U.S. patent application number 14/977006 was filed with the patent office on 2016-04-21 for fatty acid cox inhibitor derivatives and their uses.
The applicant listed for this patent is Catabasis Pharmaceuticals, Inc.. Invention is credited to Jean E. Bemis, Michael R. Jirousek, Jill C. Milne, Chi B. Vu.
Application Number | 20160106712 14/977006 |
Document ID | / |
Family ID | 44210128 |
Filed Date | 2016-04-21 |
United States Patent
Application |
20160106712 |
Kind Code |
A1 |
Milne; Jill C. ; et
al. |
April 21, 2016 |
FATTY ACID COX INHIBITOR DERIVATIVES AND THEIR USES
Abstract
The invention relates to fatty acid COX inhibitor derivatives;
compositions comprising an effective amount of a fatty acid COX
inhibitor derivative; and methods for treating or preventing a
metabolic, autoimmune inflammatory, or neurodegenerative disorder
comprising the administration of an effective amount of a fatty
acid COX inhibitor derivative.
Inventors: |
Milne; Jill C.; (Brookline,
MA) ; Jirousek; Michael R.; (Cambridge, MA) ;
Bemis; Jean E.; (Arlington, MA) ; Vu; Chi B.;
(Boston, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Catabasis Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
44210128 |
Appl. No.: |
14/977006 |
Filed: |
December 21, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13582932 |
Nov 12, 2012 |
9216224 |
|
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PCT/US11/27133 |
Mar 4, 2011 |
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14977006 |
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61310947 |
Mar 5, 2010 |
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Current U.S.
Class: |
514/419 ;
514/616 |
Current CPC
Class: |
A61P 25/04 20180101;
A61K 47/542 20170801; A61K 31/405 20130101; A61K 47/55 20170801;
A61P 19/02 20180101; A61P 29/00 20180101; A61K 31/165 20130101;
A61P 19/04 20180101 |
International
Class: |
A61K 31/405 20060101
A61K031/405; A61K 31/165 20060101 A61K031/165 |
Claims
1-11. (canceled)
12. A method of treating inflammation, swelling, stiffness, or
joint pain associated with rheumatoid arthritis, osteoarthritis,
juvenile arthritis, ankylosing spondylitis, tendinitis, bursitis,
or acute gout, the method comprising administering to a patient in
need thereof an effective amount of a compound of Formula I:
##STR00109## or a pharmaceutically acceptable salt, enantiomer, or
stereoisomer thereof; wherein R.sub.n is ##STR00110## ##STR00111##
W.sub.1 and W.sub.2 are each independently S, NH, or NR; each a, b,
c and d is independently --H, -D, --CH.sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --C(O)OR, or benzyl, or two of a, b, c, and d
can be taken together, along with the single carbon to which they
are bound, to form a cycloalkyl or heterocycle; each n, o, p, and q
is independently 0, 1 or 2; each L is independently null, --O--,
--S--, --S(O)--, --S(O).sub.2--, --S--S--,
--(C.sub.1-C.sub.6alkyl)-, --(C.sub.3-C.sub.6 cycloalkyl)-, a
heterocycle, a heteroaryl, ##STR00112## ##STR00113## ##STR00114##
wherein the representation of L is not limited directionally left
to right as is depicted, rather either the left side or the right
side of L can be bound to the W.sub.1 side of the compound of
Formula I; R.sub.6 is independently --H, -D, --C.sub.1-C.sub.4
alkyl, -halogen, cyano, oxo, thiooxo, --OH, --C(O)C.sub.1-C.sub.4
alkyl, --O-aryl, --O-benzyl, --OC(O)C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.3 alkene, C.sub.2-C.sub.3 alkyne,
--C(O)C.sub.1-C.sub.4 alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.3
alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2, --NH(C(O)C.sub.1-C.sub.3
alkyl), --N(C(O)C.sub.1-C.sub.3 alkyl).sub.2, --SH,
--S(C.sub.1-C.sub.3 alkyl), --S(O)C.sub.1-C.sub.3 alkyl, or
--S(O).sub.2C.sub.1-C.sub.3 alkyl; each g is independently 2, 3 or
4; each h is independently 1, 2, 3 or 4; m is 0, 1, 2, or 3; if m
is more than 1, then L can be the same or different; m1 is 0, 1, 2
or 3; k is 0, 1, 2, or 3; z is 1, 2, or 3; each R.sub.3 is
independently H or C.sub.1-C.sub.6 alkyl, or both R.sub.3 groups,
when taken together with the nitrogen to which they are attached,
can form a heterocycle; each R.sub.4 is independently e, H or
straight or branched C.sub.1-C.sub.10 alkyl which can be optionally
substituted with OH, NH.sub.2, CO.sub.2R, CONH.sub.2, phenyl,
C.sub.6H.sub.4OH, imidazole or arginine; each e is independently H
or any side chain of a naturally occurring amino acid; each Z is
independently --H, ##STR00115## each r is independently 2, 3, or 7;
each s is independently 3, 5, or 6; each t is independently 0 or 1;
each v is independently 1, 2, or 6; R.sub.1 and R.sub.2 are each
independently hydrogen, deuterium, --C.sub.1-C.sub.4 alkyl,
-halogen, --OH, --C(O)C.sub.1-C.sub.4 alkyl, --O-aryl, --O-benzyl,
--OC(O)C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.3 alkene,
C.sub.2-C.sub.3 alkyne, --C(O)C.sub.1-C.sub.4 alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.3 alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2,
--NH(C(O)C.sub.1-C.sub.3 alkyl), --N(C(O)C.sub.1-C.sub.3
alkyl).sub.2, --SH, --S(C.sub.1-C.sub.3 alkyl),
--S(O)C.sub.1-C.sub.3 alkyl, --S(O).sub.2C.sub.1-C.sub.3 alkyl; and
each R is independently --H, --C.sub.1-C.sub.3 alkyl, or straight
or branched C.sub.1-C.sub.4 alkyl optionally substituted with OH,
or halogen.
13. The method of claim 12, wherein R.sub.n is ##STR00116##
14. The method of claim 12, wherein R.sub.n is ##STR00117##
15. The method of claim 12, wherein R.sub.n is ##STR00118##
16. The method of claim 12, wherein W.sub.1 and W.sub.2 are each
NH.
17. The method of claim 12, wherein m is 0.
18. The method of claim 12, wherein L is --S--S--.
19. The method of claim 12, wherein L is --O--.
20. The method of claim 12, wherein L is ##STR00119##
21. The method of claim 12, wherein two of n, o, p, and q are each
1.
22. The method of claim 12, wherein r is 2, s is 6, and t is 1.
23. The method of claim 12, wherein r is 3, s is 5, and t is 1.
24. The method of claim 12, wherein n, o, p, and q are each 1.
25. The method of claim 12, wherein W.sub.1 and W.sub.2 are each
NH; m is 0; n and o are each 1; and p and q are each 0.
26. The method of claim 22, wherein W.sub.1 and W.sub.2 are each
NH; m is 0; n and o are each 1; and p and q are each 0.
27. The method of claim 23, wherein W.sub.1 and W.sub.2 are each
NH; m is 0; n and o are each 1; and p and q are each 0.
28. The method of claim 12, wherein W.sub.1 and W.sub.2 are each
NH; m is 1; n, o, p, and q are each 1; and L is --O--.
29. The method of claim 12, wherein W.sub.1 and W.sub.2 are each
NH; m is 1; n, o, p, and q are each 1; and L is ##STR00120##
30. The method of claim 12, wherein W.sub.1 and W.sub.2 are each
NH; m is 1; n, o, p, and q are each 1; and L is --S--S--.
31. The method of claim 12, wherein the compound is ##STR00121##
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-
H-indol-3-yl)acetamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide
(I-11)
32. The method of claim 12, wherein the compound is ##STR00122##
(5Z,8Z,11Z,14Z,17Z)-N-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-in-
dol-3-yl)acetamido)ethyl)icosa-5,8,11,14,17-pentaenamide
(I-12).
33. The method of claim 12, wherein the compound is ##STR00123##
4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-
-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide
(I-13).
34. The method of claim 12, wherein the compound is ##STR00124##
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-meth-
yl-1H-indol-3-yl)acetamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,1-
9-hexaenamide (I-14).
35. The method of claim 12, wherein the compound is ##STR00125##
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-me-
thyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethyl)docosa-4,7,10,13,16,19-
-hexaenamide (I-15).
36. The method of claim 12, wherein the compound is ##STR00126##
(S,4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(6-methoxynaphthalen-2-yl)propanamido)e-
thyl)docosa-4,7,10,13,16,19-hexaenamide (I-7).
37. The method of claim 12, wherein the compound is ##STR00127##
4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(4-isobutylphenyl)propanamido)ethyl)docosa-
-4,7,10,13,16,19-hexaenamide (I-1).
38. A method of treating pain associated with a menstrual period, a
migraine headache, or dental pain, the method comprising
administering to a patient in need thereof an effective amount of a
compound of Formula I: ##STR00128## or a pharmaceutically
acceptable salt, enantiomer, or stereoisomer thereof; wherein
R.sub.n is ##STR00129## ##STR00130## W.sub.1 and W.sub.2 are each
independently S, NH, or NR; each a, b, c and d is independently
--H, -D, --CH.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)OR, or
benzyl, or two of a, b, c, and d can be taken together, along with
the single carbon to which they are bound, to form a cycloalkyl or
heterocycle; each n, o, p, and q is independently 0, 1 or 2; each L
is independently null, --O--, --S--, --S(O)--, --S(O).sub.2--,
--S--S--, --(C.sub.1-C.sub.6alkyl)-,
--(C.sub.3-C.sub.6cycloalkyl)-, a heterocycle, a heteroaryl,
##STR00131## ##STR00132## ##STR00133## wherein the representation
of L is not limited directionally left to right as is depicted,
rather either the left side or the right side of L can be bound to
the W.sub.1 side of the compound of Formula I; R.sub.6 is
independently --H, -D, --C.sub.1-C.sub.4 alkyl, -halogen, cyano,
oxo, thiooxo, --OH, --C(O)C.sub.1-C.sub.4 alkyl, --O-aryl,
--O-benzyl, --OC(O)C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.3 alkene,
C.sub.2-C.sub.3 alkyne, --C(O)C.sub.1-C.sub.4 alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.3 alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2,
--NH(C(O)C.sub.1-C.sub.3 alkyl), --N(C(O)C.sub.1-C.sub.3
alkyl).sub.2, --SH, --S(C.sub.1-C.sub.3 alkyl),
--S(O)C.sub.1-C.sub.3 alkyl, or --S(O).sub.2C.sub.1-C.sub.3 alkyl;
each g is independently 2, 3 or 4; each h is independently 1, 2, 3
or 4; m is 0, 1, 2, or 3; if m is more than 1, then L can be the
same or different; m1 is 0, 1, 2 or 3; k is 0, 1, 2, or 3; z is 1,
2, or 3; each R.sub.3 is independently H or C.sub.1-C.sub.6 alkyl,
or both R.sub.3 groups, when taken together with the nitrogen to
which they are attached, can form a heterocycle; each R.sub.4 is
independently e, H or straight or branched C.sub.1-C.sub.10 alkyl
which can be optionally substituted with OH, NH.sub.2, CO.sub.2R,
CONH.sub.2, phenyl, C.sub.6H.sub.4OH, imidazole or arginine; each e
is independently H or any side chain of a naturally occurring amino
acid; each Z is independently --H, ##STR00134## each r is
independently 2, 3, or 7; each s is independently 3, 5, or 6; each
t is independently 0 or 1; each v is independently 1, 2, or 6;
R.sub.1 and R.sub.2 are each independently hydrogen, deuterium,
--C.sub.1-C.sub.4 alkyl, -halogen, --OH, --C(O)C.sub.1-C.sub.4
alkyl, --O-aryl, --O-benzyl, --OC(O)C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.3 alkene, C.sub.2-C.sub.3 alkyne,
--C(O)C.sub.1-C.sub.4 alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.3
alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2, --NH(C(O)C.sub.1-C.sub.3
alkyl), --N(C(O)C.sub.1-C.sub.3 alkyl).sub.2, --SH,
--S(C.sub.1-C.sub.3 alkyl), --S(O)C.sub.1-C.sub.3 alkyl,
--S(O).sub.2C.sub.1-C.sub.3 alkyl; and each R is independently --H,
--C.sub.1-C.sub.3 alkyl, or straight or branched C.sub.1-C.sub.4
alkyl optionally substituted with OH, or halogen.
Description
PRIORITY
[0001] The present application claims the benefit of U.S.
Provisional Application No. 61/310,947 filed Mar. 5, 2010, the
entire disclosure of which is relied on for all purposes and is
incorporated into this application by reference.
FIELD OF THE INVENTION
[0002] The invention relates to fatty acid COX inhibitor
derivatives; compositions comprising an effective amount of a fatty
acid COX inhibitor derivative; and methods for treating or
preventing a metabolic, autoimmune, inflammatory, or
neurodegenerative disorder comprising the administration of an
effective amount of a fatty acid COX inhibitor derivative. All
patents, patent applications, and publications cited herein are
hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
[0003] Oily cold water fish, such as salmon, trout, herring, and
tuna are the source of dietary marine omega-3 fatty acids, with
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) being
the key marine derived omega-3 fatty acids. Omega-3 fatty acids
have previously been shown to improve insulin sensitivity and
glucose tolerance in normoglycemic men and in obese individuals.
Omega-3 fatty acids have also been shown to improve insulin
resistance in obese and non-obese patients with an inflammatory
phenotype. Lipid, glucose, and insulin metabolism have been shown
to improve in overweight hypertensive subjects through treatment
with omega-3 fatty acids. Omega-3 fatty acids (EPA/DHA) have also
been shown to decrease triglycerides and to reduce the risk for
sudden death caused by cardiac arrhythmias in addition to improve
mortality in patients at risk of a cardiovascular event. Omega-3
fatty acids have also been taken as part of the dietary supplement
portion of therapy used to treat dyslipidemia. Last, but not least,
omega-3 fatty acids have been known to have a number of
anti-inflammatory properties. For instance, a higher intake of
omega-3 fatty acids lower levels of circulating TNF-.alpha. and
IL-6, two of the cytokines that are markedly increased during
inflammation processes (Chapkin et al, Prostaglandins, Leukot
Essent Fatty Acids 2009, 81, p. 187-191; Duda et al, Cardiovasc Res
2009, 84, p. 33-41). In addition, a higher intake of omega-3 fatty
acids has been shown to increase levels of the well-characterized
anti-inflammatory cytokine IL-10 (Bradley et al, Obesity (Silver
Spring) 2008, 16, p. 938-944). More recently, administration of
omega-3 fatty acids could protect against pathologic retinal
angiogenesis in a mouse model of oxygen-induced retinopathy (K. M.
Connor et al, Nat. Med. 2007, 13, p.868-873; P. Sapieha et al
Science Translational Medicine 2011, 3, issue 69, p. 1-12). Because
of this anti-angiogenic property, omega-3 fatty acids could
potentially be used as an anti-VEGF (vascular endothelial growth
factor) therapy for the treatment of proliferative retinopathy or
systemic diseases with perturbed vascular growth such as
cancer.
[0004] Both DHA and EPA are characterized as long chain fatty acids
(aliphatic portion between 12-22 carbons). Medium chain fatty acids
are characterized as those having the aliphatic portion between
6-12 carbons. Lipoic acid is a medium chain fatty acid found
naturally in the body. It plays many important roles such as free
radical scavenger, chelator to heavy metals and signal transduction
mediator in various inflammatory and metabolic pathways, including
the NF-.kappa.B pathway (Shay, K. P. et al. Biochinm. Biophys. Acta
2009, 1790, 1149-1160). Lipoic acid has been found to be useful in
a number of chronic diseases that are associated with oxidative
stress (for a review see Smith, A. R. et al Curr. Med. Chem. 2004,
11, p. 1135-46). Lipoic acid has now been evaluated in the clinic
for the treatment of diabetes (Morcos, M. et al Diabetes Res. Clin.
Pract. 2001, 52, p. 175-183) and diabetic neuropathy (Mijnhout, G.
S. et al Neth. J. Afed. 2010, 110, p. 158-162). Lipoic acid has
also been found to be potentially useful in treating cardiovascular
diseases (Ghibu, S. et al, 0.1. Cardiovasc. Pharmacol. 2009, 54, p.
391-8), Alzheimer's disease (Maczurek, A. et al, Adv. Drug Deliv.
Rev. 2008, 60, p. 1463-70) and multiple sclerosis (Yadav, V.
Multiple Sclerosis 2005, 11, p. 159-65; Salinthone, S. et al,
Endocr. Metab. Immune Disord. Drug Targets 2008, 8, p. 132-42).
[0005] COX inhibitors are non-steroidal anti-inflammatory agents
which act as inhibitors of cyclooxygenase (COX). COX converts
arachidonic acid to prostaglandin H2, which is subsequently
converted to the prostaglandins, potent mediators of inflammation.
COX inhibitors inhibit multiple isoforms of the cyclooxygenase
enzyme. Inhibition of COX-2 imparts the anti-inflammatory and
analgesic properties of COX inhibitors while the inhibition of
COX-1 is responsible for the unwanted effects on platelet
aggregation and the gastrointestinal tract (Rao, P.; Knaus, E. E.
J. Pharm. Sci. 2008, 11 (2), 81S-110S). More recently, there have
been reports that showed the potential benefits of administering
non-steroidal anti-inflammatory drugs, along with an antioxidant,
can protect against the development of Alzheimer's disease (P.
Sozio et al, Arch. Pharm. Chem. Life Sci. 2010, 343, p. 133-142. M.
A. Lovell et al J. Alzheimers' Disease 2003, 5, p. 229-239). In
particular, ibuprofen and indomethacin are two of the COX
inhibitors that have been shown to have a positive impact on the
production of amyloid .beta. peptide in cell cultures (S. Weggen et
al Nature 2001, 414, p. 212-216; S. Vlad et al, Neurology 2008, 70,
p. 1672-1677; A. McKee Brain Res. 2008, 1207, p. 225-236). Fatty
acid COX inhibitor derivatives are inactive against the COX enzyme
until they enter the cell and are hydrolyzed into the individual
components to produce free COX inhibitor and free fatty acid. Thus,
the side effects of COX inhibitors, including stomach ulcer and
gastrointestinal distress, are minimized.
[0006] The ability to provide the effects of COX inhibitors and
fatty acids in a synergistic way would provide benefits in treating
a variety of metabolic, autoimmune and inflammatory disorders.
SUMMARY OF THE INVENTION
[0007] The invention is based in part on the discovery of fatty
acid COX inhibitor derivatives and their demonstrated effects in
achieving improved treatment that cannot be achieved by
administering fatty acids or COX inhibitors, alone, or in simple
(non covalently linked) combination. These novel compounds are
useful to relieve the inflammation, swelling, stiffness, and joint
pain associated with rheumatoid arthritis, ostcoarthritis, juvenile
arthritis, ankylosing spondylitis, tendinitis, bursitis, and acute
gout. In addition, they are used to treat pain associates with
menstrual periods, migraine headaches, dental pain, and other types
of mild to moderate pain.
[0008] Accordingly in one aspect, a molecular conjugate is
described which comprises a COX inhibitor and a fatty acid
covalently linked, wherein the fatty acid is selected from the
group consisting of omega-3 fatty acids, fatty acids that are
metabolized in vivo to omega-3 fatty acids, and lipoic acid, and
the conjugate is capable of hydrolysis to produce free COX
inhibitor and free fatty acid, with the proviso that the molecular
conjugate is not
(5Z,8Z,11Z,14Z,17Z)-1-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-
-3-yl)acetoxy)ethyl icosa-5,8,11,14,17-pentaenoate or
5-((S)-1,2-dithiolan-3-yl)-N-(2-(2-(4-isobutylphenyl)propanamido)ethyl)pe-
ntanamide. In some embodiments, the fatty acid is selected from the
group consisting of all-cis-7,10,13-hexadecatrienoic acid,
.alpha.-linolenic acid, stcaridonic acid, eicosatrienoic acid,
eicosatetraenoic acid, eicosapentaenoic acid (EPA).
docosapentaenoic acid, docosahcxacnoic acid (DHA),
tetracosapentaenoic acid, tetracosahexaenoic acid and lipoic acid.
In other embodiments, the fatty acid is selected from
eicosapcntacnoic acid, docosahexaenoic acid and lipoic acid. In
some embodiments, the COX inhibitor is selected from the group
consisting of propionic acid derivatives such as but not limited to
ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofcn, and
oxaprozin, acetic acid derivatives such as but not limited to
indomethacin, sulindac, etodolac, and diclofenac, enolic
acid/oxicam derivatives such as but not limited to piroxicam,
meloxicam, tenoxicam, droxicam, lornoxicam, and isoxicam, and
fenamic acid derivatives such as but not limited to mefenamic acid,
meclofenamic acid, flufenamic acid, and tolfenamic acid. In some
embodiments, the hydrolysis is enzymatic. Fatty acid COX inhibitor
derivatives are inactive against the COX enzyme until they enter
the cell and are hydrolyzed into the individual components to
produce free COX inhibitor and free fatty acid. Thus, the side
effects of COX inhibitors, including stomach ulcer and
gastrointestinal distress, are minimized.
[0009] In another aspect, compounds of the Formula 1 are
described:
##STR00001##
[0010] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, enantiomers, and stereoisomers thereof;
[0011] wherein
[0012] R.sub.n is
##STR00002## ##STR00003##
[0013] W.sub.1 and W.sub.2 are each independently null, O, S, NH,
NR, or W.sub.1 and W.sub.2 can be taken together can form an
imidazolidine or piperazine group, with the proviso that W.sub.1
and W.sub.2 can not be O simultaneously;
[0014] each a, b, c and d is independently --H, -D, --CH.sub.3,
--OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)OR, or --O--Z, or benzyl,
or two of a, b, c, and d can be taken together, along with the
single carbon to which they are bound, to form a cycloalkyl or
heterocycle;
[0015] each n, o, p, and q is independently 0, 1 or 2;
[0016] each L is independently null, --O--, --S--, --S(O)--,
--S(O).sub.2--, --S--S--, --(C.sub.1-C.sub.6alkyl)-,
--(C.sub.3-C.sub.6cycloalkyl)-, a heterocycle, a heteroaryl,
##STR00004## ##STR00005##
[0017] wherein the representation of L is not limited directionally
left to right as is depicted, rather either the left side or the
right side of L can be bound to the W.sub.1 side of the compound of
Formula 1;
[0018] R.sub.6 is independently --H, -D, --C.sub.1-C.sub.4 alkyl,
-halogen, cyano, oxo, thiooxo, --OH, --C(O)C.sub.1-C.sub.4 alkyl,
--O-aryl, --O-benzyl, --OC(O)C.sub.1-C.sub.4 alkyl,
--C.sub.1-C.sub.3 alkene, --C.sub.1-C.sub.3 alkyne,
--C(O)C.sub.1-C.sub.4 alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.3
alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2, --NH(C(O)C.sub.1-C.sub.3
alkyl), --N(C(O)C.sub.1-C.sub.3 alkyl).sub.2, --SH,
--S(C.sub.1-C.sub.3 alkyl), --S(O)C.sub.1-C.sub.3 alkyl,
--S(O).sub.2C.sub.1-C.sub.3 alkyl;
[0019] each g is independently 2, 3 or 4;
[0020] each h is independently 1, 2, 3 or 4;
[0021] m is 0, 1, 2, or 3; if m is more than 1, then L can be the
same or different;
[0022] m1 is 0, 1, 2 or 3;
[0023] k is 0, 1, 2, or 3;
[0024] z is 1, 2, or 3;
[0025] each R.sub.3 is independently H or C.sub.1-C.sub.6 alkyl, or
both R.sub.3 groups, when taken together with the nitrogen to which
they are attached, can form a heterocycle;
[0026] each R.sub.4 is independently e, H or straight or branched
C.sub.1-C.sub.10alkyl which can be optionally substituted with OH,
NH.sub.2, CO.sub.2R, CONH.sub.2, phenyl, C.sub.6H.sub.4OH,
imidazole or arginine;
[0027] each e is independently H or any one of the side chains of
the naturally occurring amino acids;
[0028] each Z is independently --H,
##STR00006##
[0029] with the proviso that there is at least one
##STR00007##
[0030] in the compound;
[0031] each r is independently 2, 3, or 7;
[0032] each s is independently 3, 53, or 6;
[0033] each t is independently 0 or 1;
[0034] each v is independently 1, 2, or 6;
[0035] R.sub.1 and R.sub.2 are each independently hydrogen,
deuterium, --C.sub.1-C.sub.4 alkyl, -halogen, --OH,
--C(O)C.sub.1-C.sub.4 alkyl, --O-aryl, --O-benzyl,
--OC(O)C.sub.1-C.sub.4 alkyl, --C.sub.1-C.sub.3 alkene,
--C.sub.1-C.sub.3 alkyne, --C(O)C.sub.1-C.sub.4 alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.3 alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2,
--NH(C(O)C.sub.1-C.sub.3 alkyl), --N(C(O)C.sub.1-C.sub.3
alkyl).sub.2, --SH, --S(C.sub.1-C.sub.3 alkyl),
--S(O)C.sub.1-C.sub.3 alkyl, --S(O).sub.2C.sub.1-C.sub.3 alkyl;
and
[0036] each R is independently --H, --C.sub.1-C.sub.3 alkyl, or
straight or branched C.sub.1-C.sub.4 alkyl optionally substituted
with OH, or halogen;
[0037] provided that
[0038] when m, n, o, p, and q are each 0, W.sub.1 and W.sub.2 are
each null, and Z is
##STR00008##
[0039] then t must be 0; and
[0040] when m, n, o, p, and q are each 0, and W.sub.1 and W.sub.2
are each null, then Z must not be
##STR00009##
with the further proviso that the compound is not 5Z,8Z,11
Z,14Z,17Z)-1-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)ace-
toxy)ethyl icosa-5,8,11,14,17-pentaenoate or
5-((S)-1,2-dithiolan-3-yl)-N-(2-(2-(4-isobutylphenyl)propanamido)ethyl)pe-
ntanamide.
[0041] In Formula I, any one or more of H may be substituted with a
deuterium. It is also understood in Formula I, that a methyl
substituent can be substituted with a C.sub.1-C.sub.6 alkyl.
[0042] Also described are pharmaceutical formulations comprising at
least one fatty acid COX inhibitor derivative.
[0043] Also described herein are methods of treating a disease
susceptible to treatment with a fatty acid COX inhibitor derivative
in a patient in need thereof by administering to the patient an
effective amount of a fatty acid COX inhibitor derivative.
[0044] Also described herein are methods of treating metabolic
diseases or autoimmune disease or neurodegenerative diseases by
administering to a patient in need thereof an effective amount of a
fatty acid COX inhibitor derivative.
[0045] The invention also includes pharmaceutical compositions that
comprise an effective amount of a fatty acid COX inhibitor
derivative and a pharmaceutically acceptable carrier. The
compositions are useful for treating or preventing a metabolic
disease. The invention includes a fatty acid COX inhibitor
derivative provided as a pharmaceutically acceptable prodrug, a
hydrate, a salt, such as a pharmaceutically acceptable salt,
enantiomer, stereoisomer, or mixtures thereof.
[0046] The details of the invention are set forth in the
accompanying description below. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present invention, illustrative methods
and materials are now described. Other features, objects, and
advantages of the invention will be apparent from the description
and from the claims. In the specification and the appended claims,
the singular forms also include the plural unless the context
clearly dictates otherwise. Unless defined otherwise, all technical
and scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this
invention belongs. All patents and publications cited in this
specification are incorporated herein by reference in their
entireties.
DETAILED DESCRIPTION OF THE INVENTION
[0047] The fatty acid COX inhibitor derivatives have been designed
to bring together fatty acids and COX inhibitors into a single
molecular conjugate. The activity of the fatty acid COX inhibitor
derivatives is substantially greater than the sum of the individual
components of the molecular conjugate, suggesting that the activity
induced by the fatty acid COX inhibitor derivatives is
synergistic.
DEFINITIONS
[0048] The following definitions are used in connection with the
fatty acid COX inhibitor derivatives:
[0049] The term "fatty acid COX inhibitor derivatives" includes any
and all possible isomers, stereoisomers, enantiomers,
diastereomers, tautomers, pharmaceutically acceptable salts,
hydrates, solvates, and prodrugs of the fatty acid COX inhibitor
derivatives described herein.
[0050] The articles "a" and "an" are used in this disclosure to
refer to one or more than one (i.e., to at least one) of the
grammatical object of the article. By way of example, "an element"
means one element or more than one element.
[0051] The term "and/or" is used in this disclosure to mean either
"and" or "or" unless indicated otherwise.
[0052] Unless otherwise specifically defined, the term "aryl"
refers to cyclic, aromatic hydrocarbon groups that have 1 to 2
aromatic rings, including monocyclic or bicyclic groups such as
phenyl, biphenyl or naphthyl. Where containing two aromatic rings
(bicyclic, etc.), the aromatic rings of the aryl group may be
joined at a single point (e.g., biphenyl), or fused (e.g.,
naphthyl). The aryl group may be optionally substituted by one or
more substituents, e.g., 1 to 5 substituents, at any point of
attachment. The substituents can themselves be optionally
substituted.
[0053] "C.sub.1-C.sub.3 alkyl" refers to a straight or branched
chain saturated hydrocarbon containing 1-3 carbon atoms. Examples
of a C.sub.1-C.sub.3 alkyl group include, but are not limited to,
methyl, ethyl, propyl and isopropyl.
[0054] "C.sub.1-C.sub.4 alkyl" refers to a straight or branched
chain saturated hydrocarbon containing 1-4 carbon atoms. Examples
of a C.sub.1-C.sub.4 alkyl group include, but are not limited to,
methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and
tert-butyl.
[0055] "C.sub.1-C.sub.5 alkyl" refers to a straight or branched
chain saturated hydrocarbon containing 1-5 carbon atoms. Examples
of a C.sub.1-C.sub.5 alkyl group include, but are not limited to,
methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl,
sec-butyl and tert-butyl, isopentyl and neopentyl.
[0056] "C.sub.1-C.sub.6 alkyl" refers to a straight or branched
chain saturated hydrocarbon containing 1-6 carbon atoms. Examples
of a C.sub.1-C.sub.6 alkyl group include, but are not limited to,
methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, isopentyl, and neopentyl.
[0057] The term "cycloalkyl" refers to a cyclic hydrocarbon
containing 3-6 carbon atoms. Examples of a cycloalkyl group
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl. It is understood that any of the
substitutable hydrogens on a cycloalkyl can be substituted with
halogen, C.sub.1-C.sub.3 alkyl, hydroxyl, alkoxy and cyano
groups.
[0058] The term "heterocycle" as used herein refers to a cyclic
hydrocarbon containing 3-6 atoms wherein at least one of the atoms
is an O, N, or S. Examples of heterocycles include, but are not
limited to, aziridine, oxirane, thiirane, azetidine, oxetane,
thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,
piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine,
thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane,
and dioxane.
[0059] The term "heteroaryl" as used herein refers to a monocyclic
or bicyclic ring structure having 5 to 12 ring atoms wherein one or
more of the ring atoms is a heteroatom, e.g. N, O or S and wherein
one or more rings of the bicyclic ring structure is aromatic. Some
examples of heteroaryl are pyridyl, furyl, pyrrolyl, thienyl,
thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl,
xanthenes and dihydroindole. It is understood that any of the
substitutable hydrogens on a heteroaryl can be substituted with
halogen, C.sub.1-C.sub.3 alkyl, hydroxyl, alkoxy and cyano
groups.
[0060] The term "any one of the side chains of the naturally
occurring amino acids" as used herein means a side chain of any one
of the following amino acids: Isoleucine, Alanine, Leucine,
Asparagine, Lysine, Aspartate, Methionine, Cysteine, Phenylalanine,
Glutamate, Threonine, Glutamine, Tryptophan, Glycine, Valine,
Proline, Arginine, Serine, Histidine, and Tyrosine.
[0061] The term "fatty acid" as used herein means an omega-3 fatty
acid and fatty acids that are metabolized in vivo to omega-3 fatty
acids. Non-limiting examples of fatty acids are
all-cis-7,10,13-hexadecatrienoic acid, .alpha.-linolenic acid (ALA
or all-cis-9,12,15-octadecatrienoic acid), stearidonic acid (STD or
all-cis-6,9,12,15-octadecatetraenoic acid), eicosatrienoic acid
(ETE or all-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic
acid (ETA or all-cis-8,11,14,17-eicosatetraenoic acid),
eicosapentaenoic acid (EPA or all-cis-5,8,11,14,17-eicosapentaenoic
acid), docosapentaenoic acid (DPA, clupanodonic acid or
all-cis-7,10,13,16,19-docosapcntaenoic acid), docosahexaenoic acid
(DHA or all-cis-4,7,10,13,16,19-docosahcxaenoic acid),
tetracosapentaenoic acid (all-cis-9,12,15,18,21-docosahexaenoic
acid), or tetracosahexaenoic acid (nisinic acid or
all-cis-6,9,12,15,18,21-tetracosenoic acid). In addition, the term
"fatty acid" can also refer to medium chain fatty acids such as
lipoic acid.
[0062] The term "COX inhibitor" as used herein means any of the
class of compounds known as COX inhibitors, and any derivatives
thereof, including but not limited to propionic acid derivatives
(such as ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofcn,
and oxaprozin), acetic acid derivatives (such as indomethacin,
sulindac, etodolac, and diclofenac), enolic acid/oxicam derivatives
(such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, and
isoxicam) and fenamic acid derivatives (such as mefenamic acid,
meclofenamic acid, flufenamic acid, and tolfenamic acid).
[0063] A "subject" is a mammal, e.g., a human, mouse, rat, guinea
pig, dog, cat, horse, cow, pig, or non-human primate, such as a
monkey, chimpanzee, baboon or rhesus, and the terms "subject" and
"patient" are used interchangeably herein.
[0064] The invention also includes pharmaceutical compositions
comprising an effective amount of a fatty acid COX inhibitor
derivative and a pharmaceutically acceptable carrier.
[0065] The invention includes a fatty acid COX inhibitor derivative
provided as a pharmaceutically acceptable prodrug, hydrate, salt,
such as a pharmaceutically acceptable salt, enantiomers,
stereoisomers, or mixtures thereof.
[0066] Representative "pharmaceutically acceptable salts" include,
e.g., water-soluble and water-insoluble salts, such as the acetate,
amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,
benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,
butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,
citrate, clavulariate, dihydrochloride, edetate, edisylate,
estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexafluorophosphate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, magnesium,
malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate,
pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate),
pantothenate, phosphate/diphosphate, picrate, polygalacturonate,
propionate, p-toluenesulfonate, salicylate, stearate, subacetate,
succinate, sulfate, sulfosalicylate, suramatc, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate salts.
[0067] The term "metabolic disease" as used herein refers to
disorders, diseases and syndromes involving dyslipidemia, and the
terms metabolic disorder, metabolic disease, and metabolic syndrome
are used interchangeably herein.
[0068] An "effective amount" when used in connection with a fatty
acid COX inhibitor derivative is an amount effective for treating
or preventing a metabolic disease.
[0069] The term "carrier", as used in this disclosure, encompasses
carriers, excipients, and diluents and means a material,
composition or vehicle, such as a liquid or solid filler, diluent,
excipient, solvent or encapsulating material, involved in carrying
or transporting a pharmaceutical agent from one organ, or portion
of the body, to another organ, or portion of the body.
[0070] The term "treating", with regard to a subject, refers to
improving at least one symptom of the subject's disorder. Treating
can be curing, improving, or at least partially ameliorating the
disorder.
[0071] The term "disorder" is used in this disclosure to mean, and
is used interchangeably with, the terms disease, condition, or
illness, unless otherwise indicated.
[0072] The term "administer", "administering", or "administration"
as used in this disclosure refers to either directly administering
a compound or pharmaceutically acceptable salt of the compound or a
composition to a subject, or administering a prodrug derivative or
analog of the compound or pharmaceutically acceptable salt of the
compound or composition to the subject, which can form an
equivalent amount of active compound within the subject's body.
[0073] The term "prodrug," as used in this disclosure, means a
compound which is convertible in vivo by metabolic means (e.g., by
hydrolysis) to a fatty acid COX inhibitor derivative.
[0074] The following abbreviations are used herein and have the
indicated definitions: Boc and BOC are tert-butoxycarbonyl,
Boc.sub.2O is di-tert-butyl dicarbonate, CDI is
1,1'-carbonyldiimidazole, DCC is N,N'-dicyclohexylcarbodiimide,
DIEA is N,N-diisopropylethylamine, DMAP is 4-dimethylaminopyridine,
DOSS is sodium dioctyl sulfosuccinate, EDC and EDCI are
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, EtOAc
is ethyl acetate, h is hour, HATU is
2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate, HPMC is hydroxypropyl methylcellulose, min is
minutes, Pd/C is palladium on carbon, TFA is trifluoroacetic acid,
TGPS is tocopherol propylene glycol succinate, THF is
tetrahydrofuran, and TNF is tumor necrosis factor.
Compounds
[0075] Accordingly in one aspect, a molecular conjugate is
described which comprises a COX inhibitor and a fatty acid directly
or indirectly covalently linked, wherein the fatty acid is selected
from the group consisting of omega-3 fatty acids, fatty acids that
are metabolized in vivo to omega-3 fatty acids, and lipoic acid,
and the conjugate is capable of hydrolysis to produce free COX
inhibitor and free fatty acid, with the proviso that the molecular
conjugate is not
(5Z,8Z,11Z,14Z,17Z)-1-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-
-3-yl)acetoxy)ethyl icosa-5,8,11,14,17-pentaenoate or
5-((S)-1,2-dithiolan-3-yl)-N-(2-(2-(4-isobutylphenyl)propanamido)ethyl)-p-
entanamide.
[0076] In some embodiments, the COX inhibitor is selected from the
group consisting of propionic acid derivatives, acetic acid
derivatives, and fenamic acid derivatives. In other embodiments,
the COX inhibitor is selected from the group consisting of
ibuprofen, 2-(6-methoxynaphthalen-2-yl)propanoic acid, fenoprofen,
ketoprofen, flurbiprofen, oxaprozin, indomethacin, etodolac,
diclofenac, mefenamic acid, flufenamic acid, meclofenamic acid, and
tolfenamic acid. In other embodiments, the COX inhibitor is
selected from the group consisting of ibuprofen,
2-(6-methoxynaphthalen-2-yl)propanoic acid, and indomethacin.
[0077] In some embodiments, the fatty acid is selected from the
group consisting of all-cis-7,10,13-hexadecatrienoic acid,
.alpha.-linolenic acid, stearidonic acid, eicosatrienoic acid,
eicosatetraenoic acid, eicosapentaenoic acid (EPA),
docosapentaenoic acid, docosahexaenoic acid (DHA),
tetracosapentaenoic acid, tetracosahexaenoic acid, and lipoic acid.
In other embodiments, the fatty acid is selected from
eicosapentaenoic acid and docosahexaenoic acid. In some
embodiments, the hydrolysis is enzymatic.
[0078] In another aspect, the present invention provides fatty acid
COX inhibitor derivatives according to Formula I:
##STR00010##
and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, enantiomers and stereoisomers thereof;
[0079] wherein
[0080] W.sub.1, W.sub.2, a, c, b, d, e, k, m, m1, n, o, p, q, L, Z,
Z', r, s, t, v, z, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R and
R.sub.6 are as defined above for Formula I,
[0081] with the proviso that there is at least one of
##STR00011##
[0082] in the compound;
[0083] with the additional proviso that the compound is not
(5Z,8Z,11Z,14Z,17Z)-1-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-
-3-yl)acetoxy)ethyl icosa-5,8,11,14,17-pentaenoate or
5-((S)-1,2-dithiolan-3-yl)-N-(2-(2-(4-isobutylphenyl)propanamido)ethyl)pe-
ntanamide.
[0084] In some embodiments, one Z is
##STR00012##
and r is 2.
[0085] In some embodiments, one Z is
##STR00013##
and r is 3.
[0086] In some embodiments, one Z is
##STR00014##
and r is 7.
[0087] In other embodiments, one Z is
##STR00015##
and s is 3.
[0088] In some embodiments, one Z is
##STR00016##
and s is 5.
[0089] In some embodiments, one Z is
##STR00017##
and s is 6.
[0090] In some embodiments, one Z is
##STR00018##
and v is 1.
[0091] In other embodiments, one Z is
##STR00019##
and v is 2.
[0092] In some embodiments, one Z is
##STR00020##
and v is 6.
[0093] In some embodiments, one Z is
##STR00021##
and s is 3.
[0094] In some embodiments, one Z is
##STR00022##
and s is 5.
[0095] In other embodiments, one Z is
##STR00023##
and s is 6.
[0096] In other embodiments, Z is
##STR00024##
and t is 1.
[0097] In some embodiments, Z is
##STR00025##
[0098] and t is 1.
[0099] In some embodiments, W1 is NH.
[0100] In some embodiments, W2 is NH.
[0101] In some embodiments, W1 is O.
[0102] In some embodiments, W2 is O.
[0103] In some embodiments, W1 is null.
[0104] In some embodiments, W2 is null.
[0105] In some embodiments, W1 and W2 are each NH.
[0106] In some embodiments, W1 and W2 are each null.
[0107] In some embodiments, W1 is O and W2 is NH.
[0108] In some embodiments, W1 and W2 are each NR, and R is
CH3.
[0109] In some embodiments, m is 0.
[0110] In other embodiments, m is 1.
[0111] In other embodiments, m is 2.
[0112] In some embodiments, L is --S-- or --S--S--.
[0113] In some embodiments, L is --O--.
[0114] In some embodiments, L is --C(O)--.
[0115] In some embodiments, L is heteroaryl.
[0116] In some embodiments, L is heterocycle.
[0117] In some embodiments, L is
##STR00026##
[0118] In some embodiments, L is
##STR00027##
[0119] In some embodiments, L is
##STR00028##
[0120] In some embodiments, L is
##STR00029##
[0121] In some embodiments, L is
##STR00030##
[0122] In some embodiments, L is
##STR00031##
[0123] In some embodiments, L is
##STR00032##
[0124] In some embodiments, L is
##STR00033##
[0125] In some embodiments, L is
##STR00034##
[0126] In some embodiments, L is
##STR00035##
[0127] In some embodiments, L is
##STR00036##
[0128] In other embodiments, one of n, o, p, and q is 1.
[0129] In some embodiments, two of n, o, p, and q are each 1.
[0130] In other embodiments, three of n, o, p, and q are each
1.
[0131] In some embodiments n, o, p, and q are each 1.
[0132] In some embodiments, one d is C(O)OR.
[0133] In some embodiments, r is 2 and s is 6.
[0134] In some embodiments, r is 3 and s is 5.
[0135] In some embodiments, t is 1.
[0136] In some embodiments, W1 and W2 are each NH, m is 0, n, and o
are each 1, and p and q are each 0.
[0137] In some embodiments, W1 and W2 are each NH, m is 1, n, o, p,
and q are each 1, and L is O.
[0138] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, o, p, and q are each 1, and L is
##STR00037##
[0139] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, o, p, and q are each 1, and L is --S--S--.
[0140] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n and o are each 0, p and q are each 1, and L is
##STR00038##
[0141] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, k is O, n and o are each 0, p and q are each 1, and L is
##STR00039##
[0142] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n and o are each 1, p and q are each 0, and L is
##STR00040##
[0143] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, k is 0, n is 1, o, p and q are each 0, and L is
##STR00041##
[0144] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, o, and p are each 0, and [0145] q is 1, and L is
##STR00042##
[0146] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, k is 1, n, o, and p are each 0, and q is 1, and L is
##STR00043##
[0147] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n is 1, and o, p, and q are each 0, and L is
##STR00044##
[0148] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, k is 1, o, p, and q are each 0, and L is
##STR00045##
[0149] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, o, p, and q are each 1, and L is
##STR00046##
[0150] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, o, p, and q are each 1, and L is
##STR00047##
[0151] In some embodiments, W1 and W2 are each NH, m is 0, k is 1,
o and p are each 1, and q is 0.
[0152] In some embodiments, W1 and W2 are each NH, m is 0, n, o, p,
and q are each 1.
[0153] In some embodiments, W1 and W2 are each NH, m is 0, n and o
are each 1, p and q are each 0, and each a is CH3.
[0154] In some embodiments, W1 and W2 are each NH, m is 0, n and o
are each 1, p and q are each 0, and each b is CH3.
[0155] In some embodiments, W, and W.sub.2 are each NH, m is 1, n,
o, p, and q are each 1, R.sub.3 is H, and L is
##STR00048##
[0156] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, p and q are each 1, and o is 2, R.sub.3 is H, and L is
##STR00049##
[0157] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, o, p are each 1, and q is 2, and L is
##STR00050##
[0158] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, o, p, and q are each 1, and L is
##STR00051##
[0159] In some embodiments, W1 and W2 are each NH, m is 1, n and p
are each 1, and o and q are each 0, and L is --C(O)--.
[0160] In some embodiments, W1 and W2 are each NH, m is 1, n and p
are each 1, and o, and q are each 0, and L is
##STR00052##
[0161] In some embodiments, W1 and W.sub.2 are each NH, m is 1, n,
o, p, q are each 1, and L is
##STR00053##
[0162] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, o, p, and q are each 1, h is 1, and L is
##STR00054##
[0163] In some embodiments, W.sub.1 and W.sub.2 are each NH, m is
1, n, o, p, and q are each 1, and L is --S--.
[0164] In some embodiments, W1 and W2 are each NH, m is 1, n, o, p
are each 0, q is 1, one d is --CH.sub.3, and L is
##STR00055##
[0165] In some embodiments, W1 and W.sub.2 are each NH, m is 2, n,
o, p, and q are each 0, one L is
##STR00056##
and
##STR00057##
one L is
[0166] In some embodiments, m is 0, n, o, p, and q are each 0, and
W1 and W2 are taken together to form an optionally substituted
piperazine group.
[0167] In some embodiments, m is 1, n, o, p, and q are each 0, W1
and W2 are each null, and L is
##STR00058##
[0168] In some embodiments, m is 1, n and p are each 1, o and q are
each 0, W.sub.1 and W.sub.2 are each NH, and L is C.sub.3-C.sub.6
cycloalkyl.
[0169] In some embodiments, m is 1, n is 1, o, p, and q are each 0,
W.sub.1 and W.sub.2 are each NH, and L is C.sub.3-C.sub.6
cycloalkyl.
[0170] In some embodiments, m is 1, n, o, p, are each 0, q is 1,
W.sub.1 and W.sub.2 are each NH, and L is C.sub.3-C.sub.6
cycloalkyl.
[0171] In some embodiments, m is 1, n, o, p, and q are each 0,
W.sub.1 is NH, W.sub.2 is null, and L is
##STR00059##
[0172] In some embodiments, m is 1, n o, p, and q are each 0,
W.sub.1 is null, W.sub.2 is NH, and L is
##STR00060##
[0173] In some embodiments, m is 1, n o, p, and q are each 0, W1 is
NH, W2 is null, and L is
##STR00061##
[0174] In some embodiments, m is 1, n o, p, and q are each 0,
W.sub.1 is null, W.sub.2 is NH, and L is
##STR00062##
[0175] In some embodiments, m is 1, n is 1, o, p, and q are each 0,
W1 is NH, W2 is null, and L is
##STR00063##
[0176] In some embodiments, m is 1, n, o, p, are each 0, q is 1,
W.sub.1 is null, W.sub.2 is NH, and L is
##STR00064##
[0177] In some embodiments, m is 1, n, o, p, and q are each 0,
W.sub.1 is NH, W.sub.2 is null, and L is
##STR00065##
[0178] In some embodiments, m is 1, n, o, p, and q are each 0,
W.sub.1 is null, W.sub.2 is NH, and L is
##STR00066##
[0179] In some embodiments, m is 1, n is 1, o, p, and q are each 0,
W.sub.1 is NH, W.sub.2 is null, and L is
##STR00067##
[0180] In some embodiments, m is 1, n, o, p, are each 0, q is 1, W,
is null, W.sub.2 is NH, and L is
##STR00068##
[0181] In some embodiments, m is 1, n is 1, o, p, and q are each 0,
W.sub.1 is NH, W.sub.2 is null, and L is
##STR00069##
[0182] In some embodiments, m is 1, n, o, p, are each 0, q is 1,
W.sub.1 is null, W.sub.2 is NH, and L is
##STR00070##
[0183] In some embodiments, m is 1, n, o, p, q are each 0, W.sub.1
and W.sub.2 is null, and L is
##STR00071##
[0184] In some embodiments, m is 1, n, o, p, q are each 0, W.sub.1
and W.sub.2 is null, and L is
##STR00072##
[0185] In some embodiments, m is 1, n, o, p, q are each 0, W.sub.1
is NH, W.sub.2 is null, and L is
##STR00073##
[0186] In some embodiments, m is 1, n, o, p, q are each 0, W1 is
null, W2 is NH, and L is
##STR00074##
[0187] In some embodiments, m is 1, n, o, p, are each 0, q is 1,
W.sub.1 and W.sub.2 are each and NH, is null, L is
##STR00075##
[0188] In some embodiments, m is 1, n, o, p, are each 0, q is 1, W1
and W2 are each NH, is null, and L is a heteroaryl.
[0189] In some of the foregoing embodiments, r is 2, s is 6 and t
is 1.
[0190] In some of the foregoing embodiments, r is 3, s is 5 and t
is 1.
[0191] In some of the foregoing embodiments, Z is
##STR00076##
and
[0192] t is 1.
[0193] In some embodiments, R.sub.n is
##STR00077##
[0194] In some embodiments, R.sub.n is
##STR00078##
[0195] In some embodiments, R.sub.n is
##STR00079##
[0196] In some embodiments, R.sub.n is
##STR00080##
[0197] In some embodiments, R.sub.n is
##STR00081##
[0198] In some embodiments, R.sub.n is
##STR00082##
[0199] In some embodiments, R.sub.n is
##STR00083##
[0200] In some embodiments, R.sub.n is
##STR00084##
[0201] In some embodiments, R.sub.n is
##STR00085##
[0202] In some embodiments, R.sub.n is
##STR00086##
[0203] In some embodiments, R.sub.n is
##STR00087##
[0204] In some embodiments, R.sub.n is
##STR00088##
[0205] In some embodiments, R.sub.n is
##STR00089##
[0206] In some embodiments, R.sub.n is
##STR00090##
[0207] In Formula I, any one or more of H may be substituted with a
deuterium. It is also understood in Formula I, that a methyl
substituent can be substituted with a C.sub.1-C.sub.6 alkyl.
[0208] In other illustrative embodiments, compounds of Formula I
are as set forth below: [0209]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(4-isobutylphenyl)propanamido)ethyl)docos-
a-4,7,10,13,16,19-hexaenamide (I-1); [0210] (5Z,8Z,1
Z,14Z,17Z)-N-(2-(2-(4-isobutylphenyl)propanamido)ethyl)icosa-5,8,11,14,17-
-pentaenamide (I-2); [0211]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(4-isobutylphenyl)propanamido)ethoxy)e-
thyl)docosa-4,7,10,13,16,19-hexaenamide (I-3); [0212]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-(2-(4-isobutylphenyl)propanamido)ethyl)(-
methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-4); [0213]
6-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-2-(2-(4-isob-
utylphenyl)propanamido)hcxanoic acid (I-5); [0214]
(S,4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(6-methoxynaphthalen-2-yl)propanamido)e-
thyl)docosa-4,7,10,13,16,19-hexaenamide (I-6); [0215] (S,5Z,8Z,1
Z,14Z,17Z)-N-(2-(2-(6-methoxynaphthalen-2-yl)propanamido)ethyl)icosa-5,8,-
11,14,17-pentaenamide (I-7); [0216]
(S,4Z,7Z,10Z,13Z,16Z,9Z)-N-(2-(2-(2-(6-methoxynaphthalen-2-yl)propanamido-
)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-8); [0217]
(S,4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-(2-(6-methoxynaphthalen-2-yl)propanami-
do)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide
(I-9); [0218]
6-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-2-((S-
)-2-(6-methoxynaphthalen-2-yl)propanamido)hexanoic acid (I-10);
[0219]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-
H-indol-3-yl)acetamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide
(I-11); [0220]
(5Z,8Z,11Z,14Z,17Z)-N-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methy-
l-1H-indol-3-yl)acetamido)ethyl)icosa-5,8,11,14,17-pentaenamide
(I-12); [0221]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy--
2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexae-
namide (I-13); [0222]
(4Z,7Z,10Z,13Z,6Z,9Z)-N-(2-((2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-
-1H-indol-3-yl)acetamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19--
hexaenamide (I-14); [0223]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-me-
thyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethyl)docosa-4,7,10,13,16,19-
-hexaenamide (I-15); [0224]
2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)-6-(-
4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidohexanoic
acid (I-17); [0225]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(2-(3-phenoxyphenyl)propanamido)ethyl)-
disulfanyl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-18): [0226]
(4Z,7Z,107Z,13Z,16Z,19Z)-N-(2-(2-(2-(2,6-dichlorophenylamino)phenyl)aceta-
mido)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-19); [0227]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(3-(4,5-diphenyloxazol-2-yl)propanamido)ethy-
l)docosa-4,7,10,13,16,19-hexaenamide (I-20); [0228]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(3-benzoylphenyl)propanamido)ethyl)docosa-
-4,7,10,13,16,19-hexaenamide (I-21); [0229]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-
-b]indol-1-yl)acctamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide
(I-22); [0230]
2-(2,6-dichloro-3-methylphenylamino)-N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)--
docosa-4,7,10,13,16,19-hexaenamidoethyl)benzamide (I-23); [0231]
N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-(-
3-(trifluoromethyl)phenylamino)benzamide (I-24); and [0232]
2-(2,3-dimethylphenylamino)-N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13-
,16,19-hexaenamidoethyl)benzamide (I-25).
Methods for Using Fatty Acid COX Inhibitor Derivatives
[0233] The invention also includes methods to relieve the
inflammation, swelling, stiffness, and joint pain associated with
rheumatoid arthritis, osteoarthritis, juvenile arthritis,
ankylosing spondylitis, tendinitis, bursitis, and acute gout. In
addition, it is used to treat pain associates with menstrual
periods, migraine headaches, dental pain, and other types of mild
to moderate pain. The compounds of this invention can also be used
for treating or preventing the development of inflammatory diseases
of the central nervous system, including chronic demyelinating
diseases of the nervous system, multiple sclerosis, AIDS-related
neurodegeneration and Alzheimer's disease, infectious meningitis,
encephalomyelitis, Parkinson's disease, Huntington's disease,
amyotrophic lateral sclerosis and viral or autoimmune
encephalitis.
[0234] Also provided in the invention is a method for inhibiting,
preventing, or treating an inflammatory disorder, or symptoms of an
inflammatory disease, in a subject. Examples of such disorders
include, but are not limited to relieve the inflammation, swelling,
stiffness, and joint pain associated with rheumatoid arthritis,
osteoarthritis, juvenile arthritis, ankylosing spondylitis,
tendinitis, bursitis, and acute gout. In addition, it is used to
treat pain associates with menstrual periods, migraine headaches,
dental pain, and other types of mild to moderate pain.
[0235] Furthermore, because of the potential anti-angiogcnic
property, the compounds of this invention can potentially be used
as an anti-VEGF (vascular endothelial growth factor) therapy for
the treatment of proliferative retinopathy or systemic diseases
with perturbed vascular growth such as cancer. Examples of
eye-related diseases in which anti-VEGF therapy has been found to
be effective include wet age-related macular degeneration, central
retinal vein occlusion and diabetic macular edema. The compounds
described herein are also useful in treating a variety of cancer
such as carcinoma, sarcoma, lymphoma, leukemia, melanoma,
mesothelioma, multiople myeloma, seminoma, and cancer of the
bladder, blood, bone, brain, breast, central nervous system, colon,
endometrium, esophagus, genitourinary tract, head, larynx, liver,
lung, neck, ovary, pancreas, prostate, testicle, spleen, small
intestine, large intestine or stomach.
[0236] The invention also includes pharmaceutical compositions
useful for treating or preventing a metabolic disease, or for
inhibiting a metabolic disease, or more than one of these
activities. The compositions can be suitable for internal use and
comprise an effective amount of a fatty acid COX inhibitor
derivative and a pharmaceutically acceptable carrier. The fatty
acid COX inhibitor derivatives are especially useful in that they
demonstrate very low peripheral toxicity or no peripheral
toxicity.
[0237] In some embodiments, the subject is administered an
effective amount of a fatty acid COX inhibitor derivative.
[0238] The fatty acid COX inhibitor derivatives can each be
administered in amounts that are sufficient to treat or prevent a
metabolic disease or prevent the development thereof in
subjects.
[0239] Administration of the fatty acid COX inhibitor derivatives
can be accomplished via any mode of administration for therapeutic
agents. These modes include systemic or local administration such
as oral, nasal, parenteral, transdermal, subcutaneous, vaginal,
buccal, rectal or topical administration modes.
[0240] Depending on the intended mode of administration, the
compositions can be in solid, semi-solid or liquid dosage form,
such as, for example, injectables, tablets, suppositories, pills,
time-release capsules, elixirs, tinctures, emulsions, syrups,
powders, liquids, suspensions, or the like, sometimes in unit
dosages and consistent with conventional pharmaceutical practices.
Likewise, they can also be administered in intravenous (both bolus
and infusion), intraperitoneal, subcutaneous or intramuscular form,
all using forms well known to those skilled in the pharmaceutical
arts.
[0241] Illustrative pharmaceutical compositions are tablets and
gelatin capsules comprising a fatty acid COX inhibitor derivative
and a pharmaceutically acceptable carrier, such as: a) a diluent,
e.g., purified water, triglyceride oils, such as hydrogenated or
partially hydrogenated vegetable oil, or mixtures thereof, corn
oil, olive oil, sunflower oil, safflower oil, fish oils, such as
EPA or DHA, or their esters or triglycerides or mixtures thereof,
omega-3 fatty acids or derivatives thereof, lactose, dextrose,
sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose
and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid,
its magnesium or calcium salt, sodium oleate, sodium stearate,
magnesium stearate, sodium benzoate, sodium acetate, sodium
chloride and/or polyethylene glycol; for tablets also; c) a binder,
e.g., magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose,
magnesium carbonate, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth or sodium alginate, waxes and/or
polyvinylpyrrolidone, if desired; d) a disintegrant, e.g.,
starches, agar, methyl cellulose, bentonite, xanthan gum, alginic
acid or its sodium salt, or effervescent mixtures; e) absorbent,
colorant, flavorant and sweetener; f) an emulsifier or dispersing
agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,
labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12,
captcx 355, gclucire, vitamin E TGPS or other acceptable
emulsifier; and/or g) an agent that enhances absorption of the
compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400,
PEG200.
[0242] Liquid, particularly injectable, compositions can, for
example, be prepared by dissolution, dispersion, etc. For example,
the fatty acid COX inhibitor derivative is dissolved in or mixed
with a pharmaceutically acceptable solvent such as, for example,
water, saline, aqueous dextrose, glycerol, ethanol, and the like,
to thereby form an injectable isotonic solution or suspension.
Proteins such as albumin, chylomicron particles, or serum proteins
can be used to solubilize the fatty acid COX inhibitor
derivatives.
[0243] The fatty acid COX inhibitor derivatives can be also
formulated as a suppository that can be prepared from fatty
emulsions or suspensions; using polyalkylene glycols such as
propylene glycol, as the carrier.
[0244] The fatty acid COX inhibitor derivatives can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, containing cholesterol, stearylamine or
phosphatidylcholines. In some embodiments, a film of lipid
components is hydrated with an aqueous solution of drug to a form
lipid layer encapsulating the drug, as described in U.S. Pat. No.
5,262,564, the contents of which are herein incorporated by
reference in their entirety.
[0245] Fatty acid COX inhibitor derivatives can also be delivered
by the use of monoclonal antibodies as individual carriers to which
the fatty acid COX inhibitor derivatives are coupled. The fatty
acid COX inhibitor derivatives can also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the fatty acid
COX inhibitor derivatives can be coupled to a class of
biodegradable polymers useful in achieving controlled release of a
drug, for example, polylactic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross-linked or
amphipathic block copolymers of hydrogels. In one embodiment, fatty
acid COX inhibitor derivatives are not covalently bound to a
polymer, e.g., a polycarboxylic acid polymer, or a
polyacrylate.
[0246] Parenteral injectable administration is generally used for
subcutaneous, intramuscular or intravenous injections and
infusions. Injectables can be prepared in conventional forms,
either as liquid solutions or suspensions or solid forms suitable
for dissolving in liquid prior to injection.
[0247] Compositions can be prepared according to conventional
mixing, granulating or coating methods, respectively, and the
present pharmaceutical compositions can contain from about 0.1% to
about 90%, from about 10% to about 90%, or from about 30% to about
90% of the fatty acid COX inhibitor derivative by weight or
volume.
[0248] The dosage regimen utilizing the fatty acid COX inhibitor
derivative is selected in accordance with a variety of factors
including type, species, age, weight, sex and medical condition of
the patient; the severity of the condition to be treated; the route
of administration; the renal or hepatic function of the patient;
and the particular fatty acid COX inhibitor derivative employed. A
physician or veterinarian of ordinary skill in the art can readily
determine and prescribe the effective amount of the drug required
to prevent, counter or arrest the progress of the condition.
[0249] Effective dosage amounts of the present invention, when used
for the indicated effects, range from about 20 mg to about 5,000 mg
of the fatty acid COX inhibitor derivative per day. Compositions
for in vivo or in vitro use can contain about 20, 50, 75, 100, 150,
250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the fatty
acid COX inhibitor derivative.
[0250] In one embodiment, the compositions are in the form of a
tablet that can be scored. Effective plasma levels of the fatty
acid COX inhibitor derivative can range from about 5 ng/mL to about
5,000 ng/mL. Appropriate dosages of the fatty acid COX inhibitor
derivatives can be determined as set forth in Goodman, L. S.;
Gilman, A. The Pharmacological Basis of Therapeutics, 5th ed.;
MacMillan: New York, 1975, pp. 201-226.
[0251] Fatty acid COX inhibitor derivatives can be administered in
a single daily dose, or the total daily dosage can be administered
in divided doses of two, three or four times daily. Furthermore,
fatty acid COX inhibitor derivatives can be administered in
intranasal form via topical use of suitable intranasal vehicles, or
via transdermal routes, using those forms of transdermal skin
patches well known to those of ordinary skill in that art. To be
administered in the form of a transdermal delivery system, the
dosage administration can be continuous rather than intermittent
throughout the dosage regimen. Other illustrative topical
preparations include creams, ointments, lotions, aerosol sprays and
gels, wherein the concentration of the fatty acid COX inhibitor
derivative ranges from about 0.1% to about 15%, w/w or w/v.
Methods for Making the Fatty Acid COX Inhibitor Derivatives
[0252] Examples of synthetic pathways useful for making fatty acid
COX inhibitor derivatives of Formula I are set forth in the
Examples below and generalized in Schemes 1-10.
##STR00091##
wherein R.sub.4, r, and s are as defined above.
[0253] The mono-BOC protected amine of the formula B can be
obtained from commercial sources or prepared according to the
procedures outlined in Krapcho et al. Synthetic Commun. 1990, 20,
2559-2564. The commercially available compound A can be amidated
with the amine B using a coupling reagent such as DCC, CDI, EDC, or
optionally with a tertiary amine base and/or catalyst, e.g., DMAP,
followed by deprotection of the BOC group with acids such as TFA or
HCl in a solvent such as CH.sub.2Cl.sub.2 or dioxane to produce the
coupled compound C. Activation of compound C with a coupling agent
such as HATU in the presence of an amine such as DIEA followed by
addition of a fatty acid of formula D affords compounds of the
formula E. To those familiar in the art, the fatty acid D can also
be substituted with lipoic acid in this scheme and in the
subsequent schemes.
##STR00092##
wherein R, r, and s are as defined above.
[0254] The acylated amine of the formula F can be prepared using
the procedures outlined in Andruszkiewicz et al. Synthetic Commun.
2008, 38, 905-913. Compound A can be amidated with the amine F
using a coupling reagent such as DCC, CDI, EDC, or optionally with
a tertiary amine base and/or catalyst, e.g., DMAP, followed by
deprotection of the BOC group with acids such as TFA or HCl in a
solvent such as CH.sub.2Cl.sub.2 or dioxane to produce the coupled
compound G. Activation of compound G with a coupling agent such as
HATU in the presence of an amine such as DIEA followed by addition
of a fatty acid of formula D affords compounds of the formula
H.
##STR00093##
wherein r and s are as defined above.
[0255] Compound A can be amidated with the corresponding amine I
(where i=0, 1, 2 or 3) using a coupling reagent such as DCC, CDI,
EDC, or optionally with a tertiary amine base and/or catalyst,
e.g., DMAP, followed by deprotection of the BOC group with acids
such as TFA or HCl in a solvent such as CH.sub.2Cl.sub.2 or dioxane
to produce the coupled compound J. Activation of compound J with a
coupling agent such as HATU in the presence of an amine such as
DIEA followed by addition of a fatty acid of formula D affords
compounds of the formula K. Hydrolysis of the ester under basic
conditions such as NaOH or LiOH produces the corresponding acid,
which can be coupled with glycidol to afford compounds of the
formula L.
##STR00094##
wherein r and s are as defined above.
[0256] The amine M can be prepared according to the procedures
outlined in Dahan et al. J. Org. Chem. 2007, 72, 2289-2296.
Compound A can be coupled with the amine M using a coupling reagent
such as DCC, CDI, EDC, or optionally with a tertiary amine base
and/or catalyst, e.g., DMAP, followed by deprotection of the BOC
group with acids such as TFA or HCl in a solvent such as
CH.sub.2Cl.sub.2 or dioxane to produce the coupled compound N.
Activation of compound N with a coupling agent such as HATU in the
presence of an amine such as DIEA followed by addition of a fatty
acid of formula D affords compounds of the formula O.
##STR00095##
wherein r and s are as defined above.
[0257] Compound A can be amidated with the commercially available
amine P using a coupling reagent such as DCC, CDI, EDC, or
optionally with a tertiary amine base and/or catalyst, e.g., DMAP,
to afford compound Q. The BOC group in compound Q can be removed
with acids such as TFA or HCl in a solvent such as CH.sub.2Cl.sub.2
or dioxane and the resulting amine can be coupled with a fatty acid
of formula D using a coupling agent such as HATU in the presence of
an amine such as DIEA to afford compounds of the formula R. To
those skilled in the art, the sulfur group in formula Q can be
oxidized to the corresponding sulfoxide or sulfone using an
oxidizing agent such as H.sub.2O.sub.2 or oxone.
##STR00096##
wherein R.sub.3, r, and s are as defined above.
[0258] The amine T can be prepared from the commercially available
diamine according to the procedures outlined in Dahan et al. J.
Org. Chem. 2007, 72, 2289-2296. Compound A can be amidated with the
amine T using a coupling reagent such as DCC, CDI, EDC, or
optionally with a tertiary amine base and/or catalyst, e.g., DMAP,
to afford compound U. The BOC group of compound U can be removed
with acids such as TFA or HCl in a solvent such as CH.sub.2Cl.sub.2
or dioxane and the resulting amine can be coupled with a fatty acid
of formula D using HATU in the presence of an amine such as DIEA to
afford compounds of the formula V. To those skilled in the art, the
hydroxyl group in compound U can be further acylated or converted
to an amino group by standard mesylation chemistry followed by
displacement with sodium azide and hydrogenation over a catalyst
such as Pd/C. The amine can be further acylated or alkylated,
followed by the removal of the BOC group. The resulting amine can
be coupled with a fatty acid of the formula D to afford compounds
of the formula W.
##STR00097##
wherein r and s are as defined above.
[0259] Compound A can be amidated with the commercially available
amine X using a coupling reagent such as DCC, CDI, EDC, optionally
with a tertiary amine base and/or catalyst, e.g., DMAP to afford
compound Y. The BOC group in compound Y can be removed with acids
such as TFA or HCl in a solvent such as CH.sub.2Cl.sub.2 or
dioxane. The resulting amine can be coupled with a fatty acid of
the formula D using a coupling agent such as HATU in the presence
of an amine such as DIEA to afford compounds of the formula Z.
##STR00098##
wherein r and s are as defined above.
[0260] Compound A can be amidated with the commercially available
cysteine methyl ester using a coupling reagent such as DCC, CDI,
EDC, or optionally with a tertiary amine base and/or catalyst,
e.g., DMAP, to afford compound AA. The commercially available
maleimide derivative BB can be coupled with a fatty acid of the
formula D using a coupling agent such as HATU or EDCI to afford
compounds of the formula CC. Compound AA can be coupled to
compounds of the formula CC in a solvent such as acetonitrile to
afford compounds of the formula DD.
##STR00099##
wherein R.sub.4, a, r, and s are as defined above.
[0261] The commercially available amino acid esters EE can be
coupled with a fatty acid of the formula D using a coupling agent
such as EDCI or HATU, followed by alkaline hydrolysis of the methyl
ester to afford compounds of the formula FF. Compounds of the
formula FF can be coupled with the commercially available BOC-amino
acid derivatives GG using a coupling agent such as EDCI or HATU.
The BOC group can be removed by treatment with acids such as TFA or
HCl to afford compounds of the formula HH which can then be coupled
with compound A to afford compounds of the formula II.
##STR00100##
[0262] A fatty acid of formula A can be coupled with a
BOC-protected diamine of the general formula DA to obtain the
BOC-protected amide derivative. After treatment with HCl in
dioxane, the resulting amine can be coupled with a fatty acid of
the formula D in order to obtain compounds of the formula KK. A
variety of BOC-protected diamines are commercially available. The
following diamines can be prepared according to the procedures
outlined in the corresponding references:
##STR00101##
diamine DA1, Stocks et al, Bioorganic and Medicinal Chemistry
Letters 2010, p. 7458; diamine DA2, Fritch et al, Bioorganic and
Medicinal Chemistry Letters 2010, p. 6375; diamine DA3 and DA4,
Moffat et al, J. Med. Chem. 2010, 53, p.8663-8678). To those
familiar in the art, detailed procedures to prepare a variety of
mono-protected diamines can also be found in the following
references: WO 2004092172, WO 2004092171, and WO 2004092173.
EXAMPLES
[0263] The disclosure is further illustrated by the following
examples, which are not to be construed as limiting this disclosure
in scope or spirit to the specific procedures herein described. It
is to be understood that the examples are provided to illustrate
certain embodiments and that no limitation to the scope of the
disclosure is intended thereby. It is to be further understood that
resort may be had to various other embodiments, modifications, and
equivalents thereof which may suggest themselves to those skilled
in the art without departing from the spirit of the present
disclosure and/or scope of the appended claims.
Example 1
Effect of the Compounds of the Invention on HMOX-1 and
IL-1.beta.
[0264] RAW264.7 macrophages are seeded at a density of 100,000
cells/well in a 96-well plate in DMEM supplemented with 10% FBS and
Penn/strep. 16 hours later, medium is aspirated and replaced with
90 .mu.L/well of serum-free DMEM. The compounds of the invention
are brought up in 100% EtOH to a concentration of 100 mM and then
diluted 1:100 in 100% FBS for a stock solution consisting of 1 mM
compound and 1% EtOH. These stock solutions are then diluted 1:10
in FBS supplemented with 1% EtOH to generate a 100 .mu.M of the
fatty acid COX inhibitor. 10 .mu.L is then added to the RAW246.7
cells to generate final concentrations of 10 .mu.M of the fatty
acid COX inhibitor along with vehicle only control. The compounds
are allowed to pre-incubate for 2 hours before stimulation of 100
ng/ml LPS (10 .mu.L of 1 .mu.g/ml LPS is added to each well).
Following 3 hours of LPS stimulation, cells are washed once in
1.times.PBS, aspirated dry, and flash frozen in liquid nitrogen.
RNA is then isolated and converted to cDNA using the Cells to cDNA
kit (Ambion) according to the manufacturer's protocol. HMOX-1 and
IL-1.beta. transcript levels are then measured using Taqman
primer/probe assay sets (Applied Biosystems), normalized to GAPDH
using the deltaCt method, and the data expressed relative to
vehicle only control.
Example 2
Effects of the Compounds of the Invention on COX Activity
[0265] Cyclooxygenase (COX) is a bifunctional enzyme exhibiting
both cyclooxygenase and peroxidase activities. The cyclooxygenase
activity first converts arachidonic acid to a hydroperoxy
endoperoxide (PGG2) and then the peroxidase activity reduces the
endoperoxide to an alcohol (PGH2). PGH2 is the precursor to all
prostaglandins (as well as thromboxanes and prostacyclins) by
tissue-specific isomerases to create both pro- and
anti-inflammatory prostaglandins. The peroxidase activity of both
COX-1 and COX-2 can be measured in RAW264.7 macrophages. RAW264.7
macrophages, in turn, can be seeded and prepared according to the
protocols outlined in example 1 and treated with the compounds of
the invention or left untreated (vehicle control). The compounds of
the invention are brought up in 100% EtOH to a concentration of 100
mM and then diluted 1:100 in 100% FBS for a stock solution
consisting of 1 mM compound and 1% EtOH using the same protocols
outlined in example 1 above. The peroxidase activity of both COX-1
and Cox-2 in treated cells can then be measured by the appearance
of oxidized N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) at 590
nM. The relative effects of the compounds on each COX isoform will
be determined by incorporating COX-1 specific (SC-590) and COX-2
specific (DuP-697) inhibitors. Cox activity will be measured in
vitro using a commercially available Cox activity assay kit (Cayman
Chemicals, cat #760151) according to the manufacturer's
instructions.
Example 3
Effects of the Compounds of the Invention in an In Vivo
Prostaglandin E2 (PGE2) Metabolite Assay
[0266] Prostaglandin E2 (PGE2) is rapidly converted in vivo to its
13,14-dihydro-15-keto metabolite, with more than 90% of circulating
PGE2 cleared by a single passage through the lungs. Unfortunately,
this metabolite is not chemically stable and undergoes a variable
amount of degradation to Prostaglandin A products. For this reason,
blood, urine, or other samples from whole animals or humans often
contain very little intact PGE2, and measurement of the metabolites
is necessary to provide a reliable estimate of actual PGE2
production. To measure effects of compounds of the invention in
animal models, the commercially available Cayman Chemical's PGE
Metabolite assay (cat #514531) will be employed. This kit
essentially converts 13,14-dihydro-15-keto PGA2 and
13,14-dihydro-15-keto PGE2 to a single, stable derivative that
could be easily quantified by ELISA. Briefly, the assay is based on
the competition between Prostaglandin E Metabolite (PGEM) and a
PGEM-acetylcohinesterase (AChE) conjugate (PGEM Tracer) for a
limited number of PGEM-specific antibody binding sites, and thus
the signal is inversely proportional to the amount of PGEM found in
the urine or plasma. C57BL/6 female mice that are 8-12 weeks old
with body weight in the range of 20-30 g can be used for the study.
Mice (in groups of 10) are treated acutely with either the vehicle
(control group) or the compounds of the invention by either ip or
oral gavage. All compounds are formulated in the appropriate
vehicles (Examples of vehicles that can be used include
combinations of solvents such as polyethylene glycol and
propyleneglycol, lipids such as glycerol monooleate and soybean
oil, and surfactants such as polysorbate 80 and cremophor EL).
Ninety minutes after compound dosing, animals are treated with 0.2
mg/kg LPS (lipopolysaccharide) by intraperitoneal (IP) injection.
Ninety minutes after LPS challenge, mice are anesthetized and bled
by cardiac puncture into serum separator tubes (with sodium
heparin). Bleeds are allowed to clot at room temperature for 2
hours, and tubes are then spun for 20 minutes at 2,000.times.g.
Serum is harvested from tubes (100-150 L per animal) and frozen at
-70.degree. C. PGE2 levels are then measured indirectly using the
commercially available Cayman Chemical's PGE Metabolite assay (cat
#514531) according to the manufacturer's instructions.
[0267] Alternatively, the effect of the compounds of the invention
on PGE2 can also be carried out in RAW264.7 macrophages that have
been stimulated with LPS using the same commercially available PGE2
Metabolite assay. RAW264.7 macrophages are prepared and treated
with the compounds of the invention and then exposed to LPS
stimulation according to the protocols outlined above in Example
1.
Compounds
[0268] The following non-limiting compound examples serve to
illustrate further embodiments of the fatty acid COX inhibitor
derivatives. It is to be understood that any embodiments listed in
the Examples section are embodiments of the fatty acid COX
inhibitor derivatives and, as such, are suitable for use in the
methods and compositions described above.
Example 4
Preparation of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-
H-indol-3-yl)acetamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide
(I-11)
##STR00102##
[0270] Indomethacin (500 mg, 1.40 mmol) was taken up in 10 mL of
CH.sub.2Cl.sub.2 along with tert-butyl 2-aminomethylcarbamate (223
mg, 1.40 mmol) and EDC (295 mg, 1.54 mmol). The resulting reaction
mixture was stirred at room temperature for 18 and diluted with
CH.sub.2Cl.sub.2 (10 mL). The organic layer was washed with brine,
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification by chromatography (95% CH.sub.2Cl.sub.2, 5% MeOH)
afforded 550 mg of tert-butyl
2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethy-
lcarbamate (79% yield).
[0271] tert-Butyl
2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethy-
lcarbamate (275 mg, 0.55 mmol) was taken up in 6 mL of 4 M HCl in
dioxane and allowed to stir at room temperature for 1 h. It was
then dilted with EtOAc (10 mL) and concentrated under reduced
pressure to afford the HCl salt of
N-(2-aminoethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-ind-
ol-3-yl)acetamidc. This material was taken up in 6 mL of CH.sub.3CN
along with DHA (180 mg, 0.55 mmol), HATU (230 mg, 0.605 mmol) and
DIEA (290 .mu.L, 1.7 mmol). The resulting reaction mixture was
stirred at room temperature for 2 h and diluted with EtOAc (30 mL).
The organic layer was washed with brine, dried (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. Purification by silica gel
chromatography (95% CH.sub.2Cl.sub.2, 5% MeOH) afforded 200 mg of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-
H-indol-3-yl)acetamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide
(51% yield). MS (EI) calcd for C.sub.45H.sub.52ClN.sub.3O.sub.4:
709.36. found 710 (M+1).
Example 5
Preparation of
(5Z,8Z,11Z,14Z,17Z)-N-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-in-
dol-3-yl)acetamido)ethyl)Icosa-5,8,11,14,17-pentaenamide (I-12)
##STR00103##
[0273] The same experimental procedure detailed above for the
preparation of
(4Z,7Z,10Z,13Z,16Z,9Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-met-
hyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamid-
e was used, substituting EPA for DHA. MS (EI) calcd for
C.sub.41H.sub.50ClN.sub.3O: 683.35. found 684 (M+1).
Example 6
Preparation of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methy-
l-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide
(I-13)
##STR00104##
[0275] In a typical run, sodium hydroxide (400 mg, 10 mmol) is
dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine
dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction
mixture is stirred at room temperature for 30 min. A solution
containing Boc.sub.2O (740 mg, 3.40 mmol) in THF (15 mL) is then
added dropwise, at room temperature, over a period of 15 min. The
resulting reaction mixture is stirred at room temperature for 18 h
and then concentrated under reduced pressure. The resulting residue
is taken up in CH.sub.2Cl.sub.2 (200 mL) and stirred vigorously at
room temperature for 4 h. The mixture is filtered and the filtrate
is concentrated under reduced pressure to afford 850 mg of
tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74% yield).
[0276] tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (150 mg, 0.735
mmol) was then taken up in CH.sub.3CN (10 mL) along with
indomethacin (263 mg, 0.735 mmol) and EDCI (155 mg, 0.81 mmol). The
resulting reaction mixture was stirred at room temperature for 18
h. It was then diluted with EtOAc (20 mL), washed with saturated
aqueous NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (9:1 CH.sub.2Cl.sub.2/MeOH)
to afford 310 mg of tert-butyl
2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)e-
thoxy)ethylcarbamate (78%).
[0277] tert-Butyl
2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)e-
thoxy)ethylcarbamate was taken up in 10 mL of 4 M HCl in dioxane
and allowed to stand at room temperature for 2 h. The resulting
reaction mixture was concentrated under reduced pressure to afford
the HCl salt of
N-(2-(2-aminoethoxy)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-i-
ndol-3-yl)acetamide. This material was taken up in CH.sub.3CN (10
mL) along with
(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (187
mg, 0.57 mmol), HATU (238 mg, 0.63 mmol) and DIEA (300 .mu.L, 1.71
mmol). The resulting reaction mixture was stirred at room
temperature for 2 h, diluted with EtOAc and washed successively
with saturated aqueous NaHCO.sub.3 and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. Purification by silica gel chromatography (5%
MeOH--CH.sub.2Cl.sub.2) afforded
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methy-
l-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide.
MS (EI) calcd for C.sub.45H.sub.56ClN.sub.3O.sub.5: 753.39. found
754 (M+1).
Example 7
Preparation of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-meth-
yl-1H-indol-3-yl)acetamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,1-
9-hexaenamide (I-14)
##STR00105##
[0279] N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7
mmol) was dissolved in 100 mL of CH.sub.2Cl.sub.2, and cooled to
0.degree. C. A solution of di-tert-butylcarbonate (0.93 g, 4.27
mmol) in CH.sub.2Cl.sub.2 (10 mL) was then added dropwise at
0.degree. C. over a period of 15 min. The resulting reaction
mixture was stirred at 0 OC for 30 min and then warmed to room
temperature. After stirring at room temperature for 2 h, the
reaction mixture was diluted with CH.sub.2Cl.sub.2 (100 mL). The
organic layer was washed with brine (3.times.25 mL), dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to
afford 1.1 g of tert-butyl
2-((2-aminoethyl)(methyl)amino)ethylcarbamate.
[0280] tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate
(150 mg, 0.69 mmol) was taken up in 10 mL of CH.sub.3CN along with
indomethacin (247 mg, 0.69 mmol) and EDC (146 mg, 0.76 mmol). The
resulting reaction mixture was stirred at room temperature for 2 h
and then diluted with EtOAc (40 mL). The organic layer was washed
with brine, dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. Purification by chromatography (95% CH.sub.2Cl.sub.2, 5%
MeOH) afforded 360 mg of the Boc-protected intermediate (93%
yield). This material was taken up in 10 mL of 4 M HCl in dioxane
and allowed to stir at room temperature for 10 min. The reaction
mixture was concentrated under reduced pressure to afford the HCl
salt of
N-(2-((2-aminoethyl)methyl)amino)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy--
2-methyl-1H-indol-3-yl)acetamide.
[0281] This HCl salt of
N-(2-((2-aminoethyl)(methyl)amino)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-
-2-methyl-1H-indol-3-yl)acetamide (0.38 mmol) was taken up in 5 mL
of CH.sub.3CN along with DHA (210 mg, 0.64 mmol), HATU (267 mg,
0.67 mmol) and DIEA (334 .mu.L, 2.01 mmol). The resulting reaction
mixture was stirred at room temperature for 2 h and diluted with
EtOAc (25 mL). The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification by chromatography (95% CH.sub.2Cl.sub.2, 5% MeOH)
afforded 320 mg of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-meth-
yl-1H-indol-3-yl)acetamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,1-
9-hexaenamide (65% yield). MS (EI) calcd for
C.sub.46H.sub.59CIN.sub.4O.sub.4: 766.42. found 767 (M+1).
Example 8
Preparation of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-me-
thyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethyl)docosa-4,7,10,13,16,19-
-hexaenamide (I-15)
##STR00106##
[0283] Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved
in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room
temperature, followed by dropwise addition of Boc.sub.2O (0.97 g,
4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction
mixture was stirred at room temperature for 3 h, concentrated under
reduced pressure and the resulting residue was taken up in 1M
aqueous NaH.sub.2PO.sub.4 (20 mL). The aqueous layer was washed
with a 1:1 solution of pentane/EtOAc (10 mL), basified to pH 9 with
1M aqueous NaOH, and extracted with EtOAc. The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to afford
tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg,
44% yield).
[0284] tert-Butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (150
mg, 0.595 mmol) was taken up in CH.sub.2C2.sub.2 (10 mL) along with
indomethacin (213 mg, 0.595 mmol) and EDCI (125 mg, 0.65 mmol). The
resulting reaction mixture was stirred at room temperature for 18 h
and diluted with CH.sub.2Cl.sub.2. The organic layer was washed
with saturated aqueous NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The resulting residue was purified by chromatography
(CH.sub.2Cl.sub.2) to afford 312 mg of tert-butyl
2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamid-
o)ethyl)disulfanyl)ethylcarbamate (89% yield).
[0285] tert-Butyl
2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamid-
o)ethyl)disulfanyl)ethylcarbamate (312 mg, 0.528 mmol) was taken up
in 6 mL of 4 M HCl in dioxane and allowed to stir at room
temperature for 2 h. The resulting reaction mixture was
concentrated under reduced pressure to afford the HCl salt of
N-(2-(2-(2-aminoethyl)disulfanyl)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy--
2-methyl-1H-indol-3-yl)acetamide. This material was taken up in
CH.sub.3CN (5 mL) along with
(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (173
mg, 0.528 mmol), HATU (220 mg, 0.58 mmol) and DIEA (275 .mu.L, 1.6
mmol). The resulting reaction mixture was stirred at room
temperature for 2 h, diluted with EtOAc and washed successively
with saturated aqueous NaHCO.sub.3 and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. Purification by silica gel chromatography (5%
MeOH--CH.sub.2Cl.sub.2) afforded 220 mg of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-me-
thyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethyl)docosa-4,7,10,13,16,19-
-hexaenamide (52% yield). MS (EI) calcd for
C.sub.45H.sub.56ClN.sub.3O.sub.4S.sub.2: 801.34. found 802
(M+1).
Example 9
Preparation of
(S,4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(6-methoxynaphthalen-2-yl)propanamido)e-
thyl)docosa-4,7,10,13,16,19-hexaenamide (I-7)
##STR00107##
[0287] The same experimental procedure detailed above for the
preparation of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-me-
thyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenami-
de was used, substituting naproxen for indomethacin. MS (EI) calcd
for C.sub.38H.sub.50N.sub.2O.sub.3: 582.38. found 583 (M+1).
Example 10
Preparation of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(4-Isobutylphenyl)propanamido)ethyl)docos-
a-4,7,10,13,16,19-hexaenamide (I-1)
##STR00108##
[0289] The same experimental procedure detailed above for the
preparation of
(4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-
-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaen-
amide was used, substituting ibuprofen for indomethacin. MS (EI)
calcd for C.sub.37H.sub.54N.sub.2O.sub.7: 558.42. found 559
(M+1).
EQUIVALENTS
[0290] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific embodiments described specifically
herein. Such equivalents are intended to be encompassed in the
scope of the following claims.
* * * * *