Note: Descriptions are shown in the official language in which they were submitted.
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COMPOUNDS FOR TREATMENT OF INFLAMMATION, DIABETES AND
RELATED DISORDERS
FIELD OF THE INVENTION
[0002] The invention is directed to compounds, for example, heterocyclic
derivatives of acyl urea, thiourea, carbamate and thiocarbamate compounds,
that
provide a variety of useful pharmacological effects. The compounds are useful,
for
example, in lowering blood glucose levels in hyperglycemic disorders, such as
diabetes mellitus, and for treating related disorders, such as obesity and
hyperlipidemia. Furthermore, these compounds are useful for treatment of
disorders
associated with insulin resistance, such as polycystic ovary syndrome, and for
the
treatment of inflammation, inflammatory and immunological diseases,
particularly
those mediated by pro-inflammatory cytokines (such as TNF-alpha, IL-1 beta and
IL-
6), type 4 and type 3 phosphodiesterase (PDE4 and PDE3, respectively), p44/42
mitogen-activated protein (MAP) kinase, cyclooxygenase-2 (COX-2) and/or
inducible
nitric oxide synthase (iNOS).
BACKGROUND
[0003] The causes of diabetes mellitus are not yet known, although both
genetics and environment seem to be major factors. Type 1 diabetes, also known
as
insulin-dependent diabetes mellitus (IDDM), is an autoimmune disease in which
the
responsible autoantigen is still unidentified. Since their insulin-producing
pancreatic
cells are destroyed, Type 1 diabetics need to take insulin parenterally to
survive. On
the other hand, type 2 diabetes, also called non-insulin-dependent diabetes
mellitus
(NIDDM), the more common form, is a metabolic disorder resulting from the
body's
inability to make a sufficient amount of insulin or to properly use the
insulin that is
produced. Impaired insulin secretion and insulin resistance are considered the
major
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defects; however, the precise genetic factors involved in the mechanism remain
unknown.
[0004] Other than insulin administered parenterally and as shown in Table 1,
there are generally four major classes of oral hypoglycemic agents currently
used in
the treatment of diabetes mellitus:
Class Approved Mechanisms of Limitations
Drugs Action
Sulfonylurea four (1st stimulates hypoglycemia;
generation) pancreas to may increase
and release more cardiovascular
two (2nd insulin risk; contra-
generation) indicated in liver
and renal
dysfunction;
hyperinsulinemia
Biguanide metformin reduces glucose lactic acidosis; GI
production by side effects
liver; improves
insulin sensitivity
Alpha- acarbose reduces glucose GI side effects;
glucosidase absorption by gut requires frequent
inhibitor postprandial
dosing
Thiazolidinedione troglitazone stimulates edema; contra-
(withdrawn) nuclear PPAR- indicated in heart
rosiglitazone gamma receptor; failure; long
reduces insulin onset of action;
pioglitazone resistance weight gain;
frequent liver
function testing
TABLE 1
[0005] As is shown in the above table, each of the current agents available
for
use in treatment of diabetes mellitus has several disadvantages. Accordingly,
there
is a need for the identification and development of new agents, particularly,
water
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soluble agents which can be orally administered, for use in the treatment of
diabetes
mellitus and other hyperglycemic disorders.
[0006] Moreover, while the thiazolidinedione class has gained more
widespread use in recent years as insulin sensitizers to combat "insulin
resistance",
a condition in which the patient becomes less responsive to the effects of
insulin,
there is a need for frequent liver testing for patients using these compounds.
In fact,
the known thiazolidinediones are not effective for a significant portion of
the patient
population. In addition, the first drug in this class to be approved by the
FDA,
troglitazone, was withdrawn from the market due to problems of liver toxicity.
Thus,
there is a continuing need for nontoxic, more widely effective insulin
sensitizers.
[0007] As indicated above, the invention is also directed to the treatment of
immunological diseases or inflammation, in particular, such diseases as are
mediated by cytokines, COX-2 and iNOS. The principal elements of the immune
system are macrophages or antigen-presenting cells, T cells and B cells.
Macrophages are important mediators of inflammation and also provide the
necessary "help" for T cell stimulation and proliferation. For example,
macrophages
make the cytokines IL-1, IL-12 and TNF-alpha, all of which are potent
pro-inflammatory molecules. Cytokine production may lead to the secretion of
other
cytokines, altered cellular function, cell division or differentiation. In
addition,
activation of macrophages results in the induction of enzymes, such as COX-2
and
iNOS, and in the production of free radicals capable of damaging normal cells.
Many
factors activate macrophages, including bacterial products, superantigens and
interferon gamma. It is believed that phosphotyrosine kinases and other
cellular
kinases are involved in the activation process. Since macrophages are sentinel
to
the development of an immune response, agents that modify their function,
specifically their cytokine secretion profile, are likely to determine the
direction and
potency of the immune response.
[0008] Inflammation is the body's normal response to injury or infection.
However, in inflammatory diseases such as rheumatoid arthritis, pathologic
inflammatory processes can lead to morbidity and mortality. The cytokine tumor
necrosis factor-alpha (TNF-alpha) plays a central role in the inflammatory
response
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and has been targeted as a point of intervention in inflammatory disease. TNF-
alpha
is a polypeptide hormone released by activated macrophages and other cells. At
low
concentrations, TNF-alpha participates in the protective inflammatory response
by
activating leukocytes and promoting their migration to extravascular sites of
inflammation (Moser et al., J Clin invest, 83:444-55, 1989). At higher
concentrations,
TNF-alpha can act as.a potent pyrogen and induce the production of other pro-
inflammatory cytokines (Haworth et at., Eur J Immunol, 21:2575-79, 1991;
Brennan
et at., Lancet, 2:244-7, 1989). TNF-alpha also stimulates the synthesis of
acute-
phase proteins. In rheumatoid arthritis, a chronic and progressive
inflammatory
disease affecting about 1% of the adult U.S. population, TNF-alpha mediates
the
cytokine cascade that leads to joint damage and destruction (Arend et al.,
Arthritis
Rheum, 38:151-60, 1995). Inhibitors of TNF-alpha, including soluble TNF
receptors
(etanercept) (Goldenberg, Clin Ther, 21:75-87, 1999) and anti-TNF-alpha
antibody
(infliximab) (Luong et at., Ann Pharmacother, 34:743-60, 2000)
have recently been approved by the
U.S. Food and Drug Administration (FDA) as agents for the treatment of
rheumatoid
arthritis.
[0009] Elevated levels of TNF-alpha have also been implicated in many other
disorders and disease conditions, including cachexia (Fong et al., Am J
Physiol,
256:R659-65, 1989), septic shock syndrome (Tracey et at., Proc Soc Exp Biol
Med,
200:233-9, 1992), osteoarthritis (Venn et at., Arthritis Rheum, 36:819-26,
1993),
inflammatory bowel disease such as Crohn's disease and ulcerative colitis
(Murch et
at., Gut, 32:913-7, 1991), Behcet's disease (Akoglu at at., J Rheumatol,
17:1107-8,
1990), Kawasaki disease (Matsubara et at., Clin Immunol Immunopathol, 56:29-
36,
1990), cerebral malaria (Grau et at., N Engi J Med, 320:1586-91, 1989), adult
respiratory distress syndrome (Millar et at., Lancet 2:712-4, 1989),
asbestosis and
silicosis (Bissonnette et al., Inflammation, 13:329-39, 1989), pulmonary
sarcoidosis
(Baughman et at., J Lab Clin Med, 115:36-42, 1990), asthma (Shah et at., Clin
Exp
Allergy, 25:1038-44, 1995), AIDS (Dezube et at., J Acquir Immune Defic Syndr,
5:1099-104, 1992), meningitis (Waage et at., Lancet, 1:355-7, 1987), psoriasis
(Oh
et at., J Am Acad Dermatol, 42:829-30, 2000), spondyloarthritides such as
ankylosing spondylitis (Braun et at., Curr Opin Rheumatol 13:245-9, 2001;
Marzo-
Ortega et al., Arthritis Rheum 44:2112-7, 2001), graft versus host reaction
(Nestel et
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al., J Exp Med, 175:405-13, 1992), multiple sclerosis (Sharief et al., N Engl
J Med,
325:467-72, 1991), systemic lupus erythematosus (Maury et al., Int J Tissue
React,
11:189-93, 1989), diabetes (Hotamisligil et al., Science, 259:87-91, 1993) and
atherosclerosis (Bruunsgaard et al., Clin Exp Immunol, 121:255-60, 2000).
It can be seen from the references cited above that inhibitors of TNF-alpha
are
potentially useful in the treatment of a wide variety of diseases.
[00010] Interleukin-6 (IL-6) is another pro-inflammatory cytokine that
exhibits
pleiotropy and redundancy of action. IL-6 participates in the immune response,
inflammation and hematopoiesis. It is a potent inducer of the hepatic acute
phase
response and is a powerful stimulator of the hypothalamic-pituitary-adrenal
axis that
is under negative control by glucocorticoids. IL-6 promotes the secretion of
growth
hormone but inhibits release of thyroid stimulating hormone. Elevated levels
of IL-6
are seen in several inflammatory diseases, and inhibition of the IL-6 cytokine
subfamily has been suggested as a strategy to improve therapy for rheumatoid
arthritis (Carroll et at., Inflamm Res, 47:1-7, 1998). In addition, IL-6 has
been
implicated in the progression of atherosclerosis and the pathogenesis of
coronary
heart disease (Yudkin et at., Atherosclerosis, 148:209-14, 1999).
Overproduction of
IL-6 is also seen in steroid withdrawal syndrome, conditions related to
deregulated
vasopressin secretion, and osteoporosis associated with increased bone
resorption,
such as in cases of hyperparathyroidism and sex-steroid deficiency
(Papanicolaou et
al., Ann Intern Med, 128:127-37, 1998). Since excessive production of IL-6 is
implicated in several disease states, it is highly desirable to develop
compounds that
inhibit IL-6 secretion.
[00011] The cytokine IL-1 beta also participates in the inflammatory response.
It stimulates thymocyte proliferation, fibroblast growth factor activity, and
the release
of prostaglandin from synovial cells. Elevated or unregulated levels of the
cytokine
IL-1 beta have been associated with a number of inflammatory diseases and
other
disease states, including but not limited to adult respiratory distress
syndrome
(Meduri et at, Chest 107:1062-73, 1995), allergy (Hastie et at, Cytokine 8:730-
8,
1996), Alzheimer's disease (O'Barr et al, J Neuroimmunol 109:87-94, 2000),
anorexia (Laye et at, Am J Physiol Regul Integr Comp Physiol 279:R93-8, 2000),
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asthma (Sousa et at, Thorax 52:407-10, 1997), atherosclerosis (Dewberry et at,
Arterioscier Thromb Vasc Biol 20:2394-400, 2000), brain tumors (Ilyin et at,
Mol
Chem Neuropathol 33:125-37, 1998), cachexia (Nakatani et al, Res Commun Mol
Pathol Pharmacol 102:241-9, 1998), carcinoma (Ikemoto et at, Anticancer Res
20:317-21, 2000), chronic arthritis (van den Berg et al, Clin Exp Rheumatol
17:5105-
14, 1999), chronic fatigue syndrome (Cannon et al, J Clin Immunol 17:253-61,
1997),
CNS trauma (Hens et al, J Immunol 165:2232-9, 2000), epilepsy (De Simoni et
at,
Eur J Neurosci 12:2623-33, 2000), fibrotic lung diseases (Pan et at, Pathol
Int 46:91-
9, 1996), fulminant hepatic failure (Sekiyama et at, Clin Exp Immunol 98:71-7,
1994),
gingivitis (Biesbrock et al, Monogr Oral Sci 17:20-31, 2000),
glomerulonephritis
(Kluth et at, J Nephrol 12:66-75, 1999), Guillain-Barre syndrome (Zhu et a!,
Clin
Immunol Immunopathol 84:85-94, 1997), heat hyperaigesia (Opree et at, J
Neurosci
20:6289-93, 2000), hemorrhage and endotoxemia (Parsey et at, J Immunol
160:1007-13, 1998), inflammatory bowel disease (Olson et at, J Pediatr
Gastroenterol Nutr 16:241-6, 1993), leukemia (Estrov et al, Leuk Lymphoma
24:379-
91, 1997), leukemic arthritis (Rudwaleit et at, Arthritis Rheum 41:1695-700,
1998),
systemic lupus erythematosus (Mao et at, Autoimmunity 24:71-9, 1996), multiple
sclerosis (Martin et at, J Neuroimmunol 61:241-5, 1995), osteoarthritis
(Hemvann et
at, Osteoarthritis Cartilage 4:139-42, 1996), osteoporosis (Zheng et at,
Maturitas
26:63-71, 1997), Parkinson's disease (Bessler et al, Biomed Pharmacother
53:141-5,
1999), POEMS syndrome (Gherardi et at, Blood 83:2587-93, 1994), pre term labor
(Dudley, J Reprod Immunol 36:93-109, 1997), psoriasis (Bonifati et at, J Biol
Regul
Homeost Agents 11:133-6, 1997), reperfusion injury (Clark et at, J Surg Res
58:675-
81, 1995), rheumatoid arthritis (Seitz et at, J Rheumatol 23:1512-6, 1996),
septic
shock (van Deuren et at, Blood 90:1101-8, 1997), systemic vasculitis (Brooks
et at,
Clin Exp Immunol 106:273-9, 1996), temporal mandibular joint disease (Nordahi
et
al, Eur J Oral Sci 106:559-63, 1998), tuberculosis (Tsao et at, Tuber Lung Dis
79:279-85, 1999), viral rhinitis (Roseler et at, Eur Arch Otorhinolaryngol
Suppi 1:S61-
3, 1995). and
pain and/or inflammation resulting from strain, sprain, trauma, surgery,
infection or
other disease processes. Since overproduction of IL-1 beta is associated with
numerous disease conditions, it is desirable to develop compounds that inhibit
the
production or activity of IL-1 beta.
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[00012] Cyclooxygenase is an enzyme that catalyzes a rate-determining step in
the biosynthesis of prostaglandins, which are important mediators of
inflammation
and pain. The enzyme occurs as at least two distinct isomers, cyclooxygenase-1
(COX-1) and cyclooxygenase-2 (COX-2). The COX-1 isomer is constitutively
expressed in the gastric mucosa, platelets and other cells and is involved in
the
maintenance of homeostasis in mammals, including protecting the integrity of
the
digestive tract. The COX-2 isomer, on the other hand, is not constitutively
expressed
but rather is induced by various agents, such as cytokines, mitogens, hormones
and
growth factors. In particular, COX-2 is induced during the inflammatory
response
(DeWitt DL, Biochim Biophys Acta, 1083:121-34, 1991; Seibert et al., Receptor,
4:17-23, 1994.). Aspirin and other conventional non-steroid anti-inflammatory
drugs
(NSAIDs) are non-selective inhibitors of both COX-1 and COX-2. They can be
effective in reducing inflammatory pain and swelling, but since they hamper
the
protective action of COX-1, they produce undesirable side effects of
gastrointestinal
pathology. Therefore, agents that selectively inhibit COX-2 but not COX-1 are
preferable for treatment of inflammatory diseases. Recently, a diarylpyrazole
sulfonamide (celecoxib) that selectively inhibits COX-2 has been approved by
the
FDA for use in the treatment of osteoarthritis and adult rheumatoid arthritis
(Luong et
al., Ann Pharmacother, 34:743-60, 2000; Penning et al., J Med Chem, 40:1347-
65,
1997). Another selective COX-2 inhibitor, rofecoxib, has been approved by the
FDA
for treatment of osteoarthritis, acute pain and primary dysmenorrhea (Scott
and
Lamb, Drugs, 58:499-505, 1999; Morrison et al., Obstet Gynecol, 94:504-8,
1999;
Saag et al, Arch Fam Med, 9:1124-34, 2000). COX-2 is also expressed in many
cancers and precancerous lesions, and there is mounting evidence that
selective
COX-2 inhibitors may be useful for treating and preventing colorectal, breast
and
other cancers (Taketo MM, J Natl Cancer Inst, 90:1609-20, 1998; Fournier et
al., J
Cell Biochem Suppl, 34:97-102, 2000; Masferrer et al., Cancer Res, 60:1306-11,
2000). In 1999
celecoxib was approved by the FDA as an adjunct to usual care for patients
with
familial adenomatous polyposis, a condition which, left untreated, generally
leads to
colorectal cancer.
[00013] Production of nitric oxide by iNOS has been associated with both
beneficial and detrimental effects in inflammation, inflammatory diseases and
related
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disorders. For example, deleterious effects have been implicated in the
pathogenesis
of abdominal aortic aneurysms (Johanning et at, J Vasc Surg 33:579-86, 2001),
acute endotoxemia (Henningsson et al, Am J Physiol Cell Physiol 280:C1242-54,
2001), amyotrophic lateral sclerosis (Sasaki et at, Neurosci Left 291:44-8,
2000),
atherosclerosis (Behr-Roussel et at, Circulation 102:1033-8, 2000), bladder
cancer
(Wolf et al, Virchows Arch 437:662-6, 2000), colon cancer (Watanabe et al,
Biofactors 12:129-33, 2000), cystitis (Alfieri et at, Naunyn Schmiedebergs
Arch
Pharmacol 363:353-7, 2001), HIV-1 encephalitis (Zhao et al, J Neuroimmunol
115:182-91, 2001), inflammatory bowel disease (Singer et al, Gastroenterology
111:871-85, 1996), multiple sclerosis (Pozza et at, Brain Res 855:39-46,
2000),
osteoarthritis (Pelletier et at, Osteoarthritis Cartilage 7:416-8, 1999),
osteoporosis
(Armour et at, J Bone Miner Res 14:2137-42, 1999), portal hypertension
(Schroeder
et al, Dig Dis Sci Dec 45:2405-10, 2000), pulmonary edema in endotoxin shock
(Lee
et at, Clin Exp Pharmacol Physiol 28:315-20, 2001), rheumatoid arthritis
(van't Hof et
al, Rheumatology (Oxford) 39:1004-8, 2000), sepsis (Nishina et al, Anesth
Analg
92:959-66, 2001), severe burn/smoke inhalation injury (Soejima et at, Am J
Respir
Crit Care Med 163:745-52, 2001), and ulcerative colitis (Ikeda et at, Am J
Gastroenterol 92:1339-41, 1997).
Since the production of nitric oxide by NOS has been
implicated in the pathogenesis of inflammatory and related immunological
diseases,
it is desirable to develop compounds that inhibit NOS activity or expression.
[00014] Phosphodiesterases (PDEs) are responsible for the hydrolysis of
intracellular cyclic adenosine and guanosine monophosphate (cAMP and cGMP),
which converts these second messengers into their inactive forms. There are 11
major families of PDEs, designated PDE1 to PDE11. Type 4 phosphodiesterase
(PDE4) is found in airway smooth muscle cells and in immune and inflammatory
cells. PDE4 activity has been associated with a wide variety of inflammatory
and
autoimmune diseases, and PDE4 inhibitors have been studied as potential
therapeutic agents for such diseases as asthma, chronic obstructive pulmonary
disease, rheumatoid arthritis, multiple sclerosis and type 2 diabetes (Burnouf
and
Pruniaux, Current Pharm Des, 8:1255-96, 2002; Dal Piaz and Giovannoni, Eur J
Med Chem, 35:463-80, 2000). Type 3 phosphodiesterase (PDE3) is localized in
platelets and cardiac and vascular smooth muscle cells. Inhibitors of PDE3
have
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been proposed as possible drugs for the treatment of acute respiratory
distress
syndrome (Schermuly et al, J Pharmacol Exp Ther, 292:512-20, 2000), cancer
(Shimizu et at, Anticancer Drugs, 13:875-80, 2002; Murata et at, Anticancer
Drugs,
12:79-83, 2001), cardiomyopathy (Alharethi and Movsesian, Expert Opin Investig
Drugs, 11:1529-36, 2002), congestive heart failure (Movsesian, J Am Coll
Cardiol, 34:318-24, 1999), erectile dysfunction (Kuthe et al, Curr Opin
Investig
Drugs, 3:1489-95, 2002), and T-cell-mediated autoimmune disorders (Bielekova
et
at, J Immunol 164:1117-24,2000).
[00015] Activation of lymphocyte and macrophage immune response to
pathogens involve complex intracellular signaling pathways involving a cascade
of
various phosphorylating enzymes, kinases that ultimately regulate cytokine
production and cell apoptosis. Key kinases include p44/42 MAP kinase (also
known
as ERKI/ERK2), P38 MAP kinase, MEK, and IRAK/NFkB. While different processes
utilize different aspects of the pathway, the bacterial coat-derived protein
LPS has
been shown to activate multiple mitogen-activated protein kinases, including
the
extracellular signal-regulated receptor kinases ERK1 and ERK2. LPS-induced TNF-
alpha production by human monocytes involves activation of ERKI/ERK2 (van der
Bruggen et at, Infect Immun, 67:3824-9, 1999). As TNF-alpha is a key mediator
of
autoimmune disease, blocking the ERK pathway has potential for the treatment
of
inflammatory and immunological diseases such as lupus (Yi et al, J Immunol,
165:6627-34, 2000), rheumatoid arthritis (Neff et al, Cell Microbiol, 3:703-
12, 2001;
Schett et at, Arthritis Rheum, 43:2501-12, 2000), psoriasis (van der Bruggen
et at,
Infect Immun, 67:3824-9, 1999) and destruction of pancreatic islet beta cells
in Type
I diabetes (Pavlovic et at, Eur Cytokine Netw 11:267-74, 2000).,.
[00016] It will be appreciated from the foregoing that, while there have been
extensive prior efforts to provide compounds for inhibiting, for example, TNF-
alpha,
IL-1 beta, IL-6, COX-2, PDE4 or other agents considered responsible for
inflammation or inflammatory diseases, e.g. arthritis, there still remains a
need for
new and improved compounds for effectively treating or inhibiting such
diseases. A
principal object of the invention is to provide compounds which are effective
for such
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treatments as well as for the treatment of, for example, diabetes, coronary
heart
disease, insulin resistance and related disorders.
SUMMARY OF THE INVENTION
[00017] The invention is directed to compounds, for example, heterocyclic
derivatives of acyl urea, thiourea, carbamate and thiocarbamate compounds, for
providing a variety of useful pharmacological effects. The compounds are
useful, for
example, in lowering blood glucose levels in hyperglycemic disorders, such as
diabetes mellitus, and for treating related disorders, such as obesity and
hyperlipidemia. Furthermore, these compounds are useful for treatment of
disorders
associated with insulin resistance, such as polycystic ovary syndrome, and for
the
treatment of inflammation and immunological diseases, particularly those
mediated
by pro-inflammatory cytokines (such as TNF-alpha, IL-1 beta and IL-6), type 4
phosphodiesterase (PDE4), type 3 phosphodiesterase (PDE3), p44/42 mitogen
activated protein (MAP) kinase, cyclooxygenase-2 (COX-2) and/or inducible
nitric
oxide synthase (iNOS). In particular, the invention discloses compounds of the
Formulas I-XI11 as well as the pharmaceutically acceptable salts and solvates
thereof:
R8
R1 R9
R2 l// R1
R3 R4 -R (I) R21~ (II)
~
R7 3 R
X R11 1 12 X ~` 4 R9 R12
N
-j Nu
II
6
R10 O Y RS R8 0 Y
R8
R1 R9
R2 R1
R3 R4 R5 (III) R2
` (IV)
3
X R7 R
R 13 R12 R15 X ~` 4 R12 R13 R15
N N * j N N
R R R16 * R1s
6 y 17 5 II IIR17
R14 Y 0 R14 Y 0
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R8
R8 R R9
R~ * R9 f,
R2 ri \\ * R2 (VI)
R// (V) R3 R4 TF-R5
3 R4_ T R5
X / R7
R
X ./\ R11
R12 IYI
* XN N,R20
R6 i i
R6 R1 Y R18 R19
0
R8 R8
Ra\\ *. R9 R1 * R9
fill HET
R2 R11 3 (VII) R2 R _ (VIII)
R4 , R5 R3 4 R5
R7 X \e\ ~ X
1 R11 R12 I R11 R12
/ - * X, * X Z
R/ R13 R6 *
R6 R10 Y R10 Y Y
R8
R * ~ R9
R2 R11 // (IX) R8
R3 R4 TI-R5 R * R9
I\\ *
R7 R2 (X)
X
/` R13 R12 R3 R
~ / 4 R5
N X Z
R6
*R10 Y Y X `A
11
CA 02468302 2004-05-25
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R8
R~ R9
R8 R2 R3 R (XII)
R R9 4 R5
R2 1- (XI) R7
/~ X R11
R3 R4 I _R5
R
R6 12
B R1o
R8
R
9
rill
R2R3R ~i (XIII)
4 i R5
X R7
R11 R1z
* X rz
R6
R10 Y Y
[00018] wherein the stereocenters marked with an asterisk (*) may be R- or S-;
the bond represented by a dashed line plus a solid line may be a double bond
or a
single bond, and when the bond is a double bond it may be in the E or Z
configuration, and when the bond is a single bond the resulting stereocenters
may
have the R- or S- configuration; and
[00019] R1, R2, R3, R4, R5, R6 and R7 are each independently selected from the
group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl or fluoroalkyl; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C20 aryl, linear or branched alkylaryl,
linear or branched alkenylaryl; COOR where R is H, optionally substituted
C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted
C6-C10 aryl, sodium, potassium or other pharmaceutically acceptable
counter-ion such as calcium, magnesium, ammonium, tromethamine and
the like; CONR'R", where R' and R" are independently H, optionally
substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally
substituted C6-C10 aryl or where NR'R" represents a cyclic moiety such as
morpholine, piperidine, piperazine and the like; optionally substituted C1-C6
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amidoalkyl; NH2; CI-C20 alkylamino, bis(alkylamino), cycloalkylamino or
cyclic amino; OH; optionally substituted Cl-C20 alkoxy including
trifluoromethoxy and the like; optionally substituted C1-C20 alkanoyl;
optionally substituted C1-C20 acyloxy; halo; optionally substituted Cl-C20
alkylcarboxylamino; cyano; nitro; SO2NR"'R"" where R.. and R.... are
independently H, CI-C20 alkyl or aryl; SO2R"' where R"' is H, C1-C20 alkyl
or aryl; SO3R"' where R"' is H, C1-C20 alkyl or aryl; and C4-C8 heterocycles
such as tetrazolyl, imidazolyl, pyrrolyl, pyridyl, indolyl and the like; and
wherein when individual aromatic rings possess adjacent substituents,
these substituents may be joined to form a ring such as a methylenedioxy
or ethylenedioxy group, and the like, including lactones and lactams;
[00020] R8 and R9 are each independently selected from the group consisting
of
H; optionally substituted Cl-C20 linear or branched alkyl; optionally
substituted
C2-C20 linear or branched alkenyl; optionally substituted C6-Clo aryl or
heteroaryl; COOR where R is H, optionally substituted Cl-C20 alkyl, optionally
substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl, sodium,
potassium or other pharmaceutically acceptable counter-ion such as calcium,
magnesium, ammonium, tromethamine and the like; CONR'R", where R' and
R" are independently H, alkoxy, optionally substituted C1-C20 alkyl,
optionally
substituted C2-C20 alkenyl, optionally substituted C3-C90 cycloalkyl or
cycloalkenyl or optionally substituted C6-C10 aryl or heteroaryl, preferably 2-
,
3- or 4-pyridyl; or where NR'R" represents a cyclic moiety such as morpholine,
piperidine, hydroxypiperidine, imidazole, piperazine, methylpiperazine and the
like; NH2; Cl-C20 alkylamino, bis(alkylamino), cycloalkylamino or cyclic
amino;
OH; CI-C20 alkoxy; Cl-C20 alkanoyl; C1-C20 acyloxy; halo; C1-C20
alkylcarboxylamino; cyano; nitro; SO2NR"'R"" where R"' and R.... are
independently H, CI-C20 alkyl or aryl; SO2R"' where R"' is H, C1-C20 alkyl or
aryl; SO3R"' where R"' is H, C1-C20 alkyl or aryl; and tetrazolyl; and wherein
R8
and R9 together may be joined to form a C4-C8 heterocyclic ring, including
lactone or lactam;
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[00021] R10 and R11 are each independently selected from the group consisting
of
H; optionally substituted C1-C20 linear or branched alkyl; optionally
substituted
C2-C20 linear or branched alkenyl; optionally substituted C6-C10 aryl or
heteroaryl; COOR where R is H, optionally substituted C1-C20 alkyl, optionally
substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl, sodium,
potassium or other pharmaceutically acceptable counter-ion such as calcium,
magnesium, ammonium, tromethamine and the like; CONR'R", where R' and
R" are independently H, optionally substituted C1-C20 alkyl, optionally
substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl or where
NR'R"
represents a cyclic moiety such as morpholine, piperidine, piperazine and the
like; NH2; C1-C20 alkylamino, bis(alkylamino), cycloalkylamino or cyclic
amino;
OH; C1-C20 alkoxy; C1-C20 alkanoyl; C1-C20 acyloxy; halo; C1-C20
alkylcarboxylamino; cyano; nitro; SO2NR"'R"" where R"' and R.... are
independently H, C1-C20 alkyl or aryl; SO2R"' where R"' is H, C1-C20 alkyl or
aryl; SO3R"' where R"' is H, C1-C20 alkyl or aryl; and tetrazolyl; and wherein
R10 and R11 together may be joined to form a C4-C8 heterocyclic ring,
including lactone or lactam;
[00022] R12, R13, R18, R19 and R20 are each independently selected from the
group consisting of
H; optionally substituted C1-C20 linear or branched alkyl; optionally
substituted
C2-C20 linear or branched alkenyl; optionally substituted C6-C10 aryl or
heteroaryl; COOR where R is optionally substituted C1-C20 alkyl, optionally
substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl, sodium,
potassium or other pharmaceutically acceptable counter-ion such as calcium,
magnesium, ammonium, tromethamine and the like; CONR'R", where R' and
R" are independently H, optionally substituted C1-C20 alkyl, optionally
substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl or where
NR'R"
represents a cyclic moiety such as morpholine, piperidine, piperazine and the
like; C1-C20 alkanoyl; C1-C20 alkylamido; C6-C20 aroyl or heteroaroyl; SO2R"'
where R"' is H, C1-C20 alkyl or aryl; morpholinocarbonylmethyl;
piperazinocabonylmethyl; and piperadinocabonylmethyl;
14
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[00023] R12 and R13 may be absent, or R12 and R13 together may be an
optionally substituted heterocyclic ring, preferably morpholine, piperidine,
piperazine, and N-methyl piperidine.
[00024] R14 is selected from the group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
and fluoroalkyl; optionally substituted C2-C20 linear or branched alkenyl;
optionally substituted C6-C10 aryl or heteroaryl; COOR where R is H,
optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or
optionally substituted C6-C10 aryl, sodium, potassium or other
pharmaceutically acceptable counter-ion such as calcium, magnesium,
ammonium, tromethamine and the like; CONR'R", where Rand R" are
independently H, optionally substituted C1-C20 alkyl, optionally substituted
C2-
C20 alkenyl or optionally substituted C6-C10 aryl or where NR'R" represents a
cyclic moiety such as morpholine, piperidine, piperazine and the like; cyano;
and tetrazolyl;
[00025] R15, R16, and R17 are each independently selected from the group
consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
and fluoroalkyl; optionally substituted C2-C20 linear or branched alkenyl;
optionally substituted C6-C10 aryl or heteroaryl; COOR where R is H,
optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or
optionally substituted C6-C10 aryl, sodium, potassium or other
pharmaceutically acceptable counter-ion such as calcium, magnesium,
ammonium, tromethamine and the like; CONR'R", where Rand R" are
independently H, optionally substituted C1-C20 alkyl, optionally substituted
C2-
C20 alkenyl or optionally substituted C6-C10 aryl or where NR'R" represents a
cyclic moiety such as morpholine, piperidine, piperazine and the like; NH2; C1-
C20 alkylamino, bis(alkylamino), cycloalkylamino or cyclic amino; OH; C1-C20
alkoxy; C1-C20 alkanoyl; C1-C20 acyloxy; halo; C1-C20 alkylcarboxylamino;
cyano; nitro; SO2NR"'R"" where R"' and R"" are independently H, C1-C20 alkyl
or aryl; SO2R"' where R"' is H, C1-C20 alkyl or aryl; SO3R"' where R"' is H,
C1-
C20 alkyl or aryl; and tetrazolyl;
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[00026] X is independently selected from the group consisting of
0; N; S; S=O; SO2; or NR""', where R""' may be H or optionally substituted
C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C1-
C20 acyl, optionally substituted C1-C20 acyloxy and optionally substituted C1-
C20 alkoxycarbonyl;
[00027] Y is independently 0, S or NH;
[00028] Z is ORa where Ra is selected from the group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C10 aryl or heteroaryl; optionally
substituted
C6-C20 aroyl or heteroaroyl; optionally substituted C1-C20 alkanoyl; and
SO2R"'
where R"' is H, C1-C20 alkyl or aryl;
or
[00029] Z is NRbRc where Rb and Rc are independently* selected from the group
consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C10 aryl or heteroaryl; optionally
substituted
C3-C10 cycloalkyl or cycloalkenyl; COOZ1 where Z1 is optionally substituted
C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted
C6-
C10 aryl; optionally substituted C6-C20 aroyl or heteroaroyl; optionally
substituted C1-C20 alkanoyl; and SO2R"' where R"' is H, C1-C20 alkyl or aryl;
and wherein Rb and Rc together may be joined to form a 3-6 membered ring
such as aziridine, morpholine, piperidine, piperazine and the like;
or
[00030] Z is CRdReRf where Rd, Re and Rf are each independently selected
from the group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
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alkenyl; optionally substituted C6-C10 aryl or heteroaryl; optionally
substituted
C3-C10 cycloalkyl or cycloalkenyl; COOR where R is H, optionally substituted
C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted
C6-
C10 aryl, sodium, potassium or other pharmaceutically acceptable counter-ion
such as calcium, magnesium, ammonium, tromethamine and the like; NH2;
C1-C20 alkylamino, bis(alkylamino); cycloalkylamino or cyclic amino; OH,
optionally substituted C1-C20 alkoxy including trifluoromethoxy and the like;
optionally substituted C1-C20 alkanoyl; optionally substituted C1-C20 acyloxy;
optionally substituted C6-C20 aroyl or heteroaroyl; halo; cyano; nitro;
optionally
substituted C1-C20 alkylcarboxylamino; SO2NR"'R"" where R... and R.... are
independently H, C1-C20 alkyl or aryl; SO2R"' where R"' is H, C1-C20 alkyl or
aryl; and SO3R"' where R"' is H, C1-C20 alkyl or aryl; and wherein Rd and Re
together may be joined to form a 3-6 membered ring such as aziridine,
morpholine, piperidine, piperazine and the like; and the resulting
stereocenter
may have the R- or S- configuration; or
the grouping C(=Y)Z may represent hydrogen or R12 or may be absent.
[00031] Q is ORa where Ra is selected from the group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C10 aryl or heteroaryl; optionally
substituted
C6-C20 aroyl or heteroaroyl; optionally substituted C1-C20 alkanoyl; and
SO2R"'
where R"' is H, C1-C20 alkyl or aryl;
or
[00032] Q is NRbRc where Rb and Rc are independently selected from the group
consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C10 aryl or heteroaryl; optionally
substituted
C3-C10 cycloalkyl or cycloalkenyl; COOZ1 where Z1 is optionally substituted
C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted
C6-
C10 aryl; optionally substituted C6-C20 aroyl or heteroaroyl; optionally
substituted C1-C20 alkanoyl; and SO2R"' where R"' is H, C1-C20 alkyl or aryl;
17
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and wherein Rb and R, together may be joined to form a 3-6 membered ring
such as aziridine, morpholine, piperidine, piperazine and the like;
or
[00033] Q is SRg, SORB or SO2Rg where Rg is selected from the group
consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or floroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C1-C20 acyl; optionally substituted C1-C20
alkoxycarbonyl; C2-C20 alkoxy; optionally substituted C6-C10 aryl or
heteroaryl;
and optionally substituted C6-C10 aroyl or heteroaroyl.
[00034] Group A is optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C20 aryl, linear or branched alkylaryl,
linear
or branched alkenylaryl; optionally substituted heteroaryls like pyridine,
indole, morpholine, piperidine, piperazine, tetrazolyl and the like; COR where
R is optionally substituted C1-C20 linear or branched alkyl; optionally
substituted C2-C20 linear or branched alkenyl; optionally substituted C6-C20
aryl, linear or branched alkylaryl, linear or branched alkenylaryl; optionally
substituted heteroaryls like pyridine, indole, morpholine, piperidine,
piperazine, tetrazolyl and the like;
[00035] Group B is OH, C1-C20 alkoxy; SO2R where R may be H or linear
or branched C1-C20 alkyl.
[00036] Group Het represents a heterocyclic ring which is pyridyl,
indolyl, tetrazolyl, imidazolyl, morphonyl, piperidinyl, piperazinyl,
thiophenyl or
the like.
[00037] These compounds are useful for treating diabetes and other
diseases linked to insulin resistance, such as coronary artery disease and
peripheral vascular disease, and also for treating or inhibiting inflammation
or
inflammatory diseases such as inflammatory arthritides and collagen vascular
18
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diseases, which are caused by, for example, cytokines or inducible enzymes
such as TNF-alpha, IL-1, IL-6, iNOS and/or COX-2. The compounds are also
useful for treating or preventing other diseases mediated by cytokines, iNOS
and/or COX-2, such as cancer.
[00038] Another aspect of the invention is a method of treating diabetes
and related diseases comprising the step of administering to a subject
suffering from a diabetic or related condition a therapeutically effective
amount of a compound of Formulas I - XIII. Additionally, the invention
provides a method of treating inflammation or inflammatory diseases or
diseases mediated by cytokines, iNOS, PDE4, PDE3, p44/42 MAP kinase
and/or COX-2 by administering to a subject in need of such treatment an
effective amount of a compound according to Formulas I - XIII. Further,
pharmaceutical compositions containing a therapeutically effective amount of
one or more compounds according to Formulas I - XIII together with a
pharmaceutically or physiologically acceptable carrier, for use in the
treatments contemplated herein, are also provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[00039] FIG. 1 shows a graph of the dose-dependent increase in glucose
uptake in 3T3-L1 adipocytes treated with varying concentrations of a compound
according to the invention.
[00040] FIG. 2 shows a graph of the enhancement of glucose uptake in 3T3-L1
adipocytes treated with a compound according to the invention in addition to
varying
concentrations of insulin.
[00041] FIG. 3 shows a graph of the lowering of blood glucose levels in ob/ob
mice treated with a compound according to the invention.
[00042] FIGS. 4A and 4B show graphs of the lowering of serum triglycerides
and free fatty acid levels, respectively, in ob/ob mice treated with a
compound
according to the invention.
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[00043] FIG. 5 shows a graph of the inhibition of LPS-induced TNF-alpha
production in mouse RAW264.7 cells treated with varying concentrations of a
compound according to the invention.
[00044] FIG. 6 shows a graph of the inhibition of LPS-induced IL-1 beta
production in mouse RAW264.7 cells treated with varying concentrations of a
compound according to the invention.
[00045] FIG. 7 shows a graph of the inhibition of LPS-induced IL-6 production
in mouse RAW264.7 cells treated with varying concentrations of a compound
according to the invention.
[00046] FIG. 8 shows photos of Western blots demonstrating the inhibition of
LPS-induced iNOS and COX-2 production in mouse RAW264.7 cells treated with
varying concentrations of a compound according to the invention.
[00047] FIG. 9 shows a graph of median clinical scores over time
demonstrating improvement of collagen induced arthritis in mice using varying
concentrations of a compound according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
[00048] The invention is based on the discovery that the compounds described
herein are useful in the treatment of diabetes and other diseases linked to
insulin
resistance, such as coronary artery disease and peripheral vascular disease,
and
also for the treatment or inhibition of inflammation or inflammatory diseases
such as
inflammatory arthritides and collagen vascular diseases, which are caused by,
for
example, cytokines or inducible enzymes such as TNF-alpha, IL-1, IL-6, PDE4,
PDE3, p44/42 MAP kinase, iNOS and/or COX-2.
Definitions
[00049] As utilized herein, the following terms, unless otherwise indicated,
shall
be understood to have the following meanings:
CA 02468302 2004-05-25
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[00050] "Alkyl", alone or in combination, means a straight-chain or branched-
chain alkyl radical containing preferably 1-20 carbon atoms, more preferably 1-
10
carbon atoms, and most preferably 1-6 carbon atoms. Exemplary alkyl radicals
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-
butyl,
pentyl, isopentyl, neopentyl, iso-amyl, hexyl and the like.
[00051] "Alkenyl", alone or in combination, means a straight-chain or branched-
chain hydrocarbon radical having one or more double bonds, preferably 1-2
double
bonds and more preferably one double bond, and containing preferably 2-20
carbon
atoms, more preferably 2-10 carbon atoms, and still more preferably 2-6 carbon
atoms. Exemplary alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl,
n-
butenyl, isobutenyl, and include groups containing multiple sites of
unsaturation
such as 1,3 -butadiene andl,4-butadienyl and the like.
[00052] "Alkoxy", alone or in combination, means a radical of the type "R--O--
"
wherein R can be hydrogen, linear or branched alkyl, or linear or branched
alkenyl
as previously defined and "0" is an oxygen atom. Exemplary alkoxy radicals
include
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-
butoxy and the like.
[00053] "Alkoxycarbonyl", alone or in combination, means a radical of the type
"R--O--C(O)--" wherein "R--O--" is an alkoxy radical as previously defined and
"C(O)--" is a carbonyl radical. Exemplary alkoxycarbonyl groups include
methoxycarbonyl and ethoxycarbonyl.
[00054] "Alkylcarboxylamino" means a group RCON(R)- where R can be
independently hydrogen, linear or branched alkyl, or linear or branched
alkenyl as
previously defined.
[00055] "Alkanoyl", alone or in combination, means a radical of the type "R--
C(O)--" wherein "R" is an alkyl radical as previously defined and "--C(O)--"
is a
carbonyl radical. Exemplary alkanoyl radicals include acetyl, trifluoroacetyl,
hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl and the like.
21
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[00056] "Halo" or "halogen", alone or in combination, means chioro, bromo,
fluoro or iodo radicals.
[00057] "Aryl", alone or in combination, means an aromatic carbocyclic radical
containing about 6 to about 10 carbon atoms, which is optionally substituted
with
one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino,
azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl,
alkanoylamino,
amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino,
aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylamido, N,N-
dialkylamido,
aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, oxo and the
like.
Exemplary aryl radicals include phenyl, o-tolyl, 4-methoxyphenyl, 2-(tert-
butoxy)phenyl, 3-methyl-4-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 3-
nitrophenyl, 3-aminophenyl, 3-acetamidophenyl, 2-amino-3-(aminomethyl)phenyl,
6-
methyl-2-aminophenyl, 2-amino-3-methylphenyl, 4,6-dimethyl-2-aminophenyl, 4-
hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 4-(2-methoxyphenyl)phenyl, 2-amino-1-
naphthyl, 2-naphthyl, 1-methyl-3-amino-2-naphthyl, 2,3-diamino-1-naphthyl, 4,8-
dimethoxy-2-naphthyl and the like.
[00058] "Acyloxy" or "Acylamino" group means an oxygen or amino group,
respectively, bonded to an acyl group (RCO) where R can be hydrogen, linear or
branched alkyl, or linear or branched alkenyl.
[00059] "Alkylamido" means the group RN(H)CO- where R can be hydrogen,
linear or branched alkyl, or linear or branched alkenyl, as previously
defined.
[00060] The reference to "optionally substituted" in the definition of the
compounds throughout this disclosure is intended to include any substituent
which
does not negatively affect the activity of the compounds. Typical substitution
includes, for example, lower (C1-C6) alkyl; halogen such as fluoro, chioro and
bromo;
nitro; amino; lower alkylamino; carboxylate, lower alkyl carboxylate, hydroxy,
lower
alkoxy, sulfonamide, cyano, or the like.
[00061] The invention is directed to compounds, for example, heterocyclic
derivatives of acyl urea, thiourea, carbamate and thiocarbamate compounds,
that
22
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provide a variety of useful pharmacological effects. The compounds are useful,
for
example, in lowering blood glucose levels in hyperglycemic disorders, such as
diabetes mellitus, and for treating related disorders, such as obesity and
hyperlipidemia. Furthermore, these compounds are useful for treatment of
disorders
associated with insulin resistance, such as polycystic ovary syndrome, and for
the
.treatment of inflammation, inflammatory and immunological diseases,
particularly
those mediated by pro-inflammatory cytokines (such as TNF-alpha, IL-1 beta and
IL-
6), type 4 phosphodiesterase (PDE4), type 3 phosphodiesterase (PDE3), p44/42
mitogen activated protein (MAP) kinase, cyclooxygenase-2 (COX-2) and/or
inducible
nitric oxide synthase (NOS). In particular, the invention discloses compounds
of the
Formulas I-X111 as well as the pharmaceutically acceptable salts and solvates
thereof:
R8
R1 R9
R2R// RI
3 R4 R5 (I) R2 E./~ (II)
R3 X
R7 R4
X R11 R12 I /` R9 R12
Y
I
Rs R10 Q Y 5 R8
0 Y
R8
R1 R9
R2l// R1X
R3 R R5 (III) R2
R (IV)
R7 3 R4
R R R12 R13 R15
X R13 R12 R15 X il `/`
N N *
N N * / Y*
1s R
R5 R17R II II R,7 16
R14 Y 0 R14 Y 0
R8
R DI R$ R9 R Rs
P__ R2 * R2 (VI)
R3 R4 R5 (V) R~ RS
X R7
X R11 R12 Y
/R7 \
~i X N N' R20
1
Q 6
R6 R10 Y Ri18 R19
23
CA 02468302 2004-05-25
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R8 R8
R1 R9
R2 ( *Rs R2 HET
R// I (VII) R- (VIII)
3 R4 i R5 R3 4 I -R5
R R7
X 7 X
R11 R12 I R11 R12
Z
* X. * X Y
R/ R13 R6 * '
R6 R10 Y R10 Y Y
R8
*
R~\\ R9
R2 R11 // / I (IX) R8
R3 R4 R 5 R R9
`\YJ ~\
I R7 R2 / / / (X)
X ~~` R13 R12 R3 R4 i R5
N X Z
R6 X
R10 Y Y `A
R8
R R9
R8 R4-
R5
R R9
R2 (XI) X R7
R11
R3 R4 - .I -R5
R R12
6
B R10
R8
R1\\ R9
8211
R / i (X111)
3 R4_ i R5
R7
Z ` R11 R12 /I Y
R6
R10 Y Y
[00062] wherein the stereocenters marked with an asterisk (*) may be R- or S-;
the bond represented by a dashed line plus a solid line may be a double bond
or a
single bond, and when the bond is a double bond it may be in the E or Z
configuration, and when the bond is a single bond the resulting stereocenters
may
have the R- or S- configuration; and
24
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[00063] R1, R2, R3, R4, R5, R6 and R7 are each independently selected from the
group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl or fluoroalkyl; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C20 aryl, linear or branched alkylaryl,
linear or branched alkenylaryl; COOR where R is H, optionally substituted
C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted
C6-C10 aryl, sodium, potassium or other pharmaceutically acceptable
counter-ion such as calcium, magnesium, ammonium, tromethamine and
the like; CONR'R", where Rand R" are independently H, optionally
substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally
substituted C6-C10 aryl or where NR'R" represents a cyclic moiety such as
morpholine, piperidine, piperazine and the like; optionally substituted C1-C6
amidoalkyl; NH2; C1-C20 alkylamino, bis(alkylamino), cycloalkylamino or
cyclic amino; OH; optionally substituted C1-C20 alkoxy including
trifluoromethoxy and the like; optionally substituted C1-C20 alkanoyl;
optionally substituted C1-C20 acyloxy; halo; optionally substituted C1-C20
alkylcarboxylamino; cyano; nitro; SO2NR"'R"" where R"' and R.... are
independently H, C1-C20 alkyl or aryl; SO2R"' where R"' is H, C1-C20 alkyl
or aryl; SO3R"' where R"' is H, C1-C20 alkyl or aryl; and C4-C8 heterocycles
such as tetrazolyl, imidazolyl, pyrrolyl, pyridyl, indolyl and the like; or
when
individual aromatic rings possess adjacent substituents, these substituents
may be joined to form a ring such as a methylenedioxy or ethylenedioxy
group, and the like, including lactones and lactams;
[00064] R8 and R9 are each independently selected from the group consisting
of
H; optionally substituted C1-C20 linear or branched alkyl; optionally
substituted
C2-C20 linear or branched alkenyl; optionally substituted C6-C10 aryl or
heteroaryl; COOR where R is H, optionally substituted C1-C20 alkyl, optionally
substituted C2-C2o alkenyl or optionally substituted C6-C10 aryl, sodium,
potassium or other pharmaceutically acceptable counter-ion such as calcium,
magnesium, ammonium, tromethamine and the like; CONR'R", where Rand
CA 02468302 2004-05-25
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R" are independently H, alkoxy, optionally substituted C1-C20 alkyl,
optionally
substituted C2-C20 alkenyl, optionally substituted C3-C10 cycloalkyl or
cycloalkenyl or optionally substituted C6-C10 aryl or heteroaryl, preferably 2-
,
3- or 4-pyridyl or where NR'R" represents a cyclic moiety such as morpholine,
piperidine, hydroxypiperidine, imidazole, piperazine, methylpiperazine and the
like; NH2; C1-C20 alkylamino, bis(alkylamino), cycloalkylamino or cyclic
amino;
OH; C1-C20 alkoxy; C1-C20 alkanoyl; C1-C20 acyloxy; halo; C1-C20
alkylcarboxylamino; cyano; nitro; SO2NR"'R"" where R... and R.... are
independently H, C1-C20 alkyl or aryl; SO2R"' where R"' is H, C1-C20 alkyl or
aryl; SO3R"' where R"' is H, C1-C20 alkyl or aryl; and tetrazolyl; wherein R8
and
Rg together may be joined to form a C4-C8 heterocyclic ring, including lactone
or lactam;
[00065] R10 and R11 are each independently selected from the group consisting
of
H; optionally substituted C1-C20 linear or branched alkyl; optionally
substituted
C2-C20 linear or branched alkenyl; optionally substituted C6-C10 aryl or
heteroaryl; COOR where R is H, optionally substituted C1-C20 alkyl, optionally
substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl, sodium,
potassium or other pharmaceutically acceptable counter-ion such as calcium,
magnesium, ammonium, tromethamine and the like; CONR'R", where R' and
R" are independently H, optionally substituted C1-C20 alkyl, optionally
substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl or where
NR'R"
represents a cyclic moiety such as morpholine, piperidine, piperazine and the
like; NH2; C1-C20 alkylamino, bis(alkylamino), cycloalkylamino or cyclic
amino;
OH; C1-C20 alkoxy; C1-C20 alkanoyl; C1-C20 acyloxy; halo; C1-C20
alkylcarboxylamino; cyano; nitro; SO2NR"'R"" where R... and R..... are
independently H, C1-C20 alkyl or aryl; SO2R"' where R"' is H, C1-C20 alkyl or
aryl; SO3R"' where R"' is H, C1-C20 alkyl or aryl; and tetrazolyl; wherein R10
and R11 together may be joined to form a C4-C8 heterocyclic ring, including
lactone or lactam;
[00066] R12, R13, R18, R19 and R20 are each independently selected from the
group consisting of
26
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H; optionally substituted C1-C20 linear or branched alkyl; optionally
substituted
C2-C20 linear or branched alkenyl; optionally substituted C6-C10 aryl or
heteroaryl; COOR where R is optionally substituted C1-C20 alkyl, optionally
substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl, sodium,
potassium or other pharmaceutically acceptable counter-ion such as calcium,
magnesium, ammonium, tromethamine and the like; CONR'R", where R' and
R" are independently H, optionally substituted C1-C20 alkyl, optionally
substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl or where
NR'R"
represents a cyclic moiety such as morpholine, piperidine, piperazine and the
like; C1-C20 alkanoyl; C1-C20 alkylamido; C6-C20 aroyl or heteroaroyl; SO2R"'
where R"' is H, C1-C20 alkyl or aryl; morpholinocarbonylmethyl;
piperazinocabonylmethyl; and piperadinocabonylmethyl;
,
[00067] R12 and R13 may be absent, or R12 and R13 together may be an
optionally substituted heterocyclic ring, preferably morpholine, piperidine,
piperazine,
and N-methyl piperidine.
[00068] R14 is selected from the group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
and fluoroalkyl; optionally substituted C2-C20 linear or branched alkenyl;
optionally substituted C6-C10 aryl or heteroaryl; COOR where R is H,
optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or
optionally substituted C6-C10 aryl, sodium, potassium or other
pharmaceutically acceptable counter-ion such as calcium, magnesium,
ammonium, tromethamine and the like; CONR'R", where R' and R" are
independently H, optionally substituted C1-C20 alkyl, optionally substituted
C2-
C20 alkenyl or optionally substituted C6-C10 aryl or where NR'R" represents a
cyclic moiety such as morpholine, piperidine, piperazine and the like; cyano;
and tetrazolyl;
[00069] R15, R16, and R17 are each independently selected from the group
consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
and fluoroalkyl; optionally substituted C2-C20 linear or branched alkenyl;
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optionally substituted C6-C10 aryl or heteroaryl; COOR where R is H,
optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or
optionally substituted C6-C10 aryl, sodium, potassium or other
pharmaceutically acceptable counter-ion such as calcium, magnesium,
ammonium, tromethamine and the like; CONR'R", where Rand R" are
independently H, optionally substituted C1-C20 alkyl, optionally substituted
C2-
C20 alkenyl or optionally substituted C6-C10 aryl or where NR'R" represents a
cyclic moiety such as morpholine, piperidine, piperazine and the like; NH2; C1-
C20 alkylamino, bis(alkylamino), cycloalkylamino or cyclic amino; OH; C1-C20
alkoxy; C1-C20 alkanoyl; C1-C20 acyloxy; halo; C1-C20 alkylcarboxylamino;
cyano; nitro; SO2NR"'R'"' where R"' and R"" are independently H, C1-C20 alkyl
or aryl; SO2R"' where R"' is H, C1-C20 alkyl or aryl; SO3R"' where R"' is H,
C1-
C20 alkyl or aryl; and tetrazolyl;
[00070] X is independently selected from the group consisting of
0; N; S; S=O; SO2; or NR""', where R""' may be H or optionally substituted
C1-C20 alkyl, optionally substituted C2-C20 alkenyl, optionally substituted C1-
C20 acyl, optionally substituted C1-C20 acyloxy and optionally substituted C1-
C20 alkoxycarbonyl;
[00071] Y is independently 0, S or NH;
[00072] Z is ORa where R. is selected from the group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C10 aryl or heteroaryl; optionally
substituted
C6-C20 aroyl or heteroaroyl; optionally substituted C1-C20 alkanoyl; and
SO2R"'
where R"' is H, C1-C20 alkyl or aryl;
or
[00073] Z is NRbRc where Rb and Rc are independently selected from the group
consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
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alkenyl; optionally substituted C6-C10 aryl or heteroaryl; COOZ1 where Z1 is
optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or
optionally substituted C6-C10 aryl; optionally substituted C6-C20 aroyl or
heteroaroyl; optionally substituted C1-C20 alkanoyl; and SO2R"' where R... is
H,
C1-C20 alkyl or aryl; and wherein Rb and R,, together may be joined to form a
3-6 membered ring such as aziridine, morpholine, piperidine, piperazine and
the like;
or
[00074] Z is CRdReRf where Rd, Re and Rf are each independently selected
from the group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C10 aryl or heteroaryl; COOR where R is H,
optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or
optionally substituted C6-C10 aryl, sodium, potassium or other
pharmaceutically acceptable counter-ion such as calcium, magnesium,
ammonium, tromethamine and the like; NH2; C1-C20 alkylamino,
bis(alkylamino); cycloalkylamino or cyclic amino; OH; optionally substituted
C1-C20 alkoxy including trifluoromethoxy and the like; optionally substituted
C1-
C20 alkanoyl; optionally substituted C1-C20 acyloxy; optionally substituted C6-
C20 aroyl or heteroaroyl; halo; cyano; nitro; optionally substituted C1-C20
alkylcarboxylamino; SO2NR"'R"" where R"' and R"" are independently H, C1-
C20 alkyl or aryl; SO2R"' where R"' is H, C1-C20 alkyl or aryl; and SO3R"'
where
R"' is H, C1-C20 alkyl or aryl; and wherein Rd and Re together may be joined
to
form a 3-6 membered ring such as aziridine, morpholine, piperidine,
piperazine and the like; and the resulting stereocenter may have the R- or S-
configuration; or
the grouping -C (=Y)Z may represent hydrogen or R12 or may be absent.
[00075] Q is ORa where Ra is selected from the group consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C10 aryl or heteroaryl; optionally
substituted
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C6-C20 aroyl or heteroaroyl; optionally substituted C1-C20 alkanoyl; and
SO2R"'
where R"' is H, C1-C20 alkyl or aryl;
or
[00076] Q is NRbRr where Rb and R,, are independently selected from the group
consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or fluoroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C10 aryl or heteroaryl; optionally
substituted
C3-C10 cycloalkyl or cycloalkenyl; COOZ1 where Z1 is optionally substituted
C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted
C6-
C10 aryl; optionally substituted C6-C20 aroyl or heteroaroyl; optionally
substituted C1-C20 alkanoyl; and SO2R"' where R"' is H, C1-C20 alkyl or aryl;
and wherein Rb and Rc together may be joined to form a 3-6 membered ring
such as aziridine, morpholine, piperidine, piperazine and the like;
or
[00077] Q is SRg, SORg or SO2Rg where Rg is selected from the group
consisting of
H; optionally substituted C1-C20 linear or branched alkyl including
chloroalkyl
or floroalkyl and the like; optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C1-C20 acyl; optionally substituted C1-C20
alkoxycarbonyl; C2-C20 alkoxy; optionally substituted C6-C10 aryl or
heteroaryl;
and optionally substituted C6-C10 aroyl or heteroaroyl.
[00078] Group A is optionally substituted C2-C20 linear or branched
alkenyl; optionally substituted C6-C20 aryl, linear or branched alkylaryl,
linear
or branched alkenylaryl; optionally substituted heteroaryls like pyridine,
indole, morpholine, piperidine, piperazine, tetrazoly and the like; COR where
R is optionally substituted C1-C20 linear or branched alkyl; optionally
substituted C2-C20 linear or branched alkenyl; optionally substituted C6-C20
aryl, linear or branched alkylaryl, linear or branched alkenylaryl; optionally
substituted heteroaryls like pyridine, indole, morpholine, piperidine,
piperazine, tetrazolyl and the like;
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[00079] Group B is OH, C1-C20 alkoxy; SO2R where R may be H or linear
or branched CI-C20 alkyl.
[00080] Group Het represents a heterocyclic ring which is pyridyl,
indolyl, tetrazolyl, imidazolyl, morphonyl, piperidinyl, piperazinyl,
thiophenyl or
the like.
[00081] These compounds are useful for treating diabetes and other
diseases linked to insulin resistance, such as coronary artery disease and
peripheral vascular disease, and also for treating or inhibiting inflammation
or
inflammatory diseases such as inflammatory arthritides and collagen vascular
diseases, which are caused by, for example, cytokines or inducible enzymes
such as TNF-alpha, IL-I, IL-6, PDE4, PDE3, p44/42 MAP kinase, iNOS
and/or COX-2. The compounds are also useful for treating or preventing
other diseases mediated by cytokines, PDE4, PDE3, p44/42 MAP kinase,
iNOS and/or COX-2, such as cancer.
[00082] As indicated above, the compounds of the invention include
bonds, designated in Formulas I - XIII with a dashed line plus a solid line,
that
may be either a double bond or a single bond. When such a bond is a double
bond, it may have either the E or Z configuration. On the other hand, when
such a bond is a single bond, the resulting stereocenters may be in the R-
and/or S- configurations. Likewise, compounds of the invention with other
stereocenters, designated in Formulas I - XIII with an asterisk, may be R-
and/or S- stereoisomers. The invention contemplates racemic mixtures of
such stereoisomers as well as the individual, separated stereoisomers. The
individual stereoisomers may be obtained by the use of an optically active
resolving agent. Alternatively, a desired enantiomer may be obtained by
stereospecific synthesis using an optically pure starting material of known
configuration.
[00083] Generally, R- or S- refers to the configuration of the
stereoisomers. The determination of whether the configuration is R- (rectus)
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or S- (sinister) is based on the priority of the atoms in a compound.
Similarly,
E- or Z- configuration is used when describing compounds with double bonds
and wherein the determination is based on the priority of the atom on each
carbon of a double bond.
[00084] The following compounds are representative of the preferred
compounds according to Formula I:
[00085] 3-(3,5-Dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)-
phenoxy]-phenyl}-acrylic acid methyl ester (1);
[00086] 3-(3,5-Dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)-
phenoxy]-phenyl}-acrylic acid (6);
[00087] 3-(3,5-Dimethoxyphenyl)-2-{4-[4-(3-ethoxycarbonylamino-3-oxo-
propyl)-phenoxy]-phenyl}-acrylic acid methyl ester (8);
[00088] 2-{4-[4-(3-Benzoyloxycarbonylamino-3-oxo-propyl)-phenoxy]-
phenyl}-3-(3,5-dimethoxyphenyl)-acrylic acid methyl ester (9);
[00089] 3-(3,5-Dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)-
phenoxy]-phenyl}-propionic acid (10);
[00090] 3-(3,5-Dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidoprope nyl)-
phenoxy]-phenyl}-acrylic acid (11);
[00091] 3-(3,5-Dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)-
phenoxy]-phenyl}-acrylic acid ethyl ester (12);
[00092] 3-(3,5-Dimethoxyphenyl)-N,N-dimethyl-2-{4-[4-(3-oxo-3-
ureidopropyl)-phenoxy]-phenyl}-acrylamide (13);
[00093] 2-(4-{4-[3-(3-Cyclohexylureido)-3-oxopropyl]-phenoxy}-phenyl)-
3-(3,5-dimethoxyphenyl)-acrylic acid (14).
[00094] The following are preferred compounds according to Formula II:
[3-(4-Phenoxyphenyl)-propionyl]-urea (15);
[00095] {3-[4-(4-Methoxyphenoxy)-phenyl]-acryloyl}-urea (16).
[00096] The following are preferred compounds according to Formula III:
2-{4-[4-(3-Acetylu reidomethyl)-phenoxy]-phenyl}-3-(3, 5-d imethoxyphenyl)-
acrylic
acid methyl ester (17);
[00097] 2-{4-[4-(3-Acetylthioureidomethyl)-phenoxy]-phenyl}-3-(3,5-
dimethoxyphenyl)-acrylic acid (18).
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[00098] The following are preferred compounds according to Formula IV:
1-Acetyl-3-[4-(4-methoxyphenoxy)-benzyl]-urea (24);
[00099] Acetyl-3-[4-(3,4-d imethoxyphenoxy)-benzyl]-urea (25).
[000100] The following are more preferred compounds for their anti-
inflammatory
properties:
[000101] 3-(3,5-Dimethoxyphenyl)-N,N-dimethyl-2-{4-[4-(3-oxo-3-ureidopropyl)-
phenoxy]-phenyl}-acrylamide (13);
[000102] 2-{4-[4-(2-Carbamoylethyl)-phenoxy]-phenyl}-3-(3,5-dimethoxyphenyl)-
N,N-dimethylacrylamide (31);
[000103] 3-(4-{4-[2-(3,5-Dimethoxyphenyl)-1 -dimethylcarbamoylvinyl]-phenoxy}-
phenyl)-propionic acid ethyl ester (37);
[000104] N-{4-[2-(3,5-Dimethoxyphenyl)-1-dimethylcarbamoylvinyl]-phenyl}-3-
hydroxybenzamide (44);
[000105] 3-(3,5-Dimethoxyphenyl)-2-(4-hydroxyphenyl)-N,N-dimethylacrylamide
(49);
[000106] [3-(4-{4-[2-(3,5-Dimethoxyphenyl)-1-(piperidine-1 -carbonyl)-vinyl]-
phenoxy}-phenyl)-propiony]-urea (51);
[000107] 2-{4-[4-(3-Acetylamino-3-oxopropyl)-phenoxy]-phenyl}-3-(4-
fluorophenyl)-N, N-dimethylacrylamide (56); ,
[000108] 2-(4-{4-[2-(3,5-Dimethoxyphenyl)-1-dimethylcarbamoylvinyl]-phenoxy}-
benzyl)-malonic acid (58);
[000109] 2-(4-{4-[2-(3,5-Dimethoxyphenyl)-1-dimethylcarbamoylvinyl]-phenoxy}-
benzyl)-malonamide (59);
[000110] 3-(3,5-Dimethoxyphenyl)-N,N-dimethyl-2-[4-(pyridin-2-yloxy)-phenyl]-
acrylamide (66);
[000111] N-{4-[2-(3,5-Dimethoxyphenyl)-1-dim ethylcarbamoyl-vinyl]-phenyl}-
benzamide (67) ;
[000112] 2-{4-[4-(1-Dimethylcarbamoyl-2-pyridin-3-yl-vinyl)-phenoxy]-benzyl}-
malonamide (71);
[000113] 3-{4-[4-(2-Benzo[1,3]dioxol-5-yl-1-dimethylca rbamoyl-vinyl)-phenoxy]-
phenyl}-propionic acid ethyl ester (69);
[000114] 3-Benzo[1,3]dioxol-5-yi-2-{4-[4-(2-carbamoylethyl)-phenoxy]-phenyl}-
N,N-dimethyl-acrylamide (72);
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[000115] N,N-Dimethyl-2-{4-[4-(3-oxo-3-ureidopropyl)-phenoxy]-phenyl}-3-
pyridin-3-yl-acrylamide (73);
[000116] The following are more preferred compounds for their antidiabetic
properties:
[000117] 3-(3,5-Dimethoxyphenyl)-2-{4-[4-(3-ethoxycarbonylamino-3-oxo-
propyl)-phenoxy]-phenyl}-acrylic acid methyl ester (8);
[000118] (4-{4-[2-(3,5-Dimethoxyphenyl)-1-d imethylcarbamoyl-vinyl]-phenoxy}-
benzyl)-carbamic acid methyl ester (29);
[000119] 2-{4-[4-(2-Carbamoylethyl)-phenoxy]-phenyl}-3-(3,5-d imethoxyphenyl)-
N,N-dimethylacrylamide (31);
[000120] 3-(3,5-Dimethoxyphenyl)-N,N-dimethyl-2-{4-[4-(3-morpholin-4-yl-3-
oxopropyl)-phenoxy]-phenyl}-acrylamide (40);
[000121] [3-(4-{4-[2-(3,5-Dimethoxyphenyl)-1-(piperidine-1-carbonyl)-vinyl]-
phenoxy}-phenyl)-propionyl]-urea (51);
[000122] 2-{4-[4-(3-Acetylamino-3-oxopropyl)-phenoxy]-phenyl}-3-(4-
fluorophenyl)-N,N-dimethylacrylamide (56);
[000123] 3-(3,5-Dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)- phenoxy]-
phenyl}-N-pyridin-4-ylacrylamide (60);
[000124] N-(4-Chlorophenyl)-3-(3,5-dimethoxyphenyl)-2-{4-[4-(3-oxo-3-
ureidopropyl)-phenoxy]-phenyl}-acrylamide (61);
[000125] 3-(3,5-Dimethoxyphenyl)-N,N-dimethyl-2-(4-{4-[2-(2-morpholin-4-yl-2-
oxoethylcarbamoyl)-ethyl]-phenoxy}-phenyl)-acrylamide (63);
[000126] 3-(3,5-Dimethoxyphenyl)-N,N-dimethyl-2-(4-{4-[3-(4-methylpiperazin-1-
yl)-3-oxopropyl]-phenoxy}-phenyl)-acrylamide (64).
[000127] However, it will be appreciated that the invention also contemplates
the
provision and use of other compounds according to Formulas I - XI I I.
[000128] The compounds according to the present invention may be combined
with a physiologically acceptable carrier or vehicle to provide a
pharmaceutical
composition, such as, lyophilized powder in the form of tablet or capsule with
various
fillers and binders. Similarly, the compounds may be coadministered with other
agents. Co-administration shall mean the administration of at least two agents
to a
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subject so as to provide the beneficial effects of the combination of both
agents. For
example, the agents may be administered simultaneously or sequentially over a
period of time. The effective dosage of a compound in the composition can be
widely
varied as selected by those of ordinary skill in the art and may be
empirically
determined. Moreover, the compounds of the present invention can be used alone
or in combination with one or more additional agents depending on the
indication
and the desired therapeutic effect. For example, in the case of diabetes,
insulin
resistance and associated conditions or complications, including obesity and
hyperlipidemia, such additional agent(s) may be selected from the group
consisting
of: insulin or an insulin mimetic, a sulfonylurea (such as acetohexamide,
chiorpropamide, glimepiride, glipizide, glyburide, tolbutamide and the like)
or other
insulin secretagogue (such as nateglinide, repaglinide and the like), a
thiazolidinedione (such as pioglitazone, rosiglitazone and the like) or other
peroxisome proliferator-activated receptor (PPAR)-gamma agonist, a fibrate
(such as
bezafibrate, clofibrate, fenofibrate, gemfibrozol and the like) or other PPAR-
alpha
agonist, a PPAR-delta agonist, a biguanide (such as metformin), a statin (such
as
fluvastatin, lovastatin, pravastatin, simvastatin and the like) or other
hydroxymethylglutaryl (HMG) CoA reductase inhibitor, an alpha-glucosidase
inhibitor
(such as acarbose, miglitol, voglibose and the like), a bile acid-binding
resin (such as
cholestyramine, celestipol and the like), a high density lipoprotein (HDL)-
lowering
agent such as apolipoprotein A-I (apoAl), niacin and the like, probucol and
nicotinic
acid. In the case of inflammation, inflammatory diseases, autoimmune disease
and
other such cytokine mediated disorders, the additional agent(s) may be
selected
from the group consisting of: a nonsteroidal anti-inflammatory drug (NSAID)
(such as
diclofenac, diflunisal, ibuprofen, naproxen and the like), a cyclooxygenase-2
inhibitor
(such as celecoxib, rofecoxib and the like), a corticosteroid (such as
prednisone,
methylprednisone and the like) or other immunosuppressive agent (such as
methotrexate, leflunomide, cyclophosphamide, azathioprine and the like), a
disease-
modifying antirheumatic drug (DMARD) (such as injectable gold, penicilliamine,
hydroxychloroquine, sulfasalazine and the like), a TNF-alpha inhibitor (such
as
etanercept, infliximab and the like), other cytokine inhibitor (such as
soluble cytokine
receptor, anti-cytokine antibody and the like), other immune modulating agent
(such
as cyclosporin, tacrolimus, rapamycin and the like) and a narcotic agent (such
as
hydrocodone, morphine, codeine, tramadol and the like). The combination
therapy
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contemplated by the invention includes, for example, administration of the
inventive
compound and additional agent(s) in a single pharmaceutical formulation as
well as
administration of the inventive compound and additional agent(s) in separate
pharmaceutical formulations.
[000129] Another aspect of the invention is a method of treating diabetes and
related diseases comprising the step of administering to a subject suffering
from a
diabetic or related condition a therapeutically effective amount of a compound
of
Formulas I -X111. Additionally, the invention provides a method of treating
inflammation or inflammatory diseases or diseases mediated by cytokines, PDE4,
PDE3, p44/42 MAP kinase, iNOS and/or COX-2 by administering to a subject in
need of such treatment an effective amount of a compound according to Formulas
I -
XIII. Further, pharmaceutical compositions containing a therapeutically
effective
amount of one or more compounds according to Formulas I - XIII together with a
pharmaceutically or physiologically acceptable carrier, for use in the
treatments
contemplated herein, are also provided.
[000130] The compounds of the invention are useful for the treatment of
diabetes, characterized by the presence of elevated blood glucose levels, that
is,
hyperglycemic disorders such as diabetes mellitus, including both type 1 and 2
diabetes, as well as other hyperglycemic related disorders such as obesity,
increased cholesterol, hyperlipidemia such as hypertriglyceridemia, kidney
related
disorders and the like. The compounds are also useful for the treatment of
disorders
linked to insulin resistance and/or hyperinsulinemia, which include, in
addition to
diabetes, hyperandrogenic conditions such as polycystic ovary syndrome (Ibanez
et
al., J. Clin Endocrinol Metab, 85:3526-30, 2000; Taylor A.E., Obstet Gynecol
Clin
North Am, 27:583-95, 2000), coronary artery disease such as atherosclerosis
and
vascular restenosis, and peripheral vascular disease. Additionally, the
compounds
of the present invention are also useful for the treatment of inflammation and
immunological diseases that include those mediated by signaling pathways
linked to
pro-inflammatory cytokines, such as rheumatoid arthritis, ankylosing
spondylitis,
multiple sclerosis, inflammatory bowel disease, psoriasis, and contact and
atopic
dermatitis.
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[000131] By "treatment", it is meant that the compounds of the invention are
administered in an amount which is at least sufficient to, for example, reduce
the
blood glucose level in a patient suffering from a hyperglycemic disorder or to
inhibit
or prevent the development of pro-inflammatory cytokine or like responses in a
patient suffering from inflammatory or immunological disease. In the case of
diabetes, the compound is usually administered in the amount sufficient to
reduce
the blood glucose level, free fatty acid level, triglyceride level and/or the
like level
sufficient to improve or alleviate the symptoms and/or reduce the risk of
complications associated with elevated levels of these parameters. A variety
of
subjects may be treated with the present compounds to reduce blood glucose
levels
such as livestock, wild or rare animals, pets, as well as humans. The
compounds
may be administered to a subject suffering from hyperglycemic disorder using
any
convenient administration technique, including intravenous, intradermal,
intramuscular, subcutaneous, oral and the like. However, oral daily dosage is
preferred. The dosage delivered to the host will necessarily depend upon the
route
by which the compound is delivered, but generally ranges from about 0.1 to
about
500 mg/kg human body weight or typically from about 0.1 to about 50
mg/kg human body weight. Generally similar types of administration and dosages
are also contemplated when the compounds of the invention are used to treat
inflammatory or immunological disease.
[000132] The compounds of this invention may be used in formulations using
acceptable pharmaceutical vehicles for enteral, or parenteral, administration,
such
as, for example, water, alcohol, gelatin, gum arabic, lactose, amylase,
magnesium
stearate, talc, vegetable oils, polyalkylene glycol, and the like. The
compounds can
be formulated in solid form, e.g., as tablets, capsules, drages and
suppositories, or
in the liquid form, e.g., solutions, suspensions and emulsions. The
preparations
may also be delivered transdermally or by topical application.
[000133] The syntheses of representative compounds according to the present
invention are illustrated in Schemes I and II. Further examples illustrating
the
syntheses of additional compounds according to the present invention are also
given below.
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SCHEME I
HOOC MeO COON
F
Me0 I CHO + Ac,O
I I ~' CHO
/ Triethyamine OMe KtBuO
OMe OH OH
2
MeO COOH MeO COOH
Me (Et0)2P(0)CH2000Et Me
0 NaH
3 CHO 4 OEt
0
MeO COOH MeO COOH
Raney Ni Me I NaOEt/Urea O Me
_
0 0
OEt NyNH2
0 6 0 0
MeO I COOMe
(CH3)2SO4 OMe
3
0
NyNH2
0 0
[000134] Scheme 1 details the synthesis of compounds 1-6. Scheme 2 details
the synthesis of 17. It is to be understood that the Schemes '1 and 2 are
representative schemes and are not intended to be limited to the compounds
disclosed.
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WO 03/048108 PCT/US02/38150
SCHEME II
MeO I \ \ COOMe MeO COOMe
OMe NaBH4 OMe PBr3
O\ ^
I//` I/ OH
CHO
21 22
MeO I \ \ COOMe MeO COOMe
/ O O I
OMe )LH)LNH2 OMe
O O
Br I NYN~
O O
23 17
[000135] The following examples are provided to further illustrate the present
invention and are not intended to limit the invention in any way.
EXAMPLE 1
Synthesis of 3-(3,5-dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)-phenoxy]-
phenyl}-acrylic acid methyl ester (1) [see Scheme I]
[000136] Step 1: Synthesis of 3-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-
acrylic acid (2). To a mixture of 3,5-dimethoxybenzaldehyde (120 g, 0.72 mol)
and
p-hydroxyphenyl acetic acid (110 g, 0.72 mol) was added acetic anhydride (240
mL)
and triethylamine (161 mL, 1.6 equiv.). This non-homogeneous mixture on
heating
becomes homogeneous at -70 C. After being stirred at 130 C for 4 hr, the
mixture
was cooled to room temperature. HCI (15%, 500 mL) was added to the reaction
mixture slowly in 30min keeping temperature below 5-10 C. The solid was
dissolved
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in 3N aqueous NaOH (1.2 L) and stirred for 0.5 hr. The filtrate was acidified,
maintaining a temperature at 25-30 C, with conc. HCI (-700 ml-) to pH 1. The
precipitated product was filtered and washed with water to give crude product
(-300
g, wet cake). The crude product was dissolved by heating in ethanol and
recrystallized by adding equal volume of water. The product was dried
overnight in a
vacuum oven at 40 C. Yield: 161 g, 74%. Analysis: 1HNMR (DMSO-d6): 512.48 (br,
1H), 9.42 (s, 1H), 7.59 (s, 1H), 6.95 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz,
2H), 6.35
(t, J=2.2 Hz, 1 H), 6.27 (d, J=2.2 Hz, 2H), 3.56 (s, 6H).
[000137] (b) Step 2: Synthesis of 3-(3,5-dimethoxyphenyl)-2-(4-(4-
formylphenoxy)-phenyll-acrylic acid (3). 2 (64.0 g, 0.21 mol) was dissolved in
320
mL anhydrous DMSO under nitrogen, and potassium tert-butoxide (48.0 g, 0.43
mol) was added in lots. When the solution became homogenous, p-
fluorobenzaldehyde (27 mL, 0.22 mol) was added and the mixture was heated at
100 C for 5 hr. After cooling to room temperature, the solution was poured
into 1 L
water and extracted with ether (2 x 500 mL). The aqueous phase was acidified
with
5% HCI to - pH 4 and the precipitated product was collected by suction
filtration.
The wet filter cake was dissolved in a minimum of boiling acetone and
recrystallized
with addition of water. After chilling to 4 C for 3 hr, the solid was
collected by
vacuum filtration. The product was dried overnight at 40 C in a vacuum oven.
Yield:
62 g, 73%. Analysis: 1HNMR (DMSO-d6): 512.87 (s, 1 H), 9.94 (s, 1 H), 7.95 (d,
J=8.2
Hz, 2H), 7.72 (s, 1 H), 7.27 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.15
(d, J=8.2
Hz, 2H), 6.42 (t, J=1.6 Hz, 1H), 6.29 (d, J=2.0 Hz, 2H), 3.60 (s, 6H).
[000138] (c) Step 3: Synthesis of 3-(3,5-dimethoxyphenyl)-2-{4-f4-(2-
ethoxycarbonyl-vinyl)_phenoxyl-phenyl}-acrylic acid (4).
Triethylphosphonoacetate
(7.14 mL, 36 mmol) was added to a suspension of NaH (60% in mineral oil, 2.64
g,
66 mmol) in anhydrous THE (100 mL) at 0 C under argon, and the mixture was
stirred for 15 min. A solution of aldehyde 3, (12.12 g, 30 mmol) in THE (100
mL) was
added and the mixture was stirred for 1 h. The mixture was quenched with
saturated
aqueous ammonium chloride solution (5 mL), diluted with ethyl acetate (300 mL)
and acidified with 5% aqueous HCI to pH 1. The ethyl acetate layer was
separated,
and the aqueous layer was extracted with ethyl acetate (100 mL). The combined
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organic layers were washed with brine, dried over anhydrous MgSO4i filtered
and
concentrated. The crude product was purified by recrystallization from a
mixture of
chloroform/methanol. The compound was suspended in hot methanol (200 mL) and
a minimum volume (-30-40 mL) of chloroform was added to yield 4. Yield: 12.39
g,
87.1%. Analysis: 1HNMR (DMSO-d6): 57.77 (d, J=8.4 Hz, 2H), 7.69 (s.1H), 7.65
(d,
J=16 Hz, 2H), 7.23 (d, 8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 7.01 (d,.J=8.4 Hz,
2H),
6.57 (d, J=16 Hz, 2H), 6.41 (t, J=2 Hz, 1H), 6.28 (d, J=1.6 Hz, 2H), 4.18 (q,
J=7.2
Hz, 2H), 3.59 (s, 6H), 1.26 (t, J= 7.2 Hz, 3H).
[000139] (d) Step 4: Synthesis of 3-(3,5-dimethoxyphenyl)-2-{4-f4-(2-
TM
ethoxycarbonyl-ethyl)-phenoxyl-phenyl}-acrylic acid (5). To a suspension of
Raney
TM
Ni (10.0 g, Raney 2800 nickel in water active catalyst) in ethanol-dioxane
(2:1, 50
mL) was added a solution of 4 (13.0 g, 27.4 mmol) in a mixture of ethanol-
dioxane
(2:1, 400 mL), and the resulting mixture was stirred vigorously for 15 hr
under
hydrogen at atmospheric pressure. Completion of the reaction was monitored by
HPLC (time varies with the speed of stirring). Catalyst was filtered through a
bed of
Celite diatomaceous earth, the bed was washed with ethanol-dioxane (2:1, 200
mL), and solvent was evaporated. The solid obtained was dissolved in hot
toluene
(150 mL) and cooled at 4 C overnight. Solid separated was filtered and washed
with
ice-cold toluene (50 mL) and dried at 55 C for 6 hr. Yield: 11.61 g, 90.5%.
Analysis:
1 HNMR (DMSO-de): 512.75 (s, 1 H), 7.68 (s, 1 H), 7.26 (d, J=8.4 Hz, 2H), 7.17
(d,
J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.39 (t, J=2.0
Hz, 1 H),
6.27 (d, J=1.6 Hz, 2H), 4.06 (q, J=7.2 Hz, 2H), 3.57 (s, 6H), 2.84 (t, J=8 Hz,
2H),
2.60 (t, J=8 Hz, 2H), 1.15 (t, J=8 Hz, 3H).
[000140] (e) Step 5: Synthesis of 3-(3,5-dimethoxyphenyl)-27{4-f4-(3-oxo-3-
ureido-propyl)-phenoxyl-pheny}acrylic acid (6). To a solution of sodium
ethoxide in
ethanol (21% w/w, 65 mL) under argon was added ethyl acetate (3.12 mL), then
refiuxed for 20 min. Urea (18 g, 0.3 mol) was dissolved in the above-mentioned
sodium ethoxide in ethanol solution at 75 C. To this solution was added 5 (13
g,
0.027 mol) in one lot. After all dissolved, the resulting mixture was stirred
at 75 C for
another 5 min, cooled quickly in 15 min to 15-20 C, TFA (13 mL) added, and
then
adjusted to pH 4-5 with 5% HCL After stirring at room temperature for 1 hr,
the
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mixture was slowly added to water (520 mL). The solid separated was filtered
and
refluxed in 10% isopropanol in ethyl acetate (150 ml-) for 20 min. The mixture
was
allowed to cool to room temperature, then incubated overnight at 4 C. The
mixture
was filtered and solid was dried. Yield: 8.5 g. Analysis: 1HNMR (DMSO-d6):
812.35
(br, 1 H), 10.20 (s, 1 H), 7.75 (br, 1 H), 7.68 (s, 1 H), 7.26 (d, J=8.4 Hz,
2H), 7.17 (d,
J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.39 (t,.J=2.4
Hz, 1 H),
6.27 (d, J=2.4 Hz, 2H), 3.57 (s, 6H), 2.81 (t, J=7.2 Hz, 2H), 2.54 (t, J=7.2
Hz, 2H).
[000141] (f) Step 6: Synthesis of 3-(3,5-dimethoxyphenyl)-2-14-[4-(3-oxo-3-
ureido-propyl)-phenoxyl-phenyl}-acrylic acid methyl ester (1). To a stirred
solution of
6 (5 g, 0.01 mol) in dry DMF (35 ml-) under argon was added K2CO3 (1.38 g,
0.01
mol). To this, dimethyl sulfate (3.8 g, 0.03 mol) was added and stirred at
room
temperature for 30 min. The reaction mixture was acidified with 5% aqueous HCI
and extracted with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate and evaporated. The oily residue was dissolved in
hexane/ethyl
acetate (2:3, 30 ml-) with stirring, and incubated overnight at 4 C for
crystallization.
The solid was collected by vacuum filtration and dried. Yield: 3.3 g, 65%.
Analysis:
1HNMR (DMSO-d6): 510.17 (br, 1H), 7.72 (br, 2H), 7.72 (s, 1H), 7.25 (d, J=8.4
Hz,
2H), 7.18 (d, J=6.8 Hz, 2H), 7.21 (s overlapped, 1 H), 7.01 (d, J=6.8 Hz, 2H),
6.96 (d,
J=8.4 Hz, 2H), 6.41 (t, J=2.2 Hz, 1H), 6.28 (d, J=2.2 Hz, 2H), 3.73 (s, 3H),
3.57 (s,
6H), 2.84 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H).
EXAMPLE 2
Synthesis of 3-(3,5-dimethoxyphenyl)-2-{4-[4-(3-ethoxycarbonylamino-3-oxo-
propyl)-
phenoxy]-phenyl}-acrylic acid methyl ester (8)
[000142] 2-{4-[4-(2-Carbamoyl-ethyl)-phenoxy]-phenyl}-3-(3,5-dimethoxyphenyl)-
acrylic acid methyl ester (7) was obtained as a byproduct in the synthesis of
3-(3,5-
d imethoxy-phenyl)-2-{4-[4-(2,4-dioxoth iazolidin-5-ylmethyl)-phenoxy]-phenyl}-
acrylic
acid methyl ester, performed essentially as shown in PCT/US99/09982 (WO
99/58127). 7 (460 mg, 1.0 mmol) was taken up in dry THE (6 ml-) and cooled to -
78 C. To this solution, lithium diisopropyl amide (LDA) (2M, 0.55 mL, 1.1
mmol) was
added and stirred for 10 min. Ethyl chloroformate (0.11 mL, 1.2 mmol) was
added
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and stirred overnight at room temperature. The reaction was quenched with
saturated aqueous ammonium chloride solution and ethyl acetate (50 ml-) was
added. The organic layer was washed with brine (2 x 20 mL), dried on anhydrous
magnesium sulfate and evaporated under reduced pressure. The crude product
was purified by silica gel chromatography and eluted with hexane-ethyl acetate
(7:3). Yield: 264 mg, 49.8%.
MeO COOMe
MeO I \ \ COOMe
OMe
OMe
\ NyOEt
O /
NH2 'I
O O
O
7 8
[000143] Analysis: 1 HNMR (DMSO-d6): 810.52 (s, 1 H), 7.70 (s, 1 H), 7.24 (d,
J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4
Hz,
2H), 6.40 (t, J=2.1 Hz, 1 H), 6.27 (d, J=2.1 Hz, 2H), 4.07 (q, J=7.2 Hz, 2H),
3.70 (s,
3H), 3.56 (s, 6H), 2.76 (m, 4H), 1.19 (t, J=7.2 Hz, 3H).
EXAMPLE 3
Synthesis of 2-{4-[4-(3-benzoyloxycarbonylamin o-3-oxo-propyl)-phenoxy]-
phenyl}-3-
(3,5-dimethoxyphenyl)-acrylic acid methyl ester (9)
[000144] 7 (1.38, 3.0 mmol) prepared as in Example 2 was taken up in dry THE
(20 mL) and cooled to -78 C. To this solution, LDA (2M, 1.8 mL, 3.6 mmol) was
added and stirred for 10 min. Benzyl chloroformate (0.67 g, 39 mmol) was added
and stirred overnight at room temperature. The reaction was quenched with
saturated aqueous ammonium chloride solution, and ethyl acetate (150 mL) was
added. The organic layer was washed with brine (2 x 25 mL), dried on anhydrous
magnesium sulfate and evaporated under reduced pressure. The crude product was
purified by silica gel chromatography and eluted with hexane-ethyl acetate
(7:3).
Yield: 0.68g, 37.3%.
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MeO COOMe
MeO COOMe
OMe
OMe
O \ N
NH2 I / yOBz
O / O O
O
7 9
[000145] Analysis: 1HNMR (DMSO-d6): 510.65 (s, 1 H), 7.72 (s, 1 H), 7.38-7.39
(m, 5H), 7.25 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz,
2H), 6.94
(d, J=8.4 Hz, 2H), 6.41 (t, J=2.0 Hz, 1H), 6.28 (d, J=2.0 Hz, 2H), 5.12 (s,
2H), 3.72
(s, 3H), 3.57 (s, 6H), 2.79 (m, 4H).
EXAMPLE 4
Synthesis of 3-(3,5-d imethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)-phenoxy]-
phenyl}-propionic acid (10)
[000146] 3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2-ethoxycarbonylvinyl)-phenoxy]-
phenyl}-acrylic acid (4, 2.37 g, 5.0 mmol) was dissolved in a mixture of
ethanol-
dioxane (2:1, 150 mL), and palladium charcoal (10%, 500 mg) was added. The
mixture was stirred under hydrogen for 15 hr. Catalyst was then removed by
filtration, and solvent was evaporated under reduced pressure to yield 3-(3,5-
dimethoxy-phenyl)-2-{4-[4-(2-ethoxycarbonylethyl)-phenoxy]-phenyl}-propionic
acid
(18) quantitatively. Urea (0.21 g, 3.58 mmol) was dissolved in sodium ethoxide
(2.7
M, 2.2 mL, 5.92 mmol) at 80 C under argon, and to this a solution of 18 (1.13
g,
2.37 mmol) in anhydrous ethanol (15 mL) was added and heated at this
temperature
for 13 hr. Ethanol was evaporated under reduced pressure, water (20 mL) was
added, acidified to pH 1 by 5% aqueous HCI and extracted with ethyl acetate
(50
mL). The organic layer was washed with water (2 x 25 mL), brine (2 x 20 mL),
dried
over anhydrous magnesium sulfate and evaporated. The crude product was
purified
by silica gel chromatography and eluted with hexane-ethyl acetate (3:7)
containing
acetic acid (I%), followed by recrystallization from ethanol. Yield: 256 mg,
22.8%.
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Me0 I COOH Me0 COOH
OMe OMe
OEt H
NuNH2
0 O 0
18 10
[000147] Analysis: 1 HNMR (DMSO-d6): 812.37 (s, 1 H), 10.17 (s, 1 H), 7.74
(br,
1 H), 7.31 (d, J=9.2 Hz, 2H), 7.21 (d, J=9.2 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H),
6.90 (d,
J=8.4 Hz, 2H), 6.33 (d, J=2.0 Hz, 2H), 6.29 (t, J=2.0 Hz, 1H), 3.83 (t, J=8.0
Hz, 1H),
3.68 (s, 6H), 3.19 (dd, J= 14.4 & 8.4 Hz, 1 H), 2.88-2.80 (m, 3H), 2.59 (t,
J=8.0 Hz,
2H).
EXAMPLE 5
Synthesis of 3-(3,5-d imethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropenyl)-
phenoxy]-
phenyl}-acrylic acid (11)
[000148] Urea (0.21 g, 3.58 mmol) was dissolved in sodium ethoxide (2.7 M, 2.2
mL, 5.92 mmol) at 80 C under argon, and to this a solution of 4 (1.14 g, 2.37
mmol)
in anhydrous ethanol (15 mL) was added and heated at this temperature for 13
hr.
Ethanol was evaporated under reduced pressure, water (20 mL) was added,
acidified to pH 1 by 5% aqueous HCI and extracted with ethyl acetate (50 mL).
The
organic layer was washed with water (2 x 25 mL), brine (2 x 20 mL), dried over
anhydrous magnesium sulfate and evaporated. The crude product was purified by
silica gel chromatography and eluted with hexane-ethyl acetate (3:7)
containing
acetic acid (1 %), followed by recrystallization from ethanol. Yield: 167 mg,
14.4%.
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MeO I \ \ COOH MeO I \ \ COON
We We 30
0 CyOEt O
OyyNH2
0 0 0
4 11
[000149] Analysis: 1 HNMR (DMSO-d6): 612.51 (br, 1 H), 10.30 (s, 1 H), 7.92
(br,
1 H), 7.77 (d, J=9.2 Hz, 2H), 7.68 (s, 1 H), 7.65 (d, J=16.0 Hz, 1 H), 7.30
(br, 1 H), 7.22
(d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 7.03 (d, J=9.2 Hz, 2H), 6.73 (d,
J=16.0 Hz,
1 H), 6.40 (t, J=2.0 Hz, 1 H), 6.28 (d, J=2 Hz, 2H), 3.59 (s, 6H).
EXAMPLE 6
Synthesis of 3-(3,5-d imethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)-phenoxy]-
phenyl}-acrylic acid ethyl ester (12)
[000150] To a stirred solution of 6 (0.40 g, 0.81 mmol) in dry DMSO (3 ml-)
was
added K2C03 (0.14 g, 0.98 mmol). To this, diethyl sulfate (0.115 g, 0.91 mmol)
was
added and stirred at room temperature for 30 min. The reaction mixture was
poured
into water (30 mL) and extracted with ethyl acetate. The organic layer was
dried over
anhydrous magnesium sulfate and evaporated. The crude product was purified by
column chromatography over silica gel and eluted with hexanes-ethyl acetate
(3:1).
Yield: 0.39 g, 92.2%.
0
MeO I \ \ COON MeO I \ \ 0~~
\ I OMe \
We
O 0
/ NuNH2 I / NuNHZ
6 O y NH2
12 O y NH2
[000151] Analysis: 1 HNMR (DMSO-d6): 510.17 (s, 1 H), 7.74 (br, 1 H), 7.70 (s,
1 H), 7.25 (d, J=8.4 Hz, 2H), 7.24 (overlapped, 1 H), 7.18 (d, J=8.4 Hz, 2H),
7.00 (d,
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J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.41 (t, J=1.6 Hz, 1 H), 6.28 (d, J=1.6
Hz, 2H),
.4.19 (q, J=8.0 Hz, 2H), 3.57 (s, 6H), 2.83 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.2
Hz, 2H),
1.25 (t, J=8.0 Hz, 3H).
EXAMPLE 7
Synthesis of 3-(3,5-d imethoxyphenyl)-N,N-dimethyl-2-{4-[4-(3-oxo-3-ureido-
propyl)-
phenoxy]-phenyl}-acrylamide (13)
[000152] To a stirred solution of 6 (1.68 g, 3.43 mmol) in dry DMF (30 mL) was
added carbonyldiimidazole (1.1 g, 6.86 mmol), and the reaction mixture was
heated
to 60 C for 1 hr. The reaction mixture was cooled to 0 C and a solution of
dimethylamine in THE (2 M, 8.6 mL, 17.2 mmol) was added and stirred for 18 hr.
The reaction mixture was diluted with water (100 mL) and extracted with ethyl
acetate (100 mL). The organic phase was then rinsed sequentially with 10%
citric
acid (2 X 50mL), water (2 X 50mL), and brine (20 mL), then dried over
anhydrous
magnesium sulfate and evaporated. The crude product was purified by silica gel
chromatography using hexane-ethyl acetate (3:7) containing 1 % acetic acid.
Yield:
1.77 g, 100%.
O
MeO I \ \ COOH MeO I N,Me
Me
OMe H
NuNH2 H N NH
'I 2
O O O O
6 13
[000153] Analysis: 1 HNMR (DMSO-d6): 810.17 (br, 1H), 7.74 (br, 1H), 7.27 (d,
J=9.2 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.23 (br, 1H), 6.79 (d, J=9.2 Hz, 2H),
6.93 (d,
J=8.8 Hz, 2H), 6.56 (s, 1 H), 6.34 (t, J=2 Hz, 1 H), 6.29 (s, 1 H), 6.28 (s, 1
H), 3.58 (s,
6H), 3.05 (br, 3H), 2.90 (br, 3H), 2.82 (t, J=7.2 Hz, J=8.0 Hz, 2H), 2.59 (t,
J=8.0 Hz,
J=7.2 Hz, 2H).
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EXAMPLE 8
Synthesis of 2-(4-{4-[3-(3-cyclohexylureido)-3-oxopropyl]-phenoxy}-phenyl)-3-
(3,5-
dimethoxyphenyl)-acrylic acid (14)
[000154] Cyclohexylurea (1.3 g, 9 mmol) was dissolved in sodium ethoxide in
ethanol (21 % w/w, 3 mL) at 75 C. To this solution 5 was added (0.5 g, 1.1
mmol) in.
one lot. The resulting mixture was stirred at 75 C for 5 min, then cooled
quickly to
40-50 C. TFA (0.5 mL) was added and then 5% aqueous HCI (1 N, 0.6 mL). After
stirring at room temperature for 1 hr, the mixture was left overnight at 4 C.
The solid
separated was filtered and refluxed in ethyl acetate (4 ml-) for 20 min. The
mixture
was allowed to cool to room temperature, filtered and the crude product was
purified
by silica gel chromatography using hexane-ethyl acetate (1:1). Yield: 0.27 g,
45%.
MeO COOH MeO COOH
OMe OMe
O \ O
H H
H
/ OEt / H N y N_O
O O O
14
[000155] Analysis: 1HNMR (DMSO-d6): 512.74 (s, 1 H), 10.30 (s, 1 H), 8.32 (br,
1 H), 7.67 (s, 1 H), 7.24 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.90 (d,
J=8.4 Hz,
2H), 6.94 (d, J=8.4 Hz, 2H), 6.34 (t, J=2.4 Hz, 1 H), 6.27 (d, J=2.4 Hz, 2H),
3.58 (s,
6H), 2.83 (t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.78 (m, 2H), 1.61 (m,
2H), 1.51
(m, 1 H), 1.32-1.16 (m, 5H).
EXAMPLE 9
Synthesis of [3-(4-phenoxyphenyl)-propionyl]-urea (15)
[000156] 4-Phenoxy-benzaldehyde was reacted with triethyl phosphonoacetate
to yield 3-(4-phenoxyphenyl)-acrylic acid ethyl ester, which was then reduced
with
H2 using palladium-on-carbon catalyst to yield 3-(4-phenoxyphenyl)-propionic
acid
methyl ester (19). Urea (1.20 g, 19.99 mmol) was dissolved in sodium ethoxide
(2
M, 6.7 mL, 13.4 mmol) at 80 C under argon, and to this a solution of 19 (1.71
g,
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6.67 mmol) in anhydrous ethanol (8 ml-) was added and heated at this
temperature
for 1 hr. Ethanol was evaporated under reduced pressure, water (20 ml-) was
added, acidified to pH 1 by 5% aqueous HCI and extracted with ethyl acetate
(50
mL). The organic layer was washed with water (2 x 25 mL), brine (2 x 20 mL),
dried
over anhydrous magnesium sulfate and evaporated. The crude product was
purified
by silica gel chromatography and eluted with hexane-ethyl acetate (1:1)
containing
acetic acid (1%) followed by recrystallization from ethanol. Yield: 113 mg,
5.6%.
P P
O 0
OMe N NH2 y O O O
19 15
[000157] Analysis: 1 HNMR (DMSO-d6): 810.18 (s, 1 H), 7.74 (br, 1 H), 7.38 (d,
J=7.6 Hz, 1 H), 7.36 (d, J=7.6 Hz, 1 H), 7.22 (d, J=8.8 Hz, 2H), 7.17 (t,
J=7.2 Hz, 1 H),
6.97 (d, J=7.2 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 2.59
(t, J=7.2
Hz, 2H).
EXAMPLE 10
Synthesis of 2-{4-[4-(3-acetylureidomethyl)-phenoxy]-phenyl}-3-(3,5-
dimethoxyphenyl)-acrylic acid methyl ester (17) [see Scheme II]
[000158] Step 1: Synthesis of 3-(3,5-dimethoxyphenyl)-2-f4-(4-hydroxymethyl-
phenoxy)-phenyll-acrylic acid methyl ester (22). 3-(3,5-Dimethoxy-phenyl)-2-[4-
(4-
formylphenoxy)-phenyl]-acrylic acid methyl ester (21) was first prepared by
converting the corresponding free acid (3) to the methyl ester by addition of
DMF,
K2C03 and dimethyl sulfate in a manner analogous to Example 1(f) above. Sodium
borohydride (0.125 g, 3.3 mmol) was added to a suspension of 21 (1.26 g, 3
mmol)
in ethanol (20 ml-) and stirred at room temperature for 1 hr. The reaction was
quenched with 5% aqueous HCI, and ethanol was evaporated under reduced
pressure. Residue was taken up in ethyl acetate (50 ml-) and washed with brine
(2 x
49
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20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude
product was purified by silica gel chromatography and eluted with hexanes-
ethyl
acetate (1:1). Yield: 1.14 g, 95.0%. Analysis: 1HNMR (DMSO-d6): 87.72 (s, 1
H), 7.36
(d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.99 (d,
J=8.4 Hz,
2H), 6.41 (t, J=2.4 Hz, 1 H), 6.28 (d, J=2.4 Hz, 2H), 5.18 (t, J=6.4 Hz, 1 H),
4.49 (d,
J=4.8 Hz, 2H), 3.72 (s, 3H), 3.57 (s, 6H).
[000159] (b) Step 2: Synthesis of 2-[4-(4-b rom om ethyl p henoxy)-phenyll-3-
(3,5-
dimethoxyphenyl)-acrylic acid methyl ester (23). To a stirred solution of 22
(1.05 g,
2.5 mmol) in dichloromethane (10 mL) at 10 C, PBr3 (1 M, 3.75 mL) was added
and
stirred for 1 hr. The reaction was quenched with saturated aqueous sodium
bicarbonate solution. The organic layer was washed with water (20 mL), brine
(2 x
30 mL), dried over anhydrous magnesium sulfate and evaporated. The crude
product was purified by silica gel chromatography and eluted with hexanes-
ethyl
acetate (4:1). Yield: 0.85 g, 70.4%. Analysis: 1 HNMR (DMSO-d6): 87.73 (s,
1H), 7.49
(d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 7.00 (d,
J=8.4 Hz,
2H), 6.42 (t, J=2.4 Hz, 1 H), 6.28 (d, J=2.4 Hz, 2H), 4.74 (s, 2H), 3.73 (s,
3H), 3.58
(s, 6H).
[000160] (c) Synthesis of 2-44-[4-(3-acetylureidomethyl)-phenoxyl-phenyl}-3-
(3,5-dimethoxyphenyl)-acrylic acid methyl ester (17). To a stirred suspension
of
sodium hydride (60% in oil, 0.11 g, 2.8 mmol) in dimethylformamide (2 mL), N-
acylurea (0.11 g, 1.12 mmol) was added and stirred at room temperature for 30
min.
A solution of 23 (0.54 g, 1.12 mmol) in dimethylformamide (3 ml-) was added
and
heated overnight at 80 C. The reaction was quenched with water and extracted
with
ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine (2
x
25 mL), dried over anhydrous magnesium sulfate and evaporated. The crude
product was purified by silica gel column chromatography and eluted with
hexanes-
ethyl acetate (3:7) containing 1% acetic acid. Yield: 0.16 g, 28.4%. Analysis;
1HNMR
(DMSO-d6): 88.34 (t, J=5.6 Hz, 1 H), 7.72 (s, 1 H), 7.29 (d, J=8.4 Hz, 1 H),
7.19 (d,
J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.42 (t, J=8.4
Hz, 1 H),
6.28 (d, J=2.4 Hz, 2H), 4.24 (d, J=5.2 Hz), 3.73 (s, 3H), 3.57 (s, 6H), 1.87
(s, 3H).
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General Procedure for Conversion of Carboxylic Acids to Amides
[000161] A mixture of carboxylic acid (1.1 mmol) and carbonyldiimidazole (1.3
mmol) in DMF (20 ml-) was heated at 60 C for 30 min. After the reaction
mixture was
cooled to room temperature, a solution of amine (2M, 1 mL, 2.0 mmol) was added
and stirred for 18 hr. To the reaction mixture water (100 ml-) was added and
extracted with ethyl acetate (3 x 60 mL). The organic phase was washed with
10%
citric acid (20 mL), water (2 x 50 mL), and brine (50 mL), then dried over
anhydrous
magnesium sulfate and removed the solvent. The crude product was purified by
silica gel chromatography.
EXAMPLE 11
Synthesis of N,N-d imethyl-2-{4-[4-(3-oxo-3-ureidopropyl)-phenoxy]-phenyl}-
acetamide (26)
[000162] Urea (0.78 g, 13 mmol) and 3-[4-(4-carboxymethylphenoxy)-phenyl]-
propionic acid ethyl ester, 24 (0.5 g, 1.5 mmol) were dissolved in sodium
ethoxide in
ethanol (2M, 6.5 mL, 13 mmol) at 80 C under argon, and the reaction mixture
was
heated at this temperature for I h. The reaction was then quenched by TFA (0.5
mL)
after cooling to 5 C. Water (40 mL) was added to the reaction mixture. The
crude
product was filtered and purified by silica gel chromatography and eluted with
hexane-ethyl acetate (1:1) containing acetic acid (1 %) followed by
recrystallization
from toluene yielded 25 (0.28 g, 54%).
[000163] Analysis: 1HNMR (DMSO-d6): b 12.28 (br, 1 H), 7.73 (br, 1 H), 7.24
(d,
J=8.8 Hz, 2H), 7.23, (br, 1 H), 7.21 (d, J=8.8 Hz, 2H), 6.93, (d, J=8.8 Hz,
2H), 6.92 (d,
J=8.8 Hz, 2H), 3.54 (s, 2H), 2.81 (t, J=7.2 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H).
[000164] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using dimethyl amine as amine, 25 was converted to
26 in 97% yield.
51
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[000165] Analysis: 1 HNMR (DMSO-d6): 610.17(s, 1 H), 7.73 (s, 1 H), 7.22 (s, 1
H),
7.21 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.90
(d, J=8.0
Hz, 2H), 3.65 (s, 2H), 3.00 (s, 3H), 2.81 (t, J=8.0 Hz, 2H), 2.58 (t, J=8.0
Hz, 2H).
0
C02H CO2H C.N,Me
Me
0 O -C) N O
NH2 \ H
C02Et Y / NNH2
O O u
0 0
24 25 26
EXAMPLE 12
Synthesis of (4-{4-[2-(3,5-d imethoxyphenyl)-1-dimethylcarbamoyl-vinyl]-
phenoxy}-
benzyl)-carbamic acid methyl ester (29).
[000166] Reaction of 3-(3,5-d imethoxyphenyl)-2-{4-[4-(2,4-dioxothiazolidin-3-
ylmethyl)-phenoxy]-phenyl}-acrylic acid, 27, (0.4 g, 0.77 mmol) with 5% L1OH
(2mL)
in methanol (19 mL) was carried out at room temperature for 18 h.
The reaction mixture was acidified to pH 3 by 5% aqueous HCI and extracted
with
ethyl acetate (2 x 50 mL). The organic layer was washed with water (2 x 50
mL),
brine (2 x 20 mL), dried over anhydrous magnesium sulfate and evaporated. The
crude product was purified by silica gel chromatography and eluted with hexane-
ethyl acetate (1:1) containing acetic acid (1 %). Yield (28): 0.31 g, 83%.
Analysis: 1 HNMR (DMSO-d6): b 12.75 (br, 1 H), 7.68 (t, J=4.6 Hz, 1 H), 7.67
(s, 1 H),
7.28 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.97
(d, J=8.8
Hz, 2H), 6.39 (t, J=2.8 Hz, 1 H), 6.27 (d, J=2.4 Hz, 2H), 4.17 (d, J=6.4 Hz,
2H), 3.58
(S, 6H), 3.55 (s, 3H).
[000167] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using dimethyl amine as amine, 28 was converted to
29 in 96% yield.
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[000168] Analysis: 1HNMR (DMSO-d6): 8 7.68 (t, J=4.6 Hz, 1 H), 7.28 (d, J=8.8
Hz, 2H), 7.27 (d, J=8.8Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz,
2H), 6.57
(s, 1 H), 6.35 (t, J=2.8 Hz, 1 H), 6.28 (d, J=2.4 Hz, 2H), 4.16 (d, J=6.4 Hz,
2H), 3.59
(S, 6H), 3.55 (s, 3H), 3.05 (br, 3H), 2.91 (br, 3H).
O
N.M
e
MeO CO2H MeO I j CO2H MeO %OMez--'
Me OMe Me
O O~\- O O
N S I NuOCH3 T10CH3
u
II
0 II
O 0
27 28 29
EXAMPLE 13
Synthesis of 2-{4-[4-(2-carbamoylethyl)-phenoxy]-phenyl}-3-(3,5-
dimethoxyphenyl)-
N,N-dimethylacrylamide (31)
[000169] Urea (0.78 g, 13 mmol) and 3-(3,5-dimethoxyphenyl)-2-{4-[-4-(2-
ethoxycarbonylethyl)-phenoxy]-phenyl}-acrylic acid 5 (0.45 g, 1.5 mmol) were
dissolved in sodium ethoxide in ethanol (2M, 6.5 mL, 13 mmol) at 80 C under
argon,
and the reaction mixture was heated at this temperature for 5 h. The reaction
was
then quenched by TFA (0.5 mL) after cooling to 5 C. Water (40 mL) was added to
the reaction mixture. The crude product was filtered and purified by silica
gel
chromatography and eluted with hexane-ethyl acetate (1:1) containing acetic
acid
(1 %). Yield (30): 0.39 g, 93%.
[000170] Analysis: 1 HNMR (DMSO-d6): 5 12.73 (br, 1H), 7.68 (s, 1H), 7.29 (br,
1 H), 7.24 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H),
6.92 (d,
J=8.8 Hz, 2H), 6.78 (br, 1 H), 6.39 (t, J=2.4 Hz, 1 H), 6.27 (d, J=2 Hz, 2H),
3.57 (s,
6H), 2.79 (t, J=8.0 Hz, 2H), 2.35 (t, J=8.0 Hz, 2H).
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[000171] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using dimethyl amine as amine, 30 was converted to
31 in 98% yield.
[000172] Analysis: 1HNMR (DMSO-d6): 6 7.30 (br, 1H), 7.28 (d, J=8.8 Hz, 2H),
7.23 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.79
(br, 1 H),
6.56 (s, 1 H), 6.34 (t, J=2.4 Hz, 1 H), 6.28 (d, J=2 Hz, 2H), 3.58 (s, 6H),
3.05 (br, 3H),
2.90 (br, 3H), 2.77 (t, J=8.0 Hz, 2H), 2.34 (t, J=8.0 Hz, 2H).
0
MeO CO2H MeO I i CO2H MeO %e.
N,Me Me
OMe OMe O
OEt NH2 / NH2
O O O
30 31
EXAMPLE 14
Synthesis of 2-[4-(4-acetylaminophenoxy)-phenyl]-3-(3,5-dimethoxyphenyl)-N,N-
dimethylacrylamide (34)
[000173] Compound 2 was reacted with 1-fluoro-4-nitrobenzene in the presence
of NaH in DMF to give 3-(3,5-dimethoxyphenyl)-2-[4-(4-nitrophenoxy)-phenyl]-
acrylic
acid (32). Reduction of 32 (10 g, 24 mmol) with zinc dust (15 g, 230 mmol) in
acetic
acid (100 ml-) was accomplished at 120 C for 15 h, the mixture was cooled to
room
temperature. Water (250 ml-) was slowly added to the reaction mixture. The
precipitated product was filtered and washed with water (70 ml-) to give crude
product. The product was recrystallized from toluene. Yield (33): 9.7 g, 94%.
[000174] Analysis: 1 HNMR (DMSO-d6): 8 12.35 (br, 1 H), 9.96 (s,1 H), 7.67 (s,
1 H), 7.60 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.8Hz, 2H), 6.97 (d, J=8.8 Hz, 2H),
6.96 (d,
J=8.8 Hz, 2H), 6.34 (t, J=2.8 Hz, 1 H), 6.28 (d, J=2.4 Hz, 2H), 3.58 (S, 6H),
2.03 (s,
3H).
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[000175] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using dimethylamine as amine, 33 was converted to
34 in 98% yield.
[000176] Analysis: 1HNMR (DMSO-d6): 6 9.96 (s,1 H), 7.60 (d, J=8.8 Hz, 2H),
7.25 (d, J=8.8Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.55
(s, 1 H),
6.34 (t, J=2.8 Hz, 1 H), 6.28 (d, J=2.4 Hz, 2H), 3.58 (S, 6H), 3.04 (br, 3H),
2.90 (br,
3H), 2.03 (s, 3H).
0
MeO CO2H MeO CO2H Me0 N" Me
Me
%e~~'
OMe OMe 0 0 0 0 O
NMe ~aN 'J~ N02 H H Me
32 33 34
EXAMPLE 15
Synthesis of 3-(3,5-d imethoxyphenyl)-2-[4-(4-methanesulfonylphenoxy)-phenyl]-
N, N-
dimethylacrylamide (36)
[000177] Compound 2 (3 g, 10 mmol) was dissolved in anhydrous DMF (70 mL)
under nitrogen, and potassium carbonate (1.4 g, 10 mol) was added in lots.
When
the solution became homogeneous, 4-fluorophenyl methyl sulfone (1.74 g, 10
mmol)
was added and the mixture was heated at 150 C for 2 h. After cooling to room
temperature, the solution was poured into water (150 mL). The mixture was
acidified
with 5% HCI to - pH 4 and the solidified product was collected by suction
filtration.
The crude product was recrystallized with toluene. Yield(35): 4.3 g, 96%.
[000178] Analysis: 1 HNMR (DMSO-d6): b 12.72 (br, 1 H), 7.94 (d, J=8.8 Hz,
2H),
7.72 (s, 1 H), 7.80 (d, J=8.4Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4
Hz, 2H),
6.42 (t, J=2.8 Hz, 1 H), 6.28 (d, J=2.4 Hz, 2H), 3.59 (S, 6H), 3.21 (s, 3H).
CA 02468302 2004-05-25
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[000179] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using dimethylamine as amine, 35 was converted to
36 in 96% yield.
[000180] Analysis: 1HNMR (DMSO-d6): 8 7.93 (d, J=8.8 Hz, 2H), 7.38 (d,
J=8.4Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.62 (s, 1 H),
6.36 (t,
J=2.8 Hz, 1 H), 6.29 (d, J=2.4 Hz, 2H), 3.59 (S, 6H), 3.20 (s, 3H), 3.08 (br,
3H), 2.92
(br, 3H).
0
MeO CO2H MeO N' Me
MeO CO2H
o e o Me
e e OMe
OMe ~
OMe 0
OH O
SO2CH3 SO CH
2 3
2 35 36
EXAMPLE 16
Synthesis of 3-(4-{4-[2-(3,5-d imethoxyphenyl)-1-dimethylcarbamoylvinyl]-
phenoxy}-
phenyl)-propionic acid ethyl ester (37)
[000181] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using dimethyl amine as amine, 5 was converted to
37
in 97% yield.
[000182] Analysis: 1HNMR (DMSO-d6): b 7.28 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8
Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.56 (s, 1 H), 6.34
(t, J=2.4
Hz, 1 H), 6.28 (d, J=2 Hz, 2H), 4.04 (q, J=6.8 Hz, 2H), 3.58 (s, 6H), 3.05
(br, 3H),
2.90 (br, 3H), 2.84 (t, J=8.4 Hz, 2H), 2.61 (t, J=8.4 Hz, 2H), 1.15 (t, J=6.4
Hz, 3H).
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0
N,Me
MeO C02H MeO %e~--,
OMe O C_yOEt C1OEt
O 0
37
EXAMPLE 17
Synthesis of 2-{4-[4-(N-u re ido-2-carbamoylethyl)-phenoxy]-phenyl}-3-(3,5-
dimethoxyphenyl)-N, N- dimethylacrylamide (39)
[000183] Hydrolysis of 13 with 1N NaOH yielded 38. The 1,1-carbonyl-
diimidazole (CDI) derivative was made by the general procedure for conversion
of
carboxylic acids to amides mentioned above. The CDI intermediate of 38 was
converted to 39 by reacting this with semicarbazide in 73% yield.
[000184] Analysis: 1HNMR (DMSO-d6): b 9.48 (br, 1 H), 7.72 (br, 1 H), 7.28 (d,
J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8
Hz,
2H), 6.56 (s, 1 H), 6.34 (t, J=2.4 Hz, 1 H), 6.28 (d, J=2 Hz, 2H), 5.86 (s,
2H), 3.58 (s,
6H), 3.05 (br, 3H), 2.90 (br, 3H), 2.77 (t, J=8.0 Hz, 2H), 2.39 (t, J=8.0 Hz,
2H).
0 0
Me0 Me MeO N' Me
Me Me
OMe
OMe \ I
O H 00
IIII
N NANH
CO2H O H 2
38 39
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EXAMPLE 18
Synthesis of3-(3,5-dimethoxyphenyl)-N,N-dimethyl-2-{4-[4-(3-morpholin-4-yl-3-
oxopropyl)-phenoxy]-phenyl}-acrylamide (40)
[000185] The CDI intermediate of 38 was converted to 40 by reacting it with
morpholine in 94% yield.
[000186] Analysis:'HNMR (DMSO-d6): 6 7.27 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8
Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.56 (s, 1 H), 6.34
(t, J=2.4
Hz, 1H), 6.28 (d, J=2 Hz, 2H), 3.58 (s, 6H), 3.49 (m, 4H), 3.41 (m, 4H), 3.05
(br, 3H),
2.90 (br, 3H), 2.77 (t, J=8.0 Hz, 2H), 2.39 (t, J=8.0 Hz, 2H).
0 0
MeO N' Me MeO N' Me
%OMe--, Me / / I Me
OMe N.
O I O I ~O
NJ
C02H
O
38 40
EXAMPLE 19
Synthesis of 2-(4-{4-[2-(3,5-d imethoxyphenyl)-1-dimethylcarbamoylvinyl]-
phenoxy}-
benzyl)-malonic acid dimethyl ester (43)
[000187] Condensation of 3 with malonic acid dimethyl ester in the presence of
sodium hydride as base resulted in 41, which on reduction with zinc/acetic
acid
yielded 42. Conversion of 42 to 43 was accomplished by the general procedure
for
conversion of carboxylic acids to amides mentioned above in 94% yield.
Analysis: 1 HNMR (DMSO-d6): 6 7.29 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H),
6.96
(d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.57 (s, 1 H), 6.34 (t, J=2.4 Hz, 1
H), 6.28
(d, J=2 Hz, 2H), 3.87 (t, J=8 Hz, 1 H), 3.61 (s, 6H), 3.58 (s, 6H), 3.08 (d,
J=7.6 Hz,
2H), 3.05 (br, 3H), 2.91 (br, 3H).
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O
MeO CO2H MeO C02H Me0 Me
'Me
OMe I OMe I OMe
0) ~'CoNe
~ COZMe 0 I~ COZMe
C02Me C02Me C02Me
41 42 .43
EXAMPLE 20
Synthesis of N-{4-[2-(3,5-d imethoxyphenyl)-1-dimethylcarbamoylvinyl]-phenyl}-
3-
hydroxybenzamide (44)
[000188] A mixture of 2-(4-aminophenyl)-3-(3,5-d imethoxyphenyl)-N,N-
d imethylacrylamide, 43, (0.59 g, 1.5 mmol), benzotriazol-1-yloxytris-
(dimethylamino)-
phosphonium hexafluorophosphate (BOP,0.88g, 2.0 mmol), 3-hydroxybenzoic acid
(0.28g, 2.0 mmol), triethylamine (0.2 g, 2.0 mmol) in DMF (8.0 ml-) was
stirred for 3h
at room temperature. The reaction mixture was poured in water (50mL) and solid
separated was filtered, dried and purity was checked by HPLC (97.6%).
[000189] Analysis: 1 HNMR (DMSO-d6): S 10.29 (s, 1 H), 9.81 (s, 1 H), 7.79 (d,
J=6.8Hz, 2H), 7.43 (d, J=8.OHz, 1 H), 7.37 (t, J=7.6Hz, 2H), 7.29 (d, J=8.4Hz,
2H),
7.02 (m, 1H), 6.60 (s, 1H), 6.40 (t, J=2.OHz, 1H), 6.36 (d, J=2.OHz, 2H), 3.63
(s, 6H),
3.08 (brs, 3H), 2.96 (brs, 3H).
0 0
Meo %el N.Me MeO I N.Me
Me / / Me
OMe
NH2 HN
OH
11
0
43 44
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EXAMPLE 21
Synthesis of N,N-dimethyl-2-{4-[4-(3-oxo-3-ureidopropenyl)-phenoxy]-phenyl)-3-
pyridin-3-ylacrylamide (47)
[000190] Synthesis of 45 from 3-pyridinecarboxaldehyde was performed
following Scheme I. Urea (0.78 g, 13 mmol) and 2-{4-[4-(2-ethoxycarbonyl-
vinyl)-
phenoxy]-phenyl}-3-pridin-3-ylacrylic acid, 45 (0.5 g, 1.2 mmol) was dissolved
in
sodium ethoxide in ethanol (2M, 6.5 mL, 13 mmol) at 80 C under argon, and the
reaction mixture was heated at this temperature for 1 h. The reaction was then
quenched by TFA (0.5 mL) after cooling to 5 C. Water (40 ml-) was added to the
reaction mixture. The crude product was filtered and purified by silica gel
chromatography and eluted with hexanes-ethyl acetate (1:1) containing acetic
acid
(1 %) followed by recrystallization from toluene. Yield (46): 0.33 g, 63%.
[000191] Analysis:'HNMR (DMSO-d6): 6 12.78 (br, 1H), 10.29 (s, 1H), 8.42 (dd,
J=4.8, 1.6 Hz, 1 H), 8.35 (d, J=2.4 Hz, 1 H), 7.92 (br, 1 H), 7.66 (d, J=16
Hz, 1 H), 7.64
(d, J=8.8 Hz, 2H), 7.36 (tt, J=8.4, 1.6 Hz, 1 H), 7.30 (br, 1 H), 7.28 (m, 1
H), 7.23 (d,
J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 6.73 (d, J=16
Hz, 1H).
[000192] Following the general procedure for conversion of carboxylic acids to
amides mentioned above, 46 was converted to 47.
[000193] Analysis: 1HNMR (DMSO-d6): 8 10.30 (s, 1H), 8.39 (dd, J=4.8, 1.6 Hz,
1 H), 8.34 (d, J=2.4 Hz, 1 H), 7.92 (br, 1 H), 7.66 (d, J=16 Hz, 1 H), 7.64
(d, J=8.8 Hz,
2H), 7.45 (tt, J=8.4, 1.6 Hz, 1 H), 7.32 (br, 1 H), 7.29 (d, J=8.8 Hz, 2H),
7.26 (m, 1 H),
7.11 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.73 (d, J=16 Hz, 1 H), 6.70
(s, 1 H),
3.07 (br, 3H), 2.93 (br, 3H).
0
COC02H N' Me
Me
N N N
O I /
/ N~NH
O / NuNH2
C02Et
O O O O
45 46 47
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EXAMPLE 22
Synthesis of 3-(3,5-d imethoxyphenyl)-2-(4-hydroxyphenyl)-N,N-
dimethylacrylamide
(49)
[000194] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using dimethyl amine as amine, 2 was converted to
49.
[000195] Analysis: 1HNMR (DMSO-d6): b 9.59'(s, 1 H), 7.07 (d, J=8.8, 2H), 6.73
(d, J=8.8Hz, 2H), 6.43 (s, 1 H), 6.23 (t, J=2.4Hz, 1 H), 6.29 (d, J=2.4Hz,
2H), 3.57 (s,
6H), 2.99 (brs, 3H), 2.89 (brs, 3H).
0 0
MeO 5OMez--, OH MeO NMe
Me
OMe
OH OH
2 49
EXAMPLE 23
Synthesis of [3-(4-{4-[2-(3, 5-d imethoxyphenyl)-1-(piperid ine-1-carbonyl)-
vinyl]-
phenoxy}-phenyl)-propionyl]-urea (51)
[000196] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using piperidine as amine, 6 was converted to 51.
[000197] Analysis: 1 HNMR (DMSO-d6): 6 10.16 (s, 1 H), 7.73 (brs, 1 H), 7.26
(d,
J=8.8 Hz, 2H), 7.23 (d, J=8.8Hz, 2H), 6.98 (d, J=8.8Hz, 2H), 6.93 (d, J=8.8Hz,
2H),
6.55 (s, 1 H), 6.34 (t, J=2.4Hz, 1 H), 6.29 (d, J=2.4Hz, 2H), 3.58 (s, 6H),
3.50 (br,
4H), 2.82 (t, J=7.6Hz, 2H), 2.59 (t, J=7.6Hz, 2H), 1.58 (br, 2H) 1.40-1.45
(br, 4H).
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O O
MeO OH MeO No
Me I Me
o-
I/ N NH2 O I/ H NH2
O O O O
6 51
EXAMPLE 24
Synthesis of 3-(3,5-dimethoxyphenyl)-N,N-diethyl-2-{4-[4-(3-oxo-3-
ureidopropyl)-
phenoxy]-phenyl}-acrylamide (53)
[000198] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using diethylamine as amine, 6 was converted to 53.
[000199] Analysis: 1HNMR (DMSO-d6): 8 10.17 (s, 1 H), 7.70 (brs, 1 H), 7.26
(overlapped d, J=8.8Hz, 2H), 7.23 (overlapped d, J=8.8Hz, 2H), 6.97 (d,
J=8.8Hz,
2H), 6.92 (d, J=8.8Hz, 2H), 6.54 (s, 1H), 6.34 (t, J=2.0Hz, 1H), 6.29 (d,
J=2.OHz,
2H), 3.32-3.37 (br, 4H), 3.59 (s, 6H), 2.82 (t, J=7.6Hz, 2H), 2.59 (t,
J=7.6Hz, 2H),
1.03 (br, 3H), 0.92 (br, 3H).
o
MeO OH MeO N5J
OMe I OMe
O
O H I H
NYNH2 / N NH2
O O O Q
6 53
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EXAMPLE 25
Synthesis of 2-{4-[4-(3-acetylamino-3-oxopropyl)-phenoxy]-phenyl}-3-(4-
fluorophenyl)-N, N-dimethylacrylamide (56)
[000200] To a solution of {4-[4-(2-carbamoylethyl)-phenoxy]-phenyl}-acetic
acid,
54, (0.45g, 1.5mmol) in acetic anhydride (15 ml-) was added 4-
fluorobenzaldehyde
(0.17 mL, 1.6 mmol) and potassium acetate (0.17g, 1.8 mmol) and refluxed
overnight. Reaction mixture was poured in water (50 mL) and extracted with
ethyl
acetate (2 x 50mL). The crude product was purified by silica gel
chromatography to
yield 55.
[000201] Analysis: 1 HNMR (DMSO-d6): 6 12.50 (br, 1 H), 10.64 (s, 1 H), 7.74
(s,IH), 7.27 (d, J=8.4Hz, 2H), 7.10-7.15 (m, 6H), 6.99 (d, J=8.4Hz, 2H), 6.97
(d,
J=8.4Hz, 2H), 2.81 (d, J=6.8Hz, 2H), 2.76 (d, J=6.8Hz, 2H), 2.15 (s, 3H).
[000202] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using dimethylamine as amine, 55 was converted to
56.
[000203] Analysis: 1 HNMR (DMSO-d6): 6 10.62 (s, 1H), 7.26 (d, J=8.4Hz, 2H),
7.22 (d, J=8.4Hz, 2H), 7.15 (d, J=8.4Hz, 2H), 7.05 (d, J=8.4Hz, 2H), 6.97 (d,
J=8.OHz, 2H), 6.94 (d, J=8.OHz, 2H), 6.63 (s,1 H), 2.81 (d, J=6.8Hz, 2H), 2.76
(d,
J=6.8Hz, 2H), 2.15 (s, 3H).
0 0
0 \ OH \ N' Me
OH / / F
F I / / Me
H
NyCH3
I / H 0 CH3 / 0 0
NH2 II
0
0
54 55 56
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EXAMPLE 26
Synthesis of 2-(4-{4-[2-(3,5-dimethoxyphenyl)-1-dimethylcarbamoylvinyl]-
phenoxy}-
benzyl)-malonic acid (58) and 2-(4-{4-[2-(3,5-d imethoxyphenyl)-1-
dimethylcarbamoylvinyl]-phenoxy}-benzyl)-malonamide (59)
[0002.04] To a solution of2-(4-{4-[2-(3,5-dimethoxyphenyl)-1-
dimethylcarbamoylvinyl]-phenoxy}-benzyl)-malonic acid dimethyl ester, 43
(0.40g,
0.73mmol) in DMF (6 ml-) and ethanol (10 mL), ammonium hydroxide (20 mL, 28%)
and IN NaOH (0.36 mL, 0.36 mmol) was added and stirred overnight at room
temperature. Solvent was evaporated and the crude product was purified by
silica
gel chromatography to yield 58 and 59.
Analysis: 1HNMR (DMSO-d6+ D20) of 58: 57.20 (d, J=8.4Hz, 2H), 7.17 (d,
J=8.4Hz,
2H), 6.90 (d, J=8.4Hz, 2H), 6.81 (d, J=8.4Hz, 2H), 6.51 (s, 1 H), 6.29 (t,
J=2.OHz,
1 H), 6.21 (d, J=2.OHz, 2H), 3.53 (s, 6H), 3.13 (br, 1 H), 3.01 (brs, 3H),
2.92 (br, 2H),
2.86 (brs, 3H).
[000205] Analysis: 1HNMR (DMSO-d6) of 59:5 5 7.28 (d, J=8.8 Hz, 2H), 7.26
(br, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.03 (br, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.90
(d, J=8.8
Hz, 2H), 6.56 (s, 1 H), 6.34 (t, J=2.4 Hz, 1 H), 6.28 (d, J=2 Hz, 2H), 3.58
(s, 6H), 3.29
(t, J=8 Hz, 1 H), 3.05 (br, 3H), 2.95 (d, J=7.6 Hz, 2H), 2.91 (br, 3H).
0
MeO N' Me
Me
OMe
O 0
Me0 Me COON
N 58
CONH
Me 2
ZZ
%Wez-'
O 0
COOMe MeO N' Me
43 COOMe
Me
OMe
O CONH2
59
CONH2
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EXAMPLE 27
Synthesis of 3-(3,5-dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)- phenoxy]-
phenyl}-N-pyridin-4-ylacrylamide (60)
[000206] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using 4-aminopyridine as amine, 6 was converted to
60.
[000207] Analysis: 1 HNMR (DMSO-d6): 510.17 (s, 1 H), 8.24 (brs, 1 H), 7.71
(br,
2H), 7.53 (d, J=8.8Hz, 2H), 7.44 (s, 1 H), 7.25 (d, J=8.4Hz, 2H), 7.22 (br, 1
H), 7.03
(d, J=9.2Hz, 2H), 7.99 (d, J=8.4Hz, 2H), 6.47 (d, J=2.4Hz, 2H), 6.43 (t,
J=2.4Hz,
2H), 3.65 (s, 6H), 2.83 (t, J=7.6Hz, 2H), 2.60 (t, J=7.6Hz, 2H).
N
0
Me0 N
H
OMe
O O HuNH2
I I
O O
EXAMPLE 28
Synthesis of N-(4-chlorophenyl)-3-(3,5-d imethoxyphenyl)-2-{4-[4-(3-oxo-3-
ureidopropyl)-phenoxy]-phenyl}-acrylamide (61)
[000208] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using 4-chloroaniline as amine, 6 was converted to
61.
[000209] Analysis: 1 HNMR (DMSO-d6): 3 10.16 (s, 1 H), 8.24 (brs, 1 H), 7.65
(brs,
1 H), 7.53 (d, J=8.8Hz, 2H), 7.44 (s, 1 H), 7.25 (d, J=8.8Hz, 2H), 7.22 (br, 1
H), 7.03
(d, J=8.8Hz, 2H), 7.00 (d, J=8.8Hz, 2H), 6.47 (d, J=2.4Hz, 2H), 6.43 (d,
J=2.4Hz,
I H), 3.66 (s, 6H), 2.83 (t, J=8.OHz, 2H), 2.60 (t, J=8.OHz, 2H).
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0 / CI
MeO N
H
5e~--
0
NuNH2
I I
O O
61
EXAMPLE 29
Synthesis of 3-(3,5-d imethoxyphenyl)-N,N-dimethyl-2-(4-{4-[2-(2-morpholin-4-
yl-2-
oxoethylcarbamoyl)-ethyl]-phenoxy}-phenyl)-acry lam ide (63)
[000210] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using 2-amino-l-morpholin-4-yl-ethanone as amine, 3-
(4-{4-[2-(3 ,5-d imethoxyphenyl)-1-dimethylcarbamoylvinyl]-phenoxy}-phenyl)-
propionic acid, 38, was converted to 63.
[000211] Analysis: 1 HNMR (DMSO-d6): 8 7.99 (t, J=5.6Hz, 1 H), 7.27 (d,
J=8.8Hz, 2H), 7.24 (d, J=8.8Hz, 2H), 6.97 (d, J=8.8Hz, 2H), 6.92 (d, J=8.8Hz,
2H),
6.56 (s, 1 H), 6.34 (t, J=2.OHz, 1 H), 6.28 (d, J=2.OHz, 2H), 3.93 (d,
J=5.6Hz, 2H) 3.56
(s, 6H), 3.52-3.56 (m, 4H), 3.40-3.42 (m, 4H), 3.05 (brs, 3H), 2.91 (brs, 3H),
2.80 (t,
J=7.6Hz, 2H), 2.46 (t, J=7.6Hz, 2H).
O 0
MeO N' Me MeO NMe
Me
%OMezll' Me OMe
0 O
~ O
I/ OH ~, N'IkN
O O 0O
38 63
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EXAMPLE 30
Synthesis of 3-(3,5-dimethoxyphenyl)-N,N-dimethyl-2-(4-{4-[3-(4-m ethyl
piperazin-1-
yl)-3-oxopropyl]-phenoxy}-phenyl)-acrylamide (64)
[000212] Following the general procedure for conversion of carboxylic acids to
amides mentioned above and using 4-methylpiperazine as amine, 3-(4-{4-[2-(3,5-
d imethoxyphenyl)-1-dimethylcarbamoylvinyl]-phenoxy}-phenyl)-propionic acid,
38,
was converted to 64.
[000213] Analysis: 1HNMR (DMSO-d6): 6 7.28 (d, J=2.8Hz, 2H), 7.25 (d,
J=2.8Hz, 2H), 6.96 (d, J=8.8Hz, 2H), 6.92 (d, J=8.6Hz, 2H), 6.56 (s, 1 H),
6.34 (t,
J=2.OHz, 1 H), 6.28 (d, J=2.OHz, 2H), 6.19 (s, 6H), 3.40(dt, 2=18.0 and
4.8Hz), 3.04
(brs, 3H), 2.90 (brs, 3H), 2.79 (t, J=8.0, 2H), 2.60 (t, J=8.OHz, 2H), 2.20
(t, J=5.2Hz,
2H), 2.14 (s, 3H).
O O
MeO N' Me MeO N. Me
Me
Me
%OqMez"
OMe I
O I O NMe
OH N
O O
38 64
EXAMPLE 31
Synthesis of 3-(3,5-dimethoxyphenyl)-N,N-dimethyl-2-[4-(pyridin-2-yloxy)-
phenyl]-
acrylamide (66)
[000214] A solution of 3-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic
acid,
2, (0.6 g, 2.0 mmol), 2-fluoropyridine (0.19 g, 2.0 mmol) in dimethyl
acetamide (4.0
mL) was heated in presence of potassium carbonate (0.28 g, 2.0 mmol) at 175 C
for
2 h, and then quenched with water (25 mL), neutralized with dilute HCI and
extracted
with ethyl acetate (2 x 50mL). Organic layer was dried and evaporated. The
crude
product was purified by silica gel chromatography to yield 65 (0.15 g, 19.9%).
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[000215] A mixture of 3-(3,5-dimethoxyphenyl)- 2-[4-(pyridin-2-yloxy)-phenyl]-
acrylic acid, 65, (0.11g, 0.3 mmol), benzotriazol-l-yloxytris-(dimethylamino)-
phosphonium hexafluorophosphate (BOP, 0.15 g, 0.35 mmol), dimethylamine in THE
(2M, 0.5 mL, 1.0 mmol), triethylamine (0.035 g, 035 mmol) in DMF (6.0 mL) was
stirred for 3 h at room temperature. The reaction mixture was poured in water
(50.0
mL) and extracted with ethyl acetate (2 x 50 mL). Solvent was evaporated under
reduced pressure and residue was purified by silica gel chromatography to
yield 66.
[000216] Analysis: 1 HNMR (DMSO-d6): 6 8.14 (m, 1 H), 7.88 (m, 1 H), 7.33 (d,
J=8.8 Hz, 2H), 7.14 (m, 3H), 7.05 (d, J=8.4Hz, 2H), 6.59 (s, 1H), 6.34 (t,
J=2.OHz,
1 H), 6.31 (d, J=2.OHz, 2H), 3.58(s, 6H), 3.10 (brs, 3H), 2.92 (brs, 3H).
OH Me0 I OH MeO I N
0 0 0 `~ ) MeO %OMe
/ Me
OMe Me
OMe
OH O N O N
2 65 66
EXAMPLE 32
Measurement of Increased Glucose Uptake in 3T3-L1 Adipocytes Treated With a
Compound of the Present Invention
[000217] The effect of treatment with I on glucose uptake was measured in 3T3-
L1 differentiated adipocytes. The assay was conducted essentially according to
the
method of Tafuri SR, Endocrinology, 137, 4706-4712 (1996). The adipocytes were
incubated with different concentrations of the test compound for 48 hours in
Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum
(FBS), then washed and incubated in glucose-free, serum-free medium for 60
minutes at 37 C. Then 14C-deoxyglucose was added and the cells were incubated
for 30 minutes at room temperature. After washing, the cells were lysed (0.1%
SDS)
and the radioactivity was measured to determine the amount of glucose uptake.
Glucose uptake was calculated as a percentage of the basal level seen in cells
not
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treated with drug. As shown in FIG. 1, treatment with I resulted in a dose-
dependent
increase in glucose uptake.
EXAMPLE 33
Measurement of Enhanced Glucose Uptake in 3T3-L1 Adipocytes Treated With
Insulin in Combination with a Compound of the Present Invention
[000218] The ability of 1 to enhance insulin-stimulated glucose uptake was
assessed in 3T3-L1 adipocytes essentially as described above in Example 32.
Adipocytes were incubated with either vehicle (0.1 % DMSO) or test compound (5
M
1) for 48 hours in DMEM plus 10% FBS. The cells were then serum-starved,
incubated for 30 minutes with different concentrations of insulin, and then
glucose
uptake was carried out for 10 minutes at room temperature. When compared to
treatment with vehicle, treatment with I enhanced the stimulation of glucose
uptake
by insulin (see Figure 2).
EXAMPLE 34
Measurement of the Glucose-Lowering Effect in ob/ob Mice Treated With a
Compound of the Present Invention
[000219] The glucose-lowering effect of 1 was measured in ob/ob mice, an
animal model for type 2 diabetes. At the onset of diabetes, seven-week-old
male
ob/ob mice received daily oral doses of either vehicle (0.5% CMC) or 1 (10
mg/kg)
by gavage for seven days. Blood glucose levels were measured on day 0 (24
hours
prior to administration of the first dose), day 1 (immediately prior to the
first dose),
and on days 2, 4, 6 and 8 (24 hours following administration of the prior
dose).
Significant decreases in blood glucose levels were recorded on day 6 (36%
decrease, p < 0.05) and day 8 (23% decrease, p < 0.05) in the drug-treated
versus
the vehicle-treated animals (see Figure 3).
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EXAMPLE 35
Measurement of the Lipid-Lowering Effects in ob/ob Mice Treated With a
Compound
of the Present Invention
[000220] The lipid-lowering effects of 1 also were measured in ob/ob mice
following one week of treatment. In the experiment described above in Example
34,
the concentrations of serum triglycerides and free fatty acids were determined
on
day 8. Significant decreases were observed in the levels of serum
triglycerides (49%
lower, p < 0.05) and free fatty acids (19% lower, p < 0.05) in the drug-
treated versus
the vehicle treated mice (see Figure 4).
EXAMPLE 36
Measurement of the Inhibition of LPS-induced TNF-alpha Production in RAW264.7
Cells Treated With a Compound of the Present Invention
[000221] The ability of I to inhibit LPS-induced TNF-alpha production was
assessed in the mouse macrophage cell line RAW264.7. The RAW cells were
preincubated with either 1 pM dexamethasone (Dex) or 10, 30 or 100 pM 1 for 1
hour at 37 C in RPMI-1640 containing 10% FBS. After 1 hour LPS (0.1 pg/ml) was
added and cells were incubated an additional 6 hours. Cell supernatant was
then
collected, aliquoted and frozen at -70 C, and an aliquot used to determine the
concentration of TNF-alpha by ELISA. As shown in Figure 5, treatment with 1
significantly inhibited the LPS-induced production of TNF-alpha. The
inhibitory effect
approached that seen with dexamethasone.
EXAMPLE 37
Measurement of the Inhibition of LPS-induced IL-1 Beta Production in RAW264.7
Cells Treated With a Compound of the Present Invention
[000222] The ability of 1 to inhibit LPS-induced IL-1 beta production was also
examined in RAW264.7 cells. The RAW cells were preincubated with either 1 pM
dexamethasone (Dex) or 10, 30 or 100 pM 1 for 1 hour at 37 C in RPMI-1640
containing 10% FBS. After 1 hour LPS (0.1 pg/ml) was added and cells were
incubated an additional 6 hours. Cell supernatant was then collected,
aliquoted and
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frozen at -70 C, and an aliquot used to determine the concentration of IL-1
beta by
ELISA. As shown in Figure 6, treatment with 1 significantly inhibited the LPS-
induced
production of IL-1 beta. The inhibition seen with I was of the same
approximate
magnitude as that seen with dexamethasone.
EXAMPLE 38
Measurement of the Inhibition of LPS-induced IL-6 Production in RAW264.7 Cells
Treated With a Compound of the Present Invention
[000223] The ability of 1 to inhibit LPS-induced IL-6 production was also
measured in RAW264.7 cells. The RAW cells were preincubated with either 1 pM
dexamethasone (Dex) or 10, 30 or 100 pM I for 1 hour at 37 C in RPMI-1640
containing 10% FBS. After 1 hour LPS (0.1 pg/ml) was added and cells were
incubated an additional 6 hours. Cell supernatant was then collected,
aliquoted and
frozen at -70 C, and an aliquot used to determine the concentration of IL-6 by
ELISA. As shown in Figure 7, treatment with 1 significantly inhibited the LPS-
induced
production of IL-6. The inhibitory effect was greater than that observed with
dexamethasone.
EXAMPLE 39
Measurement of the Inhibition of LPS-induced NOS and COX-2 Production in
RAW264.7 Cells Treated With a Compound of the Present Invention
[000224] The ability of 1 to inhibit LPS-induced production of iNOS and COX-2
was also measured in RAW264.7 cells. The RAW cells were preincubated with
either
1 pM dexamethasone (Dex) or 10, 30 or 100 pM I (Test Cpd) or other reference
compound (Ref Cpd A or Ref Cpd B) for 1 hour at 37 C in RPMI-1640 containing
10% FBS. After 1 hour LPS (0.1 fag/ml) was added and cells were incubated an
additional 6 hours. Cells receiving no drug treatment, incubated with or
without LPS,
served as controls. Cells were lysed and 25 pg/well of total protein was
electrophoresed on 4-20% Tris-glycine SDS gels. Proteins were transferred to
nitrocellulose membrane, and the resulting blot was probed with antibody to
iNOS,
then stripped and reprobed with antibody to COX-2, and then stripped and
reprobed
with antibody to COX-1. As shown in Figure 8, treatment with I exhibited dose-
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dependent inhibition of LPS-induced iNOS production. In addition, treatment
with 1
selectively inhibited production of COX-2 but not COX-1 in LPS-stimulated
cells.
EXAMPLE 40
Inhibition of LPS-induced TNF-alpha Release by Human Monocytes With
Compounds of the Present Invention
[000225] Frozen human elutriated monocytes (Advanced Biotechnologies
Incorporated) were thawed and each 1-ml vial mixed with -12 ml of 10% FBS
complete medium (10% heat-inactivated fetal bovine serum in RPMI 1640 medium
supplemented with 100 U/ml penicillin, 100 pg/mI streptomycin and 50 pM 2-
mercaptoethanol). Cells were centrifuged at 800 rpm for 10 min at room
temperature using a Beckman GS-6 centrifuge with GH-3.8 rotor, and the cell
pellets were resuspended in 20% FBS complete medium (20% heat-inactivated FBS
in RPMI 1640 medium supplemented with 100 U/ml penicillin, 100 fag/ml
streptomycin and 50 pM 2-mercaptoethanol) and centrifuged again at 800 rpm for
min at room temperature. Cell pellets were resuspended in 20% FBS complete
medium, and the cell suspensions were pooled and passed through a 70-micron
cell
strainer to remove any aggregates or clumps. The cell suspension was adjusted
to
2.5 x 106 cells/ml in 20% FBS complete medium. Cell suspension (160 pl, 4 x
105
cells) was added into each well of a 96-well tissue-culture treated
polystyrene plate
and incubated at 37 C for 1 - 2.5 h. Cells were pretreated with vehicle (DMSO)
or
test compound (0.3, 1.0, 3.0, 10 or 30 pM) in 20% FBS complete medium for 1 h
at
37 C. After pretreatment, lipopolysaccharides (LPS) from Salmonella
typhimurium
in 20% FBS complete medium were added to the cells. The final concentrations
were 0.1 % DMSO and 10 ng/ml LPS in a final volume of 200 pl/well. The cells
were
incubated for 20 h at 37 C, and then the supernatants were harvested and
aliquots
of the supernatants frozen at -80 C for subsequent analysis. Cells on the
plates
were assayed for cell viability using the MTS/PMS assay (Cory AH et al.,
Cancer
Commun 3:207-212, 1991). The concentration of TNF-alpha in the cell
supernatants
was determined using quantitative sandwich enzyme immunoassay for human TNF-
alpha (R&D Systems). The mean percent inhibition of TNF-alpha release relative
to
vehicle was calculated for each concentration of test compound from multiple
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determinations. As shown in Table 2, the compounds of the invention caused
significant inhibition of LPS-induced TNF-alpha release by human monocytes.
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TABLE 2
Test Percent Inhibition of TNF-alpha Release
Compound 0.3 pM 1.0 pM 3.0 pM 10 pM 30 pM
49 - - 14% 47% 54%
31 - 51% 73% 83% 86%
37 - 17% 38% 65% 78%
13 15%' 40% '70% 78% 78%
51 - - 25% 57%
56 1% - 6% - 54%
66 27% - 53% - 84%
67 40% - 62% - 89%
44 32% - 67% - 91%
71 20% - 47% - 65%
69 1% - 22% - 50%
58 6% - 13% - 53%
59 27% - 69% - 80%
* Cell viability < 70%
EXAMPLE 41
Stimulation of Glucose Uptake in 3T3-L1 Adipocytes With Compounds of the
Present
Invention
[000226] Differentiation of mouse 3T3-L1 adipocytes was carried out using the
method of Greenberg AS, et al., J Biol Chem 276:45456-61, 2001. Briefly, 3T3-
L1
fibroblasts were differentiated to adipocytes by incubation in DMEM containing
10%
FBS, 72 pg/ml porcine insulin, 0.5 mM 3-isobutylmethylxanthine (IBMX) and 400
ng/ml dexamethasone for 2 x 48 h at 37 C. Differentiated cells were maintained
in
media containing 10% FBS without insulin, IBMX or dexamethasone until they
were
used for experiments. The effect of treatment with compounds of the invention
on
glucose uptake by differentiated adipocytes was assessed essentially according
to
the method of Tafuri SR, Endocrinology 137:4706-12, 1996. Adipocytes were
incubated with vehicle (0.1 % DMSO) or test compound (0.1, 1.0 or 10 pM) for
48 h
in DMEM containing 10% FBS, then washed and incubated in high-glucose, serum-
free medium for 3 h at 37 C. Cells were then washed, incubated for 20 min in
glucose-free, serum-free medium containing 100 nM insulin, then supplemented
with
2.5 pCi/mI 14C-deoxyglucose in 0.1 mM cold deoxyglucose and further incubated
for
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min at room temperature. After washing, cells were lysed with 0.5% SDS and the
radioactivity was measured in a scintillation counter to determine the amount
of
glucose uptake. The mean percent stimulation of glucose uptake relative to
vehicle
(set at 100%) was calculated for each concentration of test compound from
triplicate
determinations. As shown in Table 3, the compounds of the invention caused
significant stimulation of glucose uptake in differentiated adipocytes.
TABLE 3
Test Percent Stimulation of Glucose Uptake
Compound 0.1 pM 1.0 pM 10 pM
31 107% 119% 161%
8 115% 132% 171%
60 93% 120% 229%
61 93% 120% 229%
51 93% 107% 136%
29 106% 124% 120%
40 126% 117% 126%
63 107% 112% 139%
64 108% 113% 127%
56 83% 100% 126%
EXAMPLE 42
Inhibition of PDE4 and PDE3 Activity With a Compound of the Present Invention
[000227] Compound 13 was examined for its ability to inhibit the activity of
PDE4
and PDE3 enzymes. PDE4 partially purified from human U-937 promonocytic cells
and PDE3 partially purified from human platelets were used. Test compound (1,
10
or 30 pM) or vehicle (0.1 % DMSO) was incubated with 0.2 pg PDE4 enzyme or I
pg
PDE3 enzyme and 1 pM cAMP containing 0.01 pg [3H]cAMP in Tris buffer pH 7.5
for
min at 30 C. The reaction was terminated by boiling for 2 min and the
resulting
AMP was converted to adenosine by addition of 10 mg/ml snake venom
nucleotidase and further incubation at 30 C for 10 min. Unhydrolyzed cAMP was
bound to AGI-X2 resin, and remaining [3H]adenosine in the aqueous phase was
quantitated by scintillation counting. The mean percent inhibition of PDE4 or
PDE3
activity was calculated from duplicate determinations (Table 4). Compound 13
exhibited significant inhibition of both PDE4 (IC50 < 1 pM) and PDE3 (IC50 =
13.6 pM)
enzyme activities.
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TABLE 4
Enzyme Percent Inhibition of Enzyme Activity
Assay 1 pM 10 pM 30 pM
PDE4 85% 98% 102%
PDE3 20% 52% 55%
EXAMPLE 43
Inhibition of LPS-induced Phosphorylation of p44/42 MAP Kinase With a Compound
of the Present Invention
[000228] Compound 13 was examined for its ability to inhibit LPS-induced and
LPS/IFN-gamma induced phosphorylation of p44/42 MAP kinase. RAW 264.7
gamma NO(-) cells were seeded at 1 x 106/well (2 ml per well) in 6-well tissue
culture
plates one day prior to the experiment. To start the experiment, cells were
washed
2X with RPMI 1640 medium, 0.5% FBS, 100 U/ml penicillin, 100 lag/ml
streptomycin,
1 mM sodium pyruvate, and then pretreated with vehicle (0.1 % DMSO) or test
compound (10 or 30 pM) at 37 C for 1 h. After pretreatment, cells were
incubated in
RPMI 1640 medium, 10% FBS, 100 U/ml penicillin, 100 lag/ml streptomycin, 1mM
sodium pyruvate, containing 10 ng/ml LPS or LPS (10 ng/ml)/IFN-gamma (10 U/ml)
at 37 C for 15 min. Cells were then washed 2X with cold PBS (pH 7.4) and lysed
in
20 mM Tris-HCI (pH 7.5), 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% Triton,
2.5 mM sodium pyrophosphate, 1 mM beta-glycerophosphate, 1 mM Na3VO4, 1
pg/ml leupeptin, 1 mM PMSF on ice for 10 min. Lysed cells were collected and
centrifuged at -20,800 x g for 10 min at 4 C. Supernatants (lysates) were
collected,
aliquoted, and stored frozen at -80 C until use. Lysates (29 lag of total
proteins per
sample) were subjected to SDS-polyacrylamide (4-20%) gel electrophoresis, and
the
separated proteins were transferred to nitrocellulose membranes. Membranes
were
blocked with 5% non-fat dry milk, 10 mM Tris-HCI (pH 8.0), 150 mM NaCl, 0.1 %
Tween -20 at room temperature for 1 h and then were blotted with mAb against
phospho-p44/42 MAP kinase (Thr 202/Tyr 204) at room temperature for 1 h. The
membranes were then washed and incubated with a horseradish peroxidase-linked
anti-mouse secondary antibody at room temperature for I h. The signals were
detected using ECL Western blotting detection reagents. The results showed
that
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compound 13 inhibited LPS-induced phosphorylation of p44/42 MAP kinase at 30
pM but not 10 pM, while the compound inhibited LPS/IFN-gamma induced
phosphorylation of p44/42 in a dose-dependent manner at 30 pM and 10 pM (data
not shown).
EXAMPLE 44
Inhibition of Anti-CD3/Anti-CD28 Stimulated Lymphocyte Proliferation With a
Compound of the Present Invention
[000229] Compound 13 was examined for its ability to inhibit anti-CD3/anti-
CD28
stimulated lymphocyte proliferation. Binding of antigen, or antibodies, to
CD3/CD28
triggers activation and proliferation of T-lymphocytes, which are key steps
involved in
mounting an immune response (Abbas, Lichtman and Pober, Cellular and Molecular
Immunology, 3rd edition, W.B. Saunders Company, Philadelphia, 1997).
Mesenteric
lymph nodes were collected from BALB/c mice (female, -8 weeks old), and the
cells
were isolated in PBS (pH 7.4) and mixed with culture medium (RPMI 1640 medium,
10% FBS, 100 U/ml penicillin, 100 pg/ml streptomycin, 50 pM 2-
mercaptoethanol).
The cell suspension was centrifuged at 900 rpm for 10 min at room temperature
using a Beckman GS-6 centrifuge with GH-3.8 rotor. After centrifugation, cell
pellets
were resuspended in culture medium and centrifuged again at 900 rpm for 10 min
at
room temperature. Cell pellets were resuspended in culture medium and cells
were
counted. 2 x 105 lymph node cells per well were added into a 96-well cell
culture
plate. For the treatment (n=4), vehicle (DMSO) or test compound was added into
cells. Cells were treated with purified hamster anti-mouse CD3E (2 pg/ml) and
anti-
mouse CD28 (0.2 pg/ml) monoclonal antibodies or with culture medium. The final
concentrations were 0.1 % DMSO and 10 pM test compound in a final volume of
200
pl per well. Cells were incubated at 37 C for 67 h, and then cells on plates
were
centrifuged at 900 rpm for 10 min at room temperature using a Beckman GS-6
Centrifuge with GH-3.8 rotor. 150 pl of supernatant from each well was
subsequently
harvested and frozen at -80 C for further analysis (ELISA). For the cells on
the
plate, 150 pl of culture medium was added into each well to replace the
harvested
supernatants and 40 pl of MTS/PMS solution was added into each well. After
further
incubation at 37 C for 140 min, the plate was read at 505 nm in a microplate
spectrophotometer. The O.D. values (after subtracting the mean O.D. of blank
wells)
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were used to compare the proliferation of treated cells. As shown in Table 5,
10 pM
of compound 13 caused about 50% inhibition of the proliferation of mouse
mesenteric lymph node cells stimulated by anti-CD3/anti-CD28 monoclonal
antibodies. Inhibition of CD3/CD28 mediated T-cell proliferation demonstrates
compound 13 is able to block an immunologically-relevant cellular response,
probably via interactions with a step in the signal transduction cascade. This
indicates that compound 13 has immunomodulatory activity, which may be useful
for
the treatment of immunoproliferative disorders.
TABLE 5
Treatment O.D. (Mean SD)
DMSO 0.020 0.006
DMSO + anti-CD3/anti-CD28 mAbs 1.372 0.125
Test compound + anti-CD3/anti-CD28 mAbs 0.578 0.012
EXAMPLE 45
Improvement of Collagen Induced Arthritis in Mice Using a Compound of the
Present
Invention
[000230] Collagen-induced arthritis (CIA) was induced in 45 DBA/1J mice using
immunization with chicken collagen Type II. The induction schedule was as
follows:
on Day 0, 100 tag/100 pl in Complete Freund's Adjuvant (CFA) intradermally; on
Day
21, 100 tag/100 pl in Incomplete Freund's Adjuvant subcutaneously; on Day 31,
100
tag/100 pl in CFA subcutaneously; all given at the base of the tail. On Day 35
animals received lipopolysaccharides (detoxified from E. coli serotype
0111:84; 40
pg/mL) intraperitoneally. When signs of arthritis appeared, mice were assigned
into
four treatment groups: vehicle control (0.5% carboxymethylcelIulose (CMC));
compound 31 (40 mg/kg suspension in CMC); compound 31 (100 mg/kg in CMC);
positive control (dexamethasone; 5 mg/kg). The animals were dosed per oral by
gavage, twice daily for 14 days, at a dose volume of 250 pl per mouse per
dose.
The study was scored blindly to the different treatment groups. Mice were
weighed
and arthritis was scored three times a week. Arthritis was scored as a count
of
affected limbs and digits, evaluated as: erythema and swelling of tarsal, the
ankle to
the metatarsal joints, up to restriction of movement and deformity of the
joints.
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Plasma was collected from the animals 4 hours following the final dose, for
measurement of circulating drug levels. At termination, animals were
euthanized
and hind limbs removed for histopathologic examination, hind limbs were
collected in
formalin. Decalcified tissue was sectioned longitudinally, parallel to the
bones, and
hematoxylin and eosin stained sections were scored using a standard rheumatoid
arthritis scoring system by a veterinary histopathologist who was blinded to
the
treatment groups. Animals in all groups had moderate arthritis prior to the
start of
dosing (Day 0) as shown in Figure 9. The vehicle group exhibited an increase
in
severity over the course of the study with a tendency to plateau from about
Day 10.
The low dose of compound 31 had no apparent effect on the animals compared
with
vehicle controls. The high dose prevented the increase in severity, to about
the
same extent as dexamethasone. Histology showed that the vehicle group and the
low-dose compound 31 group had marked chronic inflammation of synovium with
pannus formation and destruction of bone and cartilage, while in the
dexamethasone
group the joints were within normal limits. At high dose of compound 31 there
was a
reduction in incidence and severity of pannus formation, inflammation cell
infiltration
and bone/cartilage damage. Thus a dose-dependent effect of compound 31 was
observed on both the soft tissue and bone and cartilage, consistent with a
disease-
modifying activity of the compound in this model.
[000231] It will be evident from the above that the compounds according to the
present invention not only lower blood glucose level, triglyceride level and
free fatty
acid level in diabetic conditions, but also inhibit TNF-alpha, IL-6, IL-1
beta, COX-2
and iNOS production in inflammation, as well as inhibit PDE4 and PDE3
activity,
phosphorylation of p44/42 MAP kinase and lymphocyte proliferation. The
properties
demonstrated above indicate that the compounds of the invention should be
useful in
the treatment of disorders associated with insulin resistance, hyperglycemia,
hyperlipidemia, coronary artery disease and peripheral vascular disease and
for the
treatment of inflammation, inflammatory diseases, immunological diseases,
proliferative diseases and cancer, especially those mediated by cytokines,
cyclooxygenase, phosphodiesterase and/or MAP kinase.
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EXAMPLE 46
Synthesis of N-{4-[2-(3,5-d imethoxyphenyl)-1-dimethylcarbamoylvinyl]-phenyl}-
benzamide (67)
[000232] A mixture of 2-(4-aminophenyl)-3-(3,5-dimethoxyphenyl)-N,N-
dimethylacrylamide, 43, (0.49g, 1.2 mmol) and benzoyl chloride ,(0.26 g, 1.8
mmol) in
anhydrous benzene (18.0 mL) was heated at 90 C for 2 h. Solvent was evaporated
and crude product was purified by silica gel chromatography.
[000233] Analysis: 1HNMR (DMSO-d6): S 10.33 (s, 1H), 7.96 (d, J=8.8Hz, 2H),
7.76 (d, J=8.8Hz, 1 H), 7.51-7.62 (m, 3H), 7.26 (d, J=9.2Hz, 2H), 6.55 (s, 1
H), 6.35 (t,
J=2.OHz, 1 H), 6.31 (d, J=2.OHz, 2H), 3.58 (s, 6H), 3.03 (brs, 3H), 2.91 (brs,
3H).
0 0
N,Me Me Me
MeO N' Me MeO %e'
OMe NH2 HN
O
43 67
EXAMPLE 47
Synthesis of 3-{4-[4-(2-benzo[1,3]dioxol-5-yl-1-dimethylcarbamoylvinyl)-
phenoxy]-
phenyl}-propionic acid ethyl ester (69)
[000234] A mixture of 3-{4-[4-(2-ethoxycarbonylethyl)-phenoxy]-phenyl}-2-
oxopropionic acid, 24 (1.0 g, 3.0 mmol), piperonal (0.67 g, 0.45 mmol),
triethylamine
(5.12 mL) and acetic anhydride (5 mL) was heated at 80 C for 3 h. Reaction
mixture
was poured in water (50 mL). Solid separated was filtered and boiled in
toluene,
cooled and filtered. Crude solid was purified by silica gel chromatography to
yield 68,
0.35g (yield, 25.0%).
[000235] A mixture of 4-benzo[1,3]dioxol-5-yi-3-{4-[4-(2-ethoxycarbonylethyl)-
phenoxy]-phenyl}-2-oxobut-3-enoic acid, 68, (0.08 g, 0.17 mmol), benzotriazol-
1-
yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, 0.09 g, 0.21
mmol), triethylamine (36 pL, 0.25 mmol), dimethylamine in THE (2M, 0.25 mL,
0.5
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WO 03/048108 PCT/US02/38150
mmol) in DMF (2.0 ml-) was stirred for 10 min at room temperature. Reaction
mixture
was poured in water (20 mL). Solid separated was filtered and boiled in
toluene,
cooled and filtered. Crude solid was purified by silica gel chromatography to
yield 69.
Analysis: 1HNMR (DMSO-d6): 6 7.24 (d, J=8.8Hz, 4H), 6.95 (overlapped d,
J=8.8Hz,
4H), 6.80 (d, J=8.OHz, 1 H), 6.68 (d, J=8.OHz, 1 H), 6.54 (s, 1 H), 6.51 (s, 1
H), 5.96 (s,
2H), 4.05 (q, J=4.OHz, 2H), 3.05 (brs, 3H), 2.85 (brs, 3H), 2.80 (t, J=6.OHz,
2H), 2.60
(t, J=6.OHz, 2H) and 1.15 (t, J=4.OHz, 3H).
O o 0
COOH O COOH N' Me
/ I O I/ / I 0 I/ / Me
O O O
)yOEt OEt OEt
O O O
24 68 69
EXAMPLE 48
Synthesis of 2-{4-[4-(1-dimethylcarbamoyl-2-pyridin-3-ylvinyl)-phenoxy]-
benzyl}-
malonamide (71)
[000236] To a solution of 2-{4-[4-(1-dimethylcarbamoyl-2-pyridin-3-ylvinyl)-
phenoxy]-benzyl}-malonic acid dimethyl ester, 70 (0.49 g, 1.0 mmol), in DMF (5
mL),
ammonium hydroxide (28% in water, 12 mL) was added and stirred overnight at
room temperature. Reaction mixture was poured in water (30 mL) and extracted
with chloroform (5 x 25 mL). The organic layer was dried on anhydrous
magnesium
sulfate and evaporated. The crude product was purified by silica gel
chromatography to yield 71, 0.23g (yield, 24.5%).
[000237] Analysis: 1HNMR (CDCI3 + CD3OD): 6 8.32 (m, 2H), 7.40 (m, 1 H), 7.18
(overlapped d, J= 8.0 Hz, 2H), 7.20 (overlapped d, J= 8.0 Hz, 2H), 7.12 (m,1
H), 6.92
(d, J=8.OHz, 2H), 6.84 (d, J=8.OHz, 2H), 6.60 (s, 1 H), 3.22 (d, J=12.0 Hz),
3.12 (brd,
J=12.0 Hz), 2.98 (brs, 3H), 2.96 (brs, 3H).
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WO 03/048108 PCT/US02/38150
0 0
N,Me
N' Me ~N'
LN Me I Me
I O \ COOMe OI\ CONH2
COOMe CONH2
70 71
[000238] It will be appreciated that various modifications may be made in the
invention as described above and as defined in the following claims wherein:
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