response curve to a compund. The experiment was always repeated with the order of the agonists
reversed. In control experiments with consecutive concentration-response curves to 14,15-EET,
the second concentration-response curve with compound was identical to the first. Tension was
represented as percent relaxation where 100% relaxation was basal pre-U-46619 tension. The
relaxation was plotted versus compound concentration and the EC50 determined utilizing
statistical software.
Results of Vasodilator and sEH Inhibitory Activity Assays. The results of
vasorelaxant and sEH inhibitory activities of the 33 synthesized compounds are summarized in
Table 1. Using the pharmacophoric moiety of EET, a number of EET analogs were designed
with improved solubility and resistance to auto-oxidation, etherification and metabolism by
soluble epoxide hydrolase (sEH). It is observed that these compounds possess activity analogous
to EET as evident from their vasorelaxant activity in bovine coronary artery and sEH inhibitory
(sEHi) activity. Among these, four compounds among those that were designed by replacing
COOH group of the EET pharmacophore with isosteric replacement or a heterocyclic surrogate
were studied for potential antihypertensive effect. The results of vasorelaxant and sEH inhibitory
activities of these compounds are summarized in Table 2 below.
Table 2: Characteristics of the compounds selected for testing in the in vivo models.
SEHi
Vascular relaxation
activity
Compound Structure
EC IC
50 50
relaxation
( µM) ( nM)
(10µM)
SRD-I9 109 .32 >500
LGK-I15 N 119 0.18 11
NH N
JLJ-I6 91 1.6 392
MV-IV20 96 1.3 >500
Example 5: In Vitro Testing of Four Compounds Using Rat Models of Hypertension.
Telemetry Blood Pressure Measurement. To accurately detect changes in blood
pressure and heart rate, telemetry transmitters (Data Sciences Inc., St. Paul, MN) were implanted
in rats one week prior to the experimental period according to manufacturer's specifications
while under pentobarbital anesthesia. In brief, an incision was made to expose the femoral artery
that was occluded to allow insertion of the transmitter catheter. The catheter was secured in place
with tissue glue and the transmitter body was sutured in place and the incision line was closed.
Rats were allowed to recover from surgery and were returned to individual housing. A baseline
arterial pressure was recorded for prior to the experimental period. Mean arterial pressure was
continuously recorded throughout the experimental period.
Angiotensin Hypertension. Telemetry transmitters were implanted into male
Sprague-Dawley rats (225-275 g) as described. After recording basal blood pressure, osmotic
pumps were implanted (s.c.) to deliver angiotensin at a dose of 60 ng/min. EET analogs were
administered by an osmotic pump (2mg/d, i.p.) and blood pressure was continuously monitored.
Spontaneously hypertensive rats (SHR). Telemetry transmitters were implanted
into male SHR as described. After the surgical recovery period, baseline mean arterial pressure
was recorded. In this series of experiments, EET analogs were administered by osmotic pump (2
mg/d, i.p.) and blood pressure was continuously monitored.
Protein excretion measurements. Animals were placed in a metabolic cage and
urine was collected in a conical tube. Samples were stored at -80 C until assayed. Urinary protein
excretion was assessed as an index for renal injury. Protein was determined by the Bradford
colorimetric method and creatinine was determined by the picric acid colorimetric method.
Telemetry and urinary analysis methods are further outlined in the following
publications: Imig JD, Zhao X, Zaharis CZ, Olearczyk JJ, Pollock DM, Newman JW, Kim IH,
Hammock BD. An orally active epoxide hydrolase inhibitor lowers blood pressure and provides
renal protection in salt-sensitive hypertension. Hypertension 46:975-981, 2005. PMID: 1615779;
Elmarakby AA, Quigley JE, Olearczyk JJ, Srindhar A, Cook AK, Inscho EW, Pollock DM, Imig
JD. Chemokine receptor 2b blockade inhibition provides renal protection in angiotensin II-salt
hypertension. Hypertension 50:1069-1076, 2007. PMID: 17938380; and Olearczyk JJ, Quigley
JE, Mitchell B, Yamamoto T, Kim IH, Newman JW, Lauria A, Hammock BD, Imig JD.
Inhibition of the soluble epoxide hydrolase protects the kidney from damage in hypertensive
Goto-Kakizaki rats. Clinical Science 116:61-70, 2009. PMID: 18459944. These publications are
incorporated by reference herein.
Statistical analysis. All data are presented as mean ± SEM. Mean arterial blood
pressure data were analyzed using analysis of variance (ANOVA) for repeated measurements.
Differences were considered statistically significant with p< 0.05 compared to the control.
Analyses were performed using GraphPad Prism Version 4.0 software (GraphPad Software Inc,
La Jolla, CA).
Results-Effects on blood pressure and heart rate. Spontaneously hypertensive rat
(SHR). In this model of hypertension, blood pressure lowering abilities of four selected
compounds were studied. It is observed that two of these four compounds had blood pressure
lowering effects. SRD (chemical structure shown in Figure 1A) and LGK (chemical structure
shown in Figure 2A) lacked blood pressure lowering actions in SHR. In the SRD treated SHR
group, after two weeks of treatment the blood pressure was similar to the vehicle treated SHR
group (150±5.0 vs. 141±3.0 mmHg) (see Fig. 1B-C). After two weeks of treatment, LGK did not
change the blood pressure (137±1.0 vs. 141±3.0 mmHg) compared to the vehicle in SHR (Fig. 2
C-D). Similar to their effects on blood pressure, neither SRD nor LGK affected the heart rate
(SRD, 344±23.0 vs. 331±17.0 BPM; LGK, 325±11.0 vs. 331±17.0 BPM) compared to vehicle
SHR.
Two weeks treatment with JLJ (chemical structure shown in Figure 3A) caused a
moderate decrease in blood pressure in SHR compared to vehicle treated group (131±2.0 vs.
141±3.0 mmHg) and its blood pressure lowering effect has been seen from the first week of the
treatment (Fig. 3 B-C). The compound MV (chemical structure shown in Figure 4A) also
demonstrates a similar blood pressure lowering effect in SHR and caused a 12 mmHg decrease
in blood pressure compared to vehicle (129±2.0 vs. 141±3.0 mmHg). Moreover, similar to JLJ, it
was observed that MV started to lower blood pressure within four days of the treatment in SHR
and maintained this effect until the end of the two-week treatment period (see Fig. 4 B-C). In
contrast to their blood pressure lowering effect it was further observed that, neither JLJ nor MV
had any affect on the heart rate (JLJ, 316±23.0 vs. 331±17.0 BPM; MV, 318±24.0 vs. 331±17.0
BPM) compared to vehicle SHR. Considering promising blood pressure lowering effects of JLJ
and MV in SHR model, we have further tested these compounds in another model of
hypertension, angiotensin II (Ang II) hypertension.
Ang II hypertensive rats. The compound JLJ demonstrates an attenuating effect on
the Ang II induced elevation in blood pressure from the beginning of the treatment and this was
maintained throughout the treatment period. It is observed that at the end of two-week of
treatment period JLJ markedly attenuated the Ang II induced hypertension compared to vehicle
(135±5.0 vs. 150±3.2 mmHg) (Fig. 5 A-B). Similar to JLJ, the compound MV also demonstrates
marked attenuating effect on the Ang II hypertension (107±2.0 vs. 150±3.2 mmHg) and this
attenuating effect was observed throughout the treatment period (Fig. 6 A-B). Similar to the
SHR, in ANG II hypertension neither JLJ (410±25.0 vs. 396±25.0 BPM) nor MV (385±16.0 vs.
396±25.0 BPM) demonstrates any effect on the heart rate compared to vehicle after two weeks of
treatment.
Effects of MV on sodium excretion and protein excretion in Ang II hypertension.
In the present study we have observed that the two weeks treatment with compound MV
(chemical structure shown in Figure 4A) caused natriuresis compared to vehicle (2.7±0.3 vs.
1.9±0.7 mmol/d) in Ang II hypertension. It is also observed that the compound MV decreased
the urinary protein to creatinine ratio (1.5±0.2 vs. 2.8±0.7), an indicator of renal injury, in Ang II
hypertension.
Example 6: Effect of EET Analogs in treating cisplatin nephrotoxicity
In this Example, the inventors investigated the kidney protective effect of two newly
developed orally active EET analogs in cisplatin-induced nephrotoxicity. It was demonstrated
that EET analogs offered marked reno-protection during cisplatin administration and this effect
was related to their anti-oxidative, anti-inflammatory, anti-ER stress and anti-apoptotic activities.
We have further demonstrated that while protecting the kidney from the deleterious nephrotoxic
effect of cisplatin, these EET analogs did not compromise cisplatin’s chemotherapeutic effect.
Nephrotoxicity severely limits the use of the anti-cancer drug cisplatin. Oxidative
stress, inflammation and endoplasmic reticulum (ER) stress contribute to cisplatin-induced
nephrotoxicity. We developed orally active EET analogs (including without limitation
compounds EET-A & EET-B) by modifying the carboxylate, olefins, and epoxide moieties of
EET pharmacophore. We determined if admistering the claimed EET analogs would decrease
nephrotoxicity, including cisplatin-induced nephrotoxicity. Cisplatin was administered (7mg/kg
i.p.) in rats pretreated for 7 days with EET analogs (10mg/kg/d p.o., n=5) or vehicle (n=7). On
day 5 following cisplatin injection, urine, plasma, and kidneys were collected. Cisplatin-induced
nephrotoxicity was manifest by a 3fold increase in BUN, plasma creatinine (PCr), urinary N-
acetyl-(D)-glucosaminidase activity (NAG), kidney injury molecule-1 (KIM-1), and renal
tubular cast formation. EET analogs attenuated cisplatin-induced increases in BUN (vehicle:
241±51 vs. EET-A: 108±30 & EET-B: 120±33 mg/dL), PCr (3.1±0.2 vs. 2.0±0.2 & 1.4±0.2
mg/dL), KIM-1 (296±94 vs. 85±29 & 57±13 ng/d), and NAG (3.0±0.6 vs. 0.5±0.1 & 0.6±0.2
U/d) (P<0.05). Cisplatin-induced renal tubular cast formation was reduced 50% by EET analog
treatment. EET analogs attenuated cisplatin-induced kidney TBARS formation (vehicle: 16±2 vs.
EET-A: 7±1; EET-B: 8±1 μmol/g) and cause 2folds decrease in kidney expression of NOX1
and gp91phox mRNAs (P<0.05). Cisplatin-induced nephrotoxicity was accompanied by elevated
renal inflammation and ER stress resulting in increased kidney mRNA expression of
inflammatory (TNF-α, IL-6, IL-1β) and ER stress (caspase 12, GRP78) genes. EET analogs
caused 30-70% reductions in the expression of these inflammatory and ER stress genes
(P<0.05). Cisplatin caused apoptotic signalling in the kidney with elevated Bak/Bcl2 and
Bax/Bcl2 mRNA expression ratios and renal cortical caspase 3 activity. EET analogs caused 2-
14-folds reduction in kidney Bak/Bcl2 and Bax/Bcl2 mRNA expression ratios as well as a 50%
reduction in renal caspase 3 activity (P<0.05). In an in vitro study with several cancer cell-lines,
we also demonstrate that EET analog’s kidney protective effects dose not compromise cisplatin’s
anti-cancer property. Collectively, these data demonstrate that orally active EET analogs protect
from nephrotoxcity, including cisplatin-induced nephrotoxicity, by reducing oxidative stress,
inflammation, and ER stress without affecting cisplatin’s chemotherapeutic effects. In addition,
the EET analogs will also protect against other common cisplatin side effects, including loss of
hearing.
In vivo Animal experiments. Experiments were approved and carried out according
to the guidelines of the Institutional Animal Care and Use Committee, Medical College of
Wisconsin, Milwaukee, USA. Male Wistar-Kyoto (WKY) rats weighing 180-200 g (Charles
River, MA, USA). All animals were kept in a temperature-controlled environment with a 12-h
light/dark cycle and were allowed free access to food and water at all times. An acclimatization
period of 6 days was allowed for the rats before experimentation. The rats were assigned into
four groups. Group 1 (WKY, n=5-7): Rats received drinking water ad libitum for seven days and
on day 7 DMSO (Sigma Aldrich, St. Louis, MO, USA) was administered (300-500 µl i.p.).
DMSO was used to prepare the cisplatin (CP) (Sigma Aldrich, St. Louis, MO, USA) solution
used in this study, and the maximum volume of the injection set at 500 µl. Group 2 (CP+Vehicle,
n=5-7): Rats were pretreated with vehicle (0.05% ethanol and 0.1% PEG-400 v/v) in drinking
water for seven days and then on day 7 CP was administered (7mg/kg i.p.) followed by another
five days treatment with vehicle. Group 3 (CP+EET-A, n=5-7): These rats are pretreated with the
EET analog EET-A (10mg/kg/day p.o.) for seven days in drinking water and then on day 7
administered CP as a single injection (7mg/kg i.p.) followed by another five days treatment with
EET-A. Group 4 (CP+EET-B, n=5-7): Rats of this group are pretreated with another EET analog
EET-B (10mg/kg/day) for 7 days in drinking water and then on day 7 CP was administered as a
single injection (7mg/kg i.p.) followed by another five days treatment with EET-B. Rats of
groups 2, 3 and 4 had free access to vehicle, EET-A and -B in drinking water, respectively. One
day before the rats were sacrificed, urine of each rat was collected over a 24-h period, and the
volume was measured. Five days after CP or DMSO administration, rats were anesthetized for
blood sample collection followed by euthanasia and tissue collection. Urine and plasma samples
were kept frozen at -80 C until analyzed. The kidneys were removed, washed with physiological
saline and stored at -80 C until used for RT-PCR analysis, thiobarbituric acid reactive substance
(TBARS) measurement and caspase 3 activity assay. A part of the kidney also preserved in 10%
buffered formalin for histological examination.
Biochemical analysis. The levels of blood urea nitrogen (BUN) (BioAssay Systems,
Hayward, CA, USA) and serum creatinine (Cayman Chemical Company, Ann Arbor, MI, USA)
were measured spectrophotometrically using commercial kits. Urinary content of creatinine and
protein were measured using commercial kits (Cayman Chemical Company, Ann Arbor, MI,
USA), and the activity of urinary N-acetyl-b-glucosaminidase (NAG) in the urine was measured
by a kit from Diazyme (Diazyme Laboratories, Poway, CA, USA). While urine content of kidney
injury molecule-1 (KIM-1) was measured using ELISA (R&D Systems, Inc. Minneapolis, MN,
USA).
Determination of malondialdehyde in the kidney. Malondialdehyde (MDA) is a
thiobarbituric acid reactive substance (TBARS) that is formed as an end-product of lipid
peroxidation and serves as an important index of oxidative stress. To determine the kidney MDA
level, the rat kidney was homogenized with buffer containing 1.5% potassium chloride to obtain
a 1:10 (w/v) whole kidney homogenate. Using a commercially available kit (Cayman Chemical
Company, Ann Arbor, MI, USA), MDA was measured spectrophotometrically after reaction
with thiobarbituric acid.
Determination of Caspase 3 activity. Caspase 3 activity in the kidney homogenate
was determined using a commercial fluorimetric assay kit (Sigma Aldrich, St. Louis, MO, USA).
Kidney homogenate was prepared with a lysis Buffer (50 mM HEPES, pH 7.4, with 5 mM
CHAPS and 5 mM DTT). Kidney homogenate was centrifuged at 10,000 g for 10 min and the
resulting supernatant was used for the assay. The caspase 3 fluorimetric assay is based on the
hydrolysis of the peptide substrate acetyl-Asp-Glu-ValAspamidomethylcoumarin (Ac-
DEVD-AMC) by caspase 3, resulting in the release of the fluorescent 7-amino
methylcoumarin (AMC) moiety. The caspase 3 activity is expressed as nmol of AMC/min/µL.
Real-Time PCR Analyses. Real-Time analysis was carried out to assess the
expression of oxidative (gp91phox, NOX1, SOD1, SOD2, SOD3), inflammatory (TNF-α, IL-6,
IL-1β), apoptotic (Bax, Bak, Bcl-2) and endoplasmic reticulum stress (GRP78, caspase 12)
related genes in the kidney. Total RNA was isolated from kidney homogenate using TRIzol LS
reagents (Invitrogen Life Technologies, Carlsbad, CA, USA) according to the manufacturer’s
instructions. The isolated RNA was treated with RNase-free DNase (Invitrogen, Carlsbad, CA,
USA) to remove traces of genomic DNA contamination. The mRNA samples were quantified by
spectrophotometry at 260 nm and 1 µg of total RNA was reverse-transcribed to cDNA using
iScript™ Select cDNA Synthesis Kit (Bio-Rad, Hercules, CA, USA).
The target gene expression was quantified by iScript One-Step RT-PCR Kit with
SYBR green using MyiQ Single Color Real-Time PCR Detection System (Bio-Rad
Laboratories, Hercules, CA, USA). Each amplified sample in all wells was analyzed for
homogeneity using dissociation curve analysis using iQ5 Optical System Software, Version
2.1(Bio-Rad Laboratories, Hercules, CA, USA). After denaturation at 95°C for 2 min, 40 cycles
were performed at 95°C for 10 s and at 60°C for 30 s. Each sample was run in triplicate, and the
–ΔΔCt
comparative threshold cycle (C ) method was used to quantify fold increase (2 ) in the
expression of the target genes compared to controls. In analyzing the relative expression of the
target genes, the C values were normalized to a housekeeping gene (pgk1). Statistical analyses
were carried out for at least 5-7 experimental samples in each experimental group. Primers used
in this study were designed based on several earlier reports. HAfter fixation of the kidneys with
% buffered formalin, renal tissues were sectioned and stained with periodic acid-Schiff (PAS)
reagents for histological examination. The numbers of tubules that contain proteinaceous casts
were determined at magnification of ×200 to assess tubular damage using an image analyzing
software NIS Elements AR version 3.0 (Nikon instruments inc., Melville, NY, USA). The
percentage area positive for cast was calculated from the mean of eight cortical and five
medullary fields (×200) for each kidney sample. To minimize observer bias, the cast area
calculation was performed in a blinded fashion without knowledge of the treatment group from
which the tissues are originated.
In vitro anti-tumor activity of cisplatin in the presence and absence of EET
analog. In this study, HEK293, U87MG, Hela cell-lines were obtained from the ATCC
(Manassas, VA, USA) (HEK293, U87MG, Hela), and NCCIT was collected from Department of
Pediatrics, UT Southwestern Medical Center at Dallas, TX, USA. All cell lines were maintained
in DMEM or RPIM with 10% fetal bovine serum and penicillin/streptomycin purchased from
Life Technologies (Grand Island, NY, USA). Cisplatin was purchased from either Sigma (St.
Louis, MO, USA) or CalBiochem/EMD Biosciences (Billerica, MA ,USA). Cells were seeded in
96-well plates at 500 to 4,000 cells per well depends on cell type. Twenty-four hours later, the
cells were treated with cisplatin or vehicle and/or the EET analogue EET-A at various
concentrations for 72 h. Cell viability was measured by alamar blue assay using resazurin
(Sigma Aldrich) according to the manufacturer’s guidelines. Viability results were measured by
fluorescence/absorbance in a 96-well plate reader from BMG Labtech (Cary, NC, USA) and the
IC was calculated by GraphPad Prism5 software (GraphPad Software Inc, La Jolla, CA, USA).
Statistical analysis. Results are reported as mean ± S.E.M. Statistical significance
between two measurements was determined by the two-tailed unpaired Student’s t test (and
among groups it was determined by repeated measure one-way analysis of variance followed by
Tukey’s post-hoc test) by using GraphPad Prism Version 4.0 software (GraphPad Software Inc,
La Jolla, CA, USA). Probability values of P <0.05 were considered significant where the critical
value of P was two-sided.
Results. EET analog treatment attenuates renal dysfunction and injury in
cisplatin administered rats. To investigate the effects of EET analogs in cisplatin (CP)-induced
renal dysfunction, levels of urea (blood urea nitrogen or BUN) and creatinine were measured in
the serum of both EET analog-treated and -untreated rats after five days of the CP
administration. As shown in the Figure 8, CP administration caused 3 and 9-fold increase in the
serum creatinine and BUN levels (Figures 7a and 7b), respectively (P<0.05). Treatment with
EET analogs (EET-A and –B) resulted in 30-50% reductions in the elevated levels of serum
creatinine and BUN in rats administered with CP compared to those given vehicle (DMSO)
(P<0.05). To determine the effects of EET analogs in CP-induced renal dysfunction, we further
studied urinary excretion of KIM-1, NAG and protein after five days of CP administration
(Figures 7c and 7d). There were 5 and 10-fold increases in urinary excretion of NAG and KIM-1
in the CP-administered rats compared to vehicle-administered controls (P<0.05). Moreover, we
also demonstrated that cisplatin-administration caused marked proteinuria compare to vehicle
administration (vehicle vs. cisplatin, 25.7±1 vs. 53±5.1 mg/d, P<0.05). Both EET analogs, EET-
A and EET-B resulted 30-50% reduction in the urinary excretion of NAG and KIM-1 compared
to CP-administered rats treated with vehicle (P<0.05) (Figures 7c-d).
We have also observed at least a 40% reduction of cisplatin-induced proteinuria by
both EET analogs (Vehicle vs. EET-A and –B; 53±5 vs. 33±8 and 32±3 mg/d, P<0.05). In the
present study the CP-induced kidney dysfunction was further assessed using histological
examination of the kidney. Administration of CP resulted in tubular injury as manifested by a
vacuolation and desquamation of the renal epithelial cells along with severe intra-tubular
proteinaceous cast formation in both the cortical and medullary regions of the kidney compared
to vehicle-administered rats. Both EET analogs protected the kidney in CP-administered rats
with ≥ 50% reduction of the tubular cast area in cortex and medulla compared to CP-
administered rats treated with vehicle (P<0.05) (Figures 8a-b).
EET analog treatment attenuates cisplatin-induced renal oxidative stress,
inflammatory response and endoplasmic reticulum stress. Real-Time PCR analysis of the
mRNA expressions of NADPH oxidase subunits NOX1 and gp91phox (Figure 9) demonstrated
increased expression of these oxidative marker genes in cisplatin (CP) administered rats
(P<0.05). There was 2folds attenuation in the cisplatin-induced increase in the renal
expression of NOX1 and gp91phox mRNA were reduced by EET analogs A and B (P<0.05)
(Figure 9a-b). CP-administration also resulted in a marked elevation in the kidney content of
melondialdehyde (MDA), which is one of the important indicators of oxidative stress. Treatment
with EET analogs caused 50% reduction of MDA level in the kidney of CP-administered rats
(P<0.05) (Figure 9c). It was further observed that administration of CP resulted in 2folds
reductions in the mRNA expression of superoxide dismutase (SOD) 1 and SOD3 (P<0.05) while
expression of SOD2 was unchanged. Treatment with EET analogs caused 2folds increase in
the expression of SOD1 in the CP- administered rats (P<0.05) while the expression of SOD3
remained unaltered across the experimental groups (Figures 9d-f).
To investigate the effect of EET analogs on the CP-induced inflammation that is
associated with renal dysfunction, we studied the renal expression of mRNAs that code for
tumour necrosis factor-α (TNF- α), interleukin- 6 (IL-6) and interleukin-1β. These variables
demonstrated a 2fold increase in their expression in the vehicle treated CP-administered rats
compared to the rats administered vehicle (P<0.05) (Figures 10a-c). Treatment with both EET
analogs (EET-A and B) resulted in 40-60% reductions in the renal mRNA expressions of all the
inflammatory markers in CP-administered rats (all P<0.05).
We have also observed 4-fold increase in the mRNA expressions of ER stress
markers GRP78/BiP and caspase 12 in the vehicle treated CP-administered rats compared to
vehicle-administered rats (P<0.05) (Figures 11a-b). In CP-administered rats, treatment with both
EET analogs (EET-A and B) caused 2fold reduction in the elevated renal expressions of
GRP78 and caspase 12 mRNAs compared to vehicle treatment (P<0.05) (Figures 11a-b).
EET analog treatment attenuates cisplatin-induced renal apoptosis. There was a
70% reduction in the renal expression of Bcl-2 mRNA in the vehicle treated CP-administered
rats compared to rats administered vehicle (P<0.05) (Figure 12a). EET analog treatment caused
2fold increase in the expression of the anti-apoptotic Bcl-2 in the CP-administered rats
compared to vehicle treated CP-administered rats (P<0.05) (Figure 12a). Moreover, CP
administration resulted in 4fold raise in the Bax/Bcl-2 and Bak/Bcl-2 ratios, and therefore
indicated elevated apoptotic signalling in the CP-administered rats (Figures 12b-c) (P<0.05).
EET analogs treatment caused 2fold reduction in Bax/Bcl-2 and Bak/Bcl-2 ratios compared to
CP-administered rats treated with vehicle (P<0.05) (Figures 12c-d). The CP-induced elevated
apoptotic signalling was further characterized with higher caspase 3 activity (Figure 12d) in CP-
administered rats compared to the rats administered vehicle (P<0.05). Treatment with EET
analogs attenuated such CP-induced caspase 3 activity by 50% compared to the CP-administered
rats treated with vehicle (P<0.05) (Figure 12d). These results clearly demonstrated attenuation of
CP-induced apoptotic signaling in the presence of EET analog treatment.
EET analog treatment dose not compromise the chemotherapeutic effect of
cisplatin. We demonstrate that in three different cancer cell lines, Hela, NCCIT and U87
cisplatin markedly inhibit the cell growth with IC ranged from 1.1 – 9.24 µM (Figure 13a). In a
similar approach with these cell lines, EET-A had no observable effects on cell number (Figure
13b). Moreover, concurrent application of EET-A and cisplatin did not influence the cisplatin’s
chemotherapeutic effect neither on the normal kidney cells (data not shown) nor on the NCCIT
cancer cell line (Figure 13c). It is demonstrated that when cisplatin and EET-A were used
concurrently, the IC for cisplatin was 2.60, 2.55, and 2.44 µM with 0, 1, and 10 ng/ml EET in
NCCIT cells.
Discussion. A critical limitation of cisplatin chemotherapy is the induction of
tubulointestinal inflammation, renal oxidative stress, ER stress and tubular cell apoptosis that
lead to acute kidney injury. It is reported that 40% cancer patients who treated with cisplatin
develops acute renal injury. Unfortunately, efficient pharmacotherapies to attenuate this
debilitating complication of a widely used chemotherapy like cisplatin are not available. In an
attempt to contribute to this area, current study investigated the kidney protective effect of
chronic treatment of epoxyeicosatrienoic acid (EET) analogs on cisplatin-induced
nephrotoxicity.
There is strong evidence that EET analogs have ability to protect organ by
mechanisms involving its anti-inflammatory, anti-apoptotic and anti-oxidative activities. With
this background, in the present study we hypothesized that with its strong organ protective
ability, EET will protect the kidney from cisplatin nephrotoxicity. In our attempt, we have
synthesized two novel EET analogs and investigated their kidney protective effects in cisplatin-
induced nephrotoxicity using a clinically relevant approach with chronic administration of EET
analogs in drinking water to the rat. We demonstrate that a single administration of cisplatin
caused marked renal injury evident from increased PCr, BUN, urinary excretion of renal tubular
injury markers like NAG and KIM-1 along with marked proteinuria and tubular cast formation.
Our results supports several earlier studies reported cisplatin-induced nephrotoxicity in pre-
clinical animal models. Interestingly, we also demonstrate that the chronic treatment with EET
analogs in drinking water markedly protected the kidney from cisplatin-induced nephrotoxic
injury with reductions in all renal injury markers studied in this study. In relation to our approach
in the present study, a recent study demonstrated that acute administration of sEH inhibitor could
reduce cisplatin-induced renal dysfunction in mice. However, it is known that current sEH
inhibitors are limited in effects as they undergo metabolism and incorporation into the
membrane, thus indicates a limitation of this finding in clinical translational implication.
Moreover, the study carried out by Parrish et al. did not provide evidence on the possible
mechanism by which EET or sEH inhibitor reduces renal dysfunction in cisplatin-induced
nephrotoxicity.
Currently, we demonstrate marked over-expression of mRNAs for the major
components of NADPH oxidase (NOX1 and gp91phox) in cisplatin-induced nephrotoxicty.
Over-expression of these oxidative marker genes further accompanied by increased ROS
generation evident from the elevated kidney lipid per-oxidation in the cisplatin-administered rat.
We also demonstrate reduced renal SOD1 and SOD3 expressions, and suggest that such
reduction contributes to the oxidative stress in cisplatin administered rat. Similar observations
are reported in earlier studies where cisplatin-induced nephropathy is accompanied by increased
MDA level and elevated expression and activity of NADPH oxidase. Interestingly, our study
also demonstrate that EET analogs markedly reduced the renal oxidative stress by reducing the
renal lipid per-oxidation, marked reductions in the expression of the major NADPH oxidase
subunits, and also by increased expression of SOD1. Indeed, in a recent study it is reported that
EET up-regulates the expression and activity of SOD during toxic insult, thus enhance ROS
scavenging and reduce oxidative stress. Similar to our findings, in another pathological model
characterized with renal injury, EET mediated reduction in oxidative stress and renal injury has
been reported. Apart from oxidative stress, we also demonstrate that cisplatin-induced
nephrotoxicity is further accompanied by elevated renal inflammatory response and supports
earlier evidences on important role for inflammatory mechanisms in the pathogenesis of
cisplatin-induced nephrotoxicity. Indeed, cisplatin induces increased renal expression of a variety
of inflammatory chemokines and cytokines, such as TNF-α and IL-1β.
We further demonstrate that EET analog treatment reduced renal expression of these
inflammatory markers in cisplatin-induced nephrotoxicity. Our data support earlier reports of
anti-inflammatory activity of EET that has been implicated in EET mediated organ protection in
a number of pathologies characterized with organ injury. For instance, increased bioavailability
of EET by sEH inhibition provides kidney protection in streptozotocin-induced diabetes.
Moreover, over-expression of the EET producing enzyme CYP2J2 markedly protected kidney in
a chronic renal failure model of 5/6 nephrectomy. Thus, our data clearly indicate that along with
marked reduction in oxidative stress, attenuation of cisplatin-induced renal inflammatory
responses is another mechanism by which EET analog protected kidney from cisplatin-induced
nephrotoxicity.
We have further investigated EET analog’s effect on cisplatin-induced endoplasmic
reticulum (ER) stress. There is evidence that ER is one of the sub-cellular targets of toxins and
play important role in xenobiotic-induced nephrotoxicity. In the present study we examined the
renal expression of caspase 12 and GRP78 (glucose-regulated protein 78) mRNAs to investigate
the involvement of the ER stress in cisplatin-induced nephrotoxicity. GRP78 is considered one of
the hallmarks of ER stress, while caspase 12 is an ER-specific caspase that is activated by ER
stress and specifically participates in ER stress-induced apoptosis. We observe marked up-
regulation in the renal expression of these ER stress markers that is attenuated by EET analog
treatment. Our study supports earlier observations that cisplatin-induced nephrotoxicity is
associated with ER stress. Most importantly, the present study also provided an interesting and
novel finding regarding the biological actions of EET, and demonstrates an important aspect on
the therapeutic potential of this lipid mediator in treating cisplatin-induced nephrotoxicity.
Cisplatin and other drug-related nephrotoxicity is associated with apoptosis that is
caused by elevated oxidative stress, inflammation and ER stress. It is reported that during
cisplatin-induced nephrotoxicity, the cellular stress caused by oxidative stress, inflammation and
ER stress leads to a reduction of anti-apoptotic Bcl2 and activation of the pro-apoptotic Bcl2
family proteins like the Bcl-2 associated X protein (Bax) and Bcl-2 antagonist/killer protein
(Bak) in the kidney. This enhanced pro-apoptotic signaling leads to the activation of caspase 3
followed by apoptosis of the renal cells.. Here, we demonstrate that EET analog treatment
protect the kidney from cisplatin-induced cell death by increasing the expression of anti-
apoptotic Bcl2 and reducing the pro-apoptotic Bak/Bcl2 and Bax/Bcl2 ratios along with a
marked reduction in caspase 3 activity.
We also demonstrate an EET analog mediated attenuation in the renal expression of
caspase 12 that plays an essential role in ER stress mediated apoptosis. Indeed, it is earlier
reported that EET attenuates several major apoptotic events including elevated Bcl2 protein
mediated pro-apoptotic signaling and caspase 3 activity. These observations support our view on
EET analog’s ability to reduce renal cell death in cisplatin-induced nephrotoxicity through its
effect on the Bcl2 proteins, ER stress specific caspase 12 and on the apoptosis executioner
caspase, caspase 3.
We have clearly demonstrated that EET analog treatment provides protection from
cisplatin-induced nephrotoxicity through multiple mechanisms, and strongly indicate a possible
therapeutic promise. However, it is important that before the clinical use of new cytoprotective
agents, not only protection from toxicity, but also the absence of an interference of the agent with
the anti-cancer activity of the cytotoxic agents used is demonstrated. To this end, in an in vitro
approach we have investigated whether in vitro exposure of normal kidney cells (HEK293) or
several human cancer cell- lines (Hela, NCCIT, U87) to various concentrations of an EET analog
(EET-A) influence cell growth or the cytotoxic effect of cisplatin. Considering the comparable
kidney protective effects of the two EET analogs used in this study, we have chosen one EET
analog for this particular experiment. We demonstrated that in the presence and absence of EET
analog (EET-A) cisplatin is equally potent in exerting its chemotherapeutic effect. Moreover, we
have also investigated if EET-A influence the growth of any of the cancer lines used in this
study, and clearly demonstrated that EET-A had no effect on the growth of any of these cancer
cell lines.
In conclusion, we have provided strong evidence that the kidney protective effect of
the above-identified EET analogs in drug-induced nephrotoxicitn, including cisplatin-induced
nephrotoxicity. We have demonstrated that these EET analogs offered kidney protection by the
inhibition of multiple signaling pathways that critically involve in the patho- physiology of
cisplatin-induced nephrotoxicity. This study highlighted several important biological actions of
novel EET analogs in terms of their anti-oxidative, anti-inflammatory, anti-ER stress and anti-
apoptotic activities. The results of the current study strengthen our view on the therapeutic
promise of these novel EET analogs in treating cisplatin-induced nephrotoxicity without
compromising cisplatin’s chemotherapeutic potential.
While this invention has been described in conjunction with the various exemplary
embodiments outlined above, various alternatives, modifications, variations, improvements
and/or substantial equivalents, whether known or that are or may be presently unforeseen, may
become apparent to those having at least ordinary skill in the art. Accordingly, the exemplary
embodiments according to this invention, as set forth above, are intended to be illustrative, not
limiting. Various changes may be made without departing from the spirit and scope of the
invention. Therefore, the invention is intended to embrace all known or later-developed
alternatives, modifications, variations, improvements, and/or substantial equivalents of these
exemplary embodiments. All technical publications, patents and published patent applications
cited herein are hereby incorporated by reference in their entirety for all purposes.
In the description in this specification reference may be made to subject matter that is
not within the scope of the claims of the current application. That subject matter should be
readily identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the claims of this application.
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In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of the
common general knowledge in the art.
Claims (21)
1. A compound selected from the group consisting of
2. The compound of claim 1, wherein the structure is
3. The compound of claim 1, wherein the structure is
4. A compound selected from the group consisting of or .
5. A composition comprising a compound of anyone of claims 1 to 4 and a pharmaceutically acceptable carrier.
6. A method of reducing hypertension in a non-human subject, comprising administering to said non-human subject a therapeutically effective amount of a compound according to claims 1 to 4, wherein hypertension in said subject is reduced.
7. A use of a compound in any one of claims 1 to 4 in the manufacture of a medicament.
8. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for treating hypertension in a subject.
9. A compound according to any one of claims 1 to 4 for use in the treatment of hypertension in a subject.
10. A method of reducing nephrotoxicity in a non-human subject, comprising administering to said non-human subject a therapeutically effective amount of a compound according to any one of claims 1 to 4, wherein nephrotoxicity in said subject is reduced.
11. The method of claim 10, wherein the nephrotoxicity is drug-induced.
12. The method of claim 11, wherein the nephrotoxicity is cisplatin-induced.
13. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for treating drug-induced nephrotoxicity in a subject.
14. A compound according to any one of claims 1 to 4 for use in the treatment of drug- induced nephrotoxicity in a subject.
15. A method of reducing cisplatin nephrotoxicity in a non-human subject, comprising administering to said non-human subject a therapeutically effective amount of a compound according to any one of claims 1 to 4, wherein cisplatin nephrotoxicity in said subject is reduced.
16. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for treating cisplatin nephrotoxicity in a subject.
17. A compound according to any one of claims 1 to 4 for use in the treatment of cisplatin nephrotoxicity in a subject.
18. A compound as claimed in any one of claims 1 or 4 substantially as herein described or exemplified and with or without reference to the accompanying drawings.
19. A composition as claimed in claim 5 substantially as herein described or exemplified and with or without reference to the accompanying drawings.
20. A method as claimed in any one of claims 6, 10 or 15 substantially as herein described or exemplified and with or without reference to the accompanying drawings.
21. A use as claimed in any one of claims 7, 8, 13 and 16 substantially as herein described or exemplified and with or without reference to the accompanying drawings.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161472410P | 2011-04-06 | 2011-04-06 | |
US61/472,410 | 2011-04-06 | ||
US201261608361P | 2012-03-08 | 2012-03-08 | |
US61/608,361 | 2012-03-08 | ||
PCT/US2012/032090 WO2012138706A1 (en) | 2011-04-06 | 2012-04-04 | Epoxyeicosatrienoic acid analogs and methods of making and using the same |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ617402A NZ617402A (en) | 2015-10-30 |
NZ617402B2 true NZ617402B2 (en) | 2016-02-02 |
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