Note: Descriptions are shown in the official language in which they were submitted.
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METHODS AND COMPOSITIONS FOR TREATING OR PREVENTING
PSYCHIATRIC DISORDERS WITH COX-2 INHIBITORS ALONE AND
IN COMBINATION WITH ANTIDEPRESSANT AGENTS
BACKGROUND OF THE INVENTION
(1 ) Field of the Invention:
[0001] The present invention relates generally to the use of an
enzyme inhibitor alone and in combination with an antidepressant agent
for the treatment or prevention of psychiatric disorders, and in particular to
the use of a cyclooxygenase-2 inhibitor alone and in combination with an
antidepressant agent.
(2) Description of the Related Art:
[0002] Many people in the United States and around the world
suffer from some form or combination of psychiatric disorders. A broad
spectrum of psychiatric disorders has now been recognized, many of
which have overlapping and interacting etiologies. Two of the most
widespread and prevalent of the psychiatric disorders are depression (un,i-
polar disorder or major depressive disorder) and manic depression (bi-
polar disorder).
[0003] The most common category of psychiatric disorders is mood
disorders, accounting for 25% of patients in public mental institutions, 65%
of psychiatric outpatients, and 10% of all patients seen in nonpsychiatric
medical settings. Mood disorders are a group of typically recurrent
illnesses characterized by pervasive disturbances, psychomotor
dysfunction and vegetative symptoms, including depression, manic
depression, dysthymic disorders, and cyclothymic disorder. Some type of
mood disorder affects 20% of women and 12% of men during their lifetime,
with a major part of these figures representing subjects suffering from
depression. See The Merck Manual of Diagnosis & Therapy, Beers &
Brakow, 17t~' edition, Published by Merck Research Labs, Sec. 15, Chap.
1 ~9, Psychiatric Disorders, Mood Disorders (1999).
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[0004] A subject suffering from depression may display a variety of
symptoms and moods. The mood of a subject suffering from depression
can generally be depressed, irritable, anxious, miserable, morbid,
preoccupied with guilt, self-degenerating, indecisive, helpless, hopeless, or
any combination thereof. The subject may also have social withdrawal,
recurrent thoughts of death or suicide, sleep disorders, decreased ability to
concentrate, diminished interest in usual activities, or any combination of
these symptoms.
[0005] While the exact cause of depression and other mood
disorders is unknown, it has been suggested that impaired limbic-
diencephalic function is the final pathway causing mood disorders. Also,
cholinergic, catecholaminergic (noradrenergic or dopaminergic) and
serotonergic (5-HT) neurotransmission imbalances have been implicated
as a cause of many mood disorders. Most antidepressant agents are
directed toward these systems as a treatment or prevention of psychiatric
disorders.
(0006] Other causes of mood disorders can be stressors that
4
provoke affective episodes either psychologically or biologically.
Traumatic life events, especially separations, commonly precede
depressive and manic depressive episodes. This type of mood disorder
may arise in a subject with any type of personality, although, such events
may trigger depression symptoms from manifesting in a subject suffering
from a subtle mood disorder rather than its cause.
[0007] Some subjects suffering from one or more psychiatric
disorders also have signs of physical pain, sickness, headaches, or other
physical conditions. Subjects diagnosed with one or more psychiatric
disorders are often treated as outpatients, although other patients require
full-time supervision and treatment. Antidepressant agents play a large
role in this treatment, usually in combination with supportive therapy.
Many different types of antidepressant agents with varying functionalities
have emerged over the years and are used as pharmaceutical therapies.
See Ables, A., et al., Am. Fam. Physician 67(3):547-54 (2003). These
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antidepressant agents are helpful to the patient by helping to treat and
prevent the emergence of symptoms associated with the psychiatric
disorder. See Hegarty K. et al., Aust. Fam. Physician 32(4):229-34, 236-7,
239 (2003). In fact, symptom remission is usually the goal of treatment of
a subject suffering from a psychiatric disorder.
[0008] An example of one of the most prevalently prescribed
antidepressant agents is the compound sertraline (Zoloft~). Sertraline
was initially introduced for the treatment of depression, but it is now used
to treat a wide variety of psychiatric disorders. See Khouzam H., et al.,
Compr. Ther. 29(1):47-53 (2003). Sertraline acts as a selective serotonin
reuptake inhibitor (SSRI). However, it is structurally unrelated to other
SSRIs, tricyclic, tetracyclic, or other available antidepressant agents.
[0009] Even after treatment with an antidepressant agent, a subject
suffering from depression often continues to have symptoms. See Menza
M., et al., J. Clin. Psychiatry 64(5):516-23 (2003).
[0010] Some subjects also develop physical side effects during
treatment with an antidepressant agent. These side effects may include
sexual dysfunction, sickness, headaches, pain, sleep disorders, physical
dependence and addiction to the antidepressant agent, and other adverse
side effects. Also, many subjects suffering from depression do not
respond as expected to conventional treatment with antidepressant drugs.
[0011] Moreover, the treatment of psychiatric disorders with only
antidepressant agents fails to address all the underlying causes of
psychiatric disorders. This is problematic because some psychiatric
disorders are thought to arise, in part, from the release of inflammatory
mediators formed within the brain. For example, several clinical studies
have suggested that depression may be accompanied by an activation of
the inflammatory response system. See Tiemeier, H., et al., Epidemiology
14(1):103-7 (2003). Another study reported that an association exists
between depression and the presence of low-grade systemic
inflammation. See Danner, M., et al., Psychosom. Med. 65(3):347-56
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(2003). Conventional antidepressants fail to address this inflammatory
aspect of psychiatric disorders.
[0012] Inhibitors of the cyclooxygenase-2 (Cox-2) enzyme have
been increasingly recognized as having beneficial effects on inflammation.
For example, typical of the development of many inflammatory symptoms
is upregulation of the Cox-2 enzyme. Cox-2 is an enzyme produced by an
inducible gene, which is responsible for the biosynthesis of prostaglandins
in inflammatory cells. Inflammation causes the induction of the Cox-2
enzyme, leading to the release of prostanoids (prostaglandin E2), which
sensitize peripheral nociceptor terminals and produce localized
inflammation and edema. See e.g., Samad, T., et al., Nature
410(6827):471-5 (2001 ).
(0013] Historically, physicians have treated inflammation-related
disorders with a regimen of nonsteroidal anti-inflammatory drugs
(NSAIDS), such as, for example, aspirin and ibuprofen. Undesirably,
however, some NSAIDS are known to cause gastrointestinal (GI) bleeding
or ulcers in patients undergoing consistent long term regimens of NSAID
therapy. See Henry, D., et al., Lancet 337:730 (1991 ).
[0014] A reduction of unwanted side effects of common NSAIDS
was made possible by the discovery that two cyclooxygenases are
involved in the transformation of arachidonic acid as the first step in the
prostaglandin synthesis pathway. These enzymes exist in two forms and
have been termed cyclooxygenase-1 (Cox-1 ) and cyclooxygenase-2 (Cox-
2). See Needleman, P. et al., J. Rheumatol. 24, Suppl. 49:6-8 (1997).
[0015] Cox-1 is a constitutive enzyme responsible for the
biosynthesis of prostaglandins in the gastric mucosa and in the kidney.
Cox-2 is an enzyme that is produced by an inducible gene that is
responsible for the biosynthesis of prostaglandins in inflammatory cells.
Inflammation causes the induction of Cox-2, leading to the release of
prostanoids (prostaglandin E2), which sensitize peripheral nociceptor
terminals and produce localized pain hypersensitivity, inflammation, and
oedema. See Samad, T., et al., Nature 410(6827):471-5 (2001 ).
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[0016] Many common NSAIDs are now known to be inhibitors of
both Cox-1 and Cox-2. Accordingly, when administered in sufficiently high
levels, these NSAIDs not only alleviate the inflammatory consequences of
Cox-2 activity, but also inhibit the beneficial gastric maintenance activities
of Cox-1. .
[0017] Research into the area of arachidonic acid metabolism has
resulted in the discovery of compounds that selectively inhibit the Cox-2
enzyme to a greater extent than the activity of Cox-1. The Cox-2 selective
inhibitors are believed to offer advantages that include the capacity to
prevent or reduce inflammation while avoiding harmful side effects
associated with the inhibition of Cox-1. Thus, Cox-2 selective inhibitors
have shown great promise for use in therapies -- especially in therapies
that require maintenance administration, such as for pain and inflammation
control.
[0018] While Cox-2 inhibitors have been described heretofore for
treating pain and inflammation, they have not been described for the
treatment or prevention of psychiatric disorders.
[0019] Despite the recent advances that have been made in
understanding psychiatric disorders, they remain notoriously difficult to
treat or prevent. Although significant progress has been made in the field
of antidepressant agents, a continuing need still exists for better
antidepressant agents that also have fewer side-effects and a more
targeted functionality. From the foregoing, it can be seen that a need
exists for improved methods and therapeutic compositions to treat
psychiatric disorders. It would also be useful to provide an improved
method and composition for reducing the symptoms associated with
psychiatric disorders. Likewise, methods and compositions that improve
patient outcomes following treatment with antidepressant agents would be
desirable. Also, methods and compositions that reduce dosages or
reduce unwanted side effects in conventional treatments for psychiatric
disorders are desirable. Finally, methods and compositions that improve
the efficacy of treating psychiatric disorders that are resistant in a
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particular subject to known methods of therapy alone would also be
desirable.
SUMMARY OF THE INVENTION
[0020] Briefly, therefore, the present invention is directed to a novel
method of treating or preventing a psychiatric disorder in a subject
comprising administering to the subject at least one Cox-2 inhibitor.
[0021] The present invention is also directed to a novel method ofi
treating or preventing a psychiatric disorder in a subject comprising
administering to the subject at least one Cox-2 inhibitor in combination
with an antidepressant agent.
[0022] The present invention is also directed to a novel therapeutic
composition comprising a Cox-2 inhibitor and an antidepressant agent.
[0023] The present invention is also directed to a novel
pharmaceutical comprising a Cox-2 inhibitor, an antidepressant agent, and
a pharmaceutically acceptable carrier.
[0024] The present invention is also directed to a novel kit for
preventing or treating psychiatric disorders in a subject that is in need of
such prevention or treatment, the kit comprising one dosage form
comprising a Cox-2 inhibitor and a second dosage form comprising an
antidepressant agent.
[0025] Among the several advantages found to be achieved by the
present invention, therefore, may be noted the provision of improved
methods, therapeutic compositions, pharmaceutical compositions, and hits
for the prevention or treatment of psychiatric disorders such as
depression. Other advantages achieved by the present invention includ a
improved methods, compositions, and kits for reducing both the
inflammation and depression symptoms that may be associated with
psychiatric disorders. Still other advantages achieved by the present
invention include methods, compositions, and kits that improve patient
recurrences of psychiatric symptoms. In addition, the present invention
provides methods, compositions, and kits that reduce dosages or reduce
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unwanted side effects in conventional treatments for psychiatric disorders.
Finally, the present invention provides methods and compositions that
improve the efficacy of treating a psychiatric disorder that is considered
resistant or intractable to known methods of therapy alone.
DETAILED DESCRIPTION
[0026] In accordance with the present invention, it has been
discovered that the treatment and/or prevention of psychiatric disorders,
including such disorders as depression and manic depression, is provided
by a therapy comprising a Cox-2 inhibitor alone or in combination with an
antidepressant agent.
[0027] For purposes of the present invention, the novel therapy
comprising at least one Cox-2 inhibitor alone or in combination with at
least one antidepressant agent is useful for the purpose of preventing or
treating psychiatric disorders. The present therapy is also useful for the
purpose of preventing or treating psychiatric disorders in a subject that is
in need of such prevention or treatment.
[0028] The therapy of the present invention is useful, for example,
to reduce such psychiatric disorder symptoms as a mood that is
depressed, irritable, anxious, miserable, morbid, preoccupied with guilt,
self-degenerating, indecisive, helpless, hopeless, or any combination of
the foregoing. The subject may also have social withdrawal, recurrent
thoughts of death or suicide, sleep disorders, decreased ability to
concentrate, diminished interest in usual activities, or any combination of
these symptoms. The therapy of the present invention would also be
useful to prevent the occurrence of such symptoms.
[0029] The methods and compositions of the present invention are
also useful to reduce the number of hospitalizations of subjects suffering
from a chronic psychiatric disorder.
[0030] The administration of a Cox-2 inhibitor alone or in
combination with at least one antidepressant agent for the prevention or
treatment of a psychiatric disorder is an unexpectedly effective treatment
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and preventative therapy. Such administration is effective for improving
the symptoms of a psychiatric disorder while avoiding or reducing certain
disadvantages of current treatments. The therapy of a Cox-2 inhibitor
alone or in combination with at least one antidepressant agent is also
useful for decreasing the required number of separate dosages, thus,
potentially improving patient compliance.
[0031] Therapies comprising at least one Cox-2 inhibitor alone or in
combination with at least one antidepressant agent are useful not only for
improving psychiatric disorder symptoms and shortening recovery times,
but also for reducing or eliminating the dosages of antidepressant agents
that are normally required. The elimination of or administration of lower
dosages of antidepressant agents provides a reduction in side effects
corresponding to such antidepressant agents.
[0032] Another embodiment of the present invention is a
combination therapy for treating or preventing psychiatric disorders and
psychiatric disorder symptoms in a subject in need of such treatment and
prevention comprising at least one Cox-2 inhibitor and at least ore
antidepressant agent.
[0033] Such administration is effective for improving the symptoms
of psychiatric disorders while avoiding or reducing certain disadvantages
of current treatments. The combination therapy of a Cox-2 inhibitor and an
antidepressant agent is also useful for decreasing the required number of
separate dosages, thus, potentially improving patient compliance. For
example, in one embodiment, the combination therapy of the present
invention is useful for reducing the dosing frequency of conventional
antidepressant treatment agents. One antidepressant agent, buproprion
(Wellbutrin~), is typically dosed three to four times daily. Dosing three to
four times daily may become problematic for a subject suffering from a
neurodegenerative symptom, such as short term memory loss or from
seriously ill subjects who have difficulty complying with multiple doses/day.
Thus, administering the combination therapy of the present invention to a
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subject undergoing dosing with buproprion may reduce the required
number of separate doses normally prescribed with buproprion.
[0034] Combination therapies comprising Cox-2 inhibitors and
antidepressant agents are useful not only for improving psychiatric
disorder symptoms and shortening recovery times, but also for reducing
the dosages of conventional antidepressant agents that are normally
required.
[0035] For example, the combination therapy is effective for
lowering the dosages of antidepressant agents that are normally
prescribed as a monotherapy. The administration of lower dosages of
antidepressant agents provides a reduction in side effects corresponding
to such agents. Reduced dosages of antidepressant agents are beneficial
where normal dosages often exhibit harmful side effects, for example, with
such conventional antidepressant agents as fluoxetine (Prozac~). In
some patients, fluoxetine causes sexual dysfunction, which can lead to
reduced patient compliance with the treatment regimen.
[0036] The administration of a Cox-2 inhibitor in combination with an
antidepressant agent is an effective treatment for
psychiatric°disorders and
psychiatric disorder-related symptoms, and in preferred embodiments, is
superior to the use of either agent alone.
[0037] Moreover, in one embodiment, the combination therapy
demonstrates a synergistic efficacy for treating and preventing psychiatric
disorders and psychiatric disorder-related complications that is greater
than what would be expected from simply combining the two therapies.
[0038] The term "synergistic" refers to the combination of a Cox-2
inhibitor and an antidepressant agent as a combined therapy having an
efficacy for the prevention and treatment of psychiatric disorders that is
greater than what would be expected merely from the sum of their
individual effects.
[0039] The synergistic effects of the embodiments of the present
invention's combination therapy encompass additional advantages for the
treatment and prevention of psychiatric disorders. Such additional
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advantages include, but are not limited to, lowering the required dose of
antidepressant agents, reducing the side effects of antidepressant agents,
and rendering those agents more tolerable to subjects in need of
psychiatric disorder therapy.
[0040] As used herein, the phrases "combination therapy", "co-
administration", "co-administering", "administration with'.', "administering",
"combination", or "co-therapy", when referring to the embodiment of the
present invention that comprises the use of a Cox-2 inhibitor in
combination with an antidepressant agent, are intended to embrace
administration of each agent in a sequential manner in a regimen that will
provide beneficial effects of the drug combination, and is intended as well
to embrace co-administration of these agents in a substantially
simultaneous manner. Thus, the Cox-2 inhibitor and antidepressant agent
may be administered in one therapeutic dosage form, such as in a single
capsule, tablet, or injection, or in two separate therapeutic dosage forms,
such as in separate capsules, tablets, or injections.
[0041] Sequential administration of such treatments encompasses
both relatively short and relatively long periods between the administration
of each of the drugs of the present method. However, for purposes of the
present invention, the second drug is administered while the first drug is
still having an efficacious effect on the subject.
[0042] Preferably, the second of the two drugs is to be given to the
subject within the therapeutic response time of the first drug to be
administered. For example, the combination therapy of the present
invention encompasses administration of a Cox-2 inhibitor to the subject
and the later administration of an antidepressant agent, as long as the
antidepressant agent is administered to the subject while the Cox-2
inhibitor is still present in the subject at a level, which in combination
with
the level of the antidepressant agent is therapeutically effective, and vice
versa.
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[0043] As used herein, the term "therapeutic response time" means
the duration of time that a compound is present or detectable within a
subject's body at therapeutic concentrations.
[0044] As used herein, the term "monotherapy" is intended to
embrace administration of a Cox-2 inhibitor to a subject suffering from a
psychiatric disorder as a single therapeutic treatment without any
additional therapeutic treatment comprising an antidepressant agent.
However, the Cox-2 inhibitor may still be administered in multiple dosage
forms. Thus, the Cox-2 inhibitor may be administered in one therapeutic
dosage form, such as in a single capsule, tablet, or injection, or in two
separate therapeutic dosage forms, such as in separate capsules, tablets,
or injections.
[0045] In one embodiment, the present invention provides a method
for treating or preventing psychiatric disorders in a subject in need of such
treatment or prevention.
[0046] In another embodiment, the present invention provides a
method for preventing psychiatric disorders in a subject comprising
administering to the subject a Cox-2 inhibitor alone or in combination with
an antidepressant agent.
[0047] As used herein, the terms "to prevent", "preventing", or
"prevention" refer to any reduction, no matter how slight, of a subject's
predisposition or risk for developing a psychiatric disorder. This definition
includes either preventing the onset of a psychiatric disorder altogether or
preventing the onset of a preclinically evident stage of a psychiatric
disorder in individuals at risk.
[0048] In yet another embodiment, the present invention provides a
method for treating psychiatric disorders in a subject comprising
administering to the subject a Cox-2 inhibitor alone or in combination with
an antidepressant agent.
[0049] As used herein, the terms "treating", "treatment", "treated", or
"to treat," mean to alleviate symptoms, eliminate the cause of symptoms
either on a temporary or permanent basis, or to alter or slow the
a
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appearance of symptoms or symptom worsening. The term "treatment"
includes alleviation or elimination of the cause of the symptoms associated
with, but not limited to, any of the psychiatric disorders or psychiatric
disorder-related symptoms described herein.
[0050] Without being bound by this or any other theory, it is believed
that a therapy comprising a Cox-2 inhibitor alone or in combination with an
antidepressant agent is efficacious for preventing or treating psychiatric
disorders and psychiatric disorder-related symptoms.
[0051] The combination therapy embodiment of the present
invention also provides for the treatment of psychiatric disorder-related
symptoms, which may arise indirectly from having a psychiatric disorder,
by treating the underlying psychiatric disorder itself. For example, if a
subject is suffering from a psychiatric disorder-related symptom, such as a
depressed mood, the treatment of the underlying psychiatric disorder,
such as depression, by the methods and compositions of the present
invention will likewise improve the symptoms of the associated
complication.
[0052] The present invention encompasses a novel method of
preventing or treating psychiatric disorders and psychiatric disorder-related
symptoms in a subject that is in need of such prevention or treatment
comprising administering to the subject at least one Cox-2 inhibitor. In a
second embodiment, the present invention encompasses a novel method
of preventing or treating psychiatric disorders and psychiatric disorder-
related symptoms in a subject that is in need of such prevention or
treatment comprising administering to the subject at least one Cox-2
inhibitor and one or more antidepressant agents.
[0053] A component of the present invention is a Cox-2 inhibitor.
[0054] Inhibitors of the cyclooxygenase pathway in the metabolism
of arachidonic acid used in the prevention and treatment of psychiatric
disorders may inhibit enzyme activity through a variety of mechanisms. By
the way of example, the inhibitors used in the methods described herein
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may block the enzyme activity directly by acting as a substrate for the
enzyme.
[0055] The terms "cyclooxygenase-2 inhibitor", or "Cox-2 inhibitor",
which can be used interchangeably herein, embrace compounds which
inhibit the Cox-2 enzyme regardless of the degree of inhibition of the Cox-
1 enzyme, and include pharmaceutically acceptable salts of those
compounds. Thus, for purposes of the present invention, a compound is
considered a Cox-2 inhibitor irrespective of whether the compound inhibits
the Cox-2 enzyme to an equal, greater, or lesser degree than the Cox-1
enzyme.
[0056] In one embodiment of the present invention, it is preferred
that the Cox-2 inhibitor compound is a non-steroidal anti-inflammatory
drug (NSAID). Therefore, preferred materials that can serve as the Cox-2
inhibitor of the present invention include non-steroidal anti-inflammatory
drug compounds, a pharmaceutically acceptable salt thereof, or a pure (-)
or (+) optical isomeric form thereof.
[0057] Examples of NSAID compounds that are useful in~the
present invention include acemetacin, acetyl salicylic acid, alclofenac,
alminoprofen, azapropazone, benorylate, benoxaprofen, bucloxic acid,
carprofen, choline magnesium trisalicylate, clidanac, clopinac, dapsone,
diclofenac, diflunisal, droxicam, etodolac, fenoprofen, fenbufen,
fenclofenec, fentiazac, floctafenine, flufenisal, flurbiprofen, (r)-
flurbiprofen,
(s)-flurbiprofen, furofenac, feprazone, flufenamic acid, fluprofen, ibufenac,
ibuprofen, indometacin, indomethacin, indoprofen, isoxepac, isoxicam,
ketoprofen, ketorolac, miroprofen, piroxicam, meloxicam, mefenamic,
mefenamic acid, meclofenamic acid, meclofen, nabumetone, naproxen,
niflumic acid, oxaprozin, oxipinac, oxyphenbutazone, phenylbutazone,
podophyllotoxin derivatives, proglumetacin, piprofen, pirprofen,
prapoprofen, salicylic acid, salicylate, sudoxicam, suprofen, sulindac,
tenoxicam, tiaprofenic acid, tiopinac, tioxaprofen, tolfenamic acid, tolmetin,
zidometacin, zomepirac, and 2-fluoro-a-methyl[1,1'-biphenyl]-4-acetic acid,
4-(nitrooxy)butyl ester.
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[0058] In a preferred embodiment, the Cox-2 inhibitor is a Cox-2
selective inhibitor. The term "Cox-2 selective inhibitor" embraces
compounds which selectively inhibit the Cox-2 enzyme over the Cox-1
enzyme, and also include pharmaceutically acceptable salts and prodrugs
of those compounds.
[0059] In practice, the selectivity of a Cox-2 inhibitor varies
depending upon the condition under which the test is performed and on
the inhibitors being tested. However, for the purposes of this specification,
the selectivity of a Cox-2 inhibitor can be measured as a ratio of the in
vitro
or in vivo IC50 value for inhibition of Cox-1, divided by the IC50 value for
inhibition of Cox-2 (Cox-1 IC50/Cox-2 IC50). A Cox-2 selective inhibitor is
any inhibitor for which the ratio of Cox-1 IC50 to Cox-2 IC50 is greater
than 1. In preferred embodiments, this ratio is greater than 2, more
preferably greater than 5, yet more preferably greater than 10, still more
preferably greater than 50, and more preferably still greater than 100.
[0060] As used herein, the term "IC50" refers to the concentration of
a compound that is required to produce 50% inhibition of cyclooxygenase
activity. Preferred Cox-2 selective inhibitors of the present invention have
a Cox-2 IC50 of less than about 1 p,M, more preferred of less than about
0.5 ~,M, and even more preferred of less than about 0.2 ~M.
[0061] Preferred Cox-2 selective inhibitors have a Cox-1 IC50 of
greater than about 1 ~M, and more preferably of greater than 20 p,M.
Such preferred selectivity may indicate an ability to reduce the incidence of
common NSAID-induced side effects.
[0062] Also included within the scope of the present invention are
compounds that act as prodrugs of Cox-2-selective inhibitors. As used
herein in reference to Cox-2 selective inhibitors, the term "prodrug" refers
to a chemical compound that can be converted into an active Cox-2
selective inhibitor by metabolic or simple chemical processes within the
body of the subject. One example of a prodrug for a Cox-2 selective
inhibitor is parecoxib, which is a therapeutically effective prodrug of the
tricyclic Cox-2 selective inhibitor valdecoxib. An example of a preferred
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Cox-2 selective inhibitor prodrug is sodium parecoxib. A class of prodrugs
of Cox-2 inhibitors is described in U.S. Patent No. 5,932,598.
[0063] The Cox-2 selective inhibitor of the present invention can be,
for example, the Cox-2 selective inhibitor meloxicam, Formula B-1 (CAS
registry number 71125-38-7), or a pharmaceutically acceptable salt or
prodrug thereof.
CH3 B-1
[0064] In another embodiment of the invention the Cox-2 selective
inhibitor can be the Cox-2 selective inhibitor RS 57067, 6-[[5-(4-
chlorobenzoyl)-1,4-dimethyl-1 H-pyrrol-2-yl]methyl]-3(2H)-pyridazinone,
Formula B-2 (CAS registry number 179382-91-3), or a pharmaceutically
acceptable salt or prodrug thereof.
B-2
'I .~",
[0065] As used herein, the term "alkyl", either alone or within other
terms such as "haloalkyl" and "alkylsulfonyl"; embraces linear or branched
radicals having one to about twenty carbon atoms. Lower alkyl radicals
have one to about ten carbon atoms. The number of carbon atoms can
also be expressed as "C~-C5", for example. Examples of lower alkyl
radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like.
[0066] The term "alkenyl" refers to an unsaturated, acyclic
hydrocarbon radical, linear or branched, in so much as it contains at least
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one double bond. The alkenyl radicals may be optionally substituted with
groups such as those defined below. Examples of suitable alkenyl
radicals include propenyl, 2-chloropropylenyl, buten-1y1, isobutenyl,
penten-1y1, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-
hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like.
[0067] The term "alkynyl" refers to an unsaturated, acyclic
hydrocarbon radical, linear or branched, in so much as it contains one or
more triple bonds, such radicals preferably containing 2 to about 6 carbon
atoms, more preferably from 2 to about 3 carbon atoms. The alkynyl
radicals may be optionally substituted with groups such as described
below. Examples of suitable alkynyl radicals include ethynyl, propynyl,
hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-
methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyn-2-yl, hexyn-3-yl,
3,3-dimethylbutyn-1-yl radicals, and the like.
(0068] The term "oxo" means a single double-bonded oxygen.
[0069] The terms "hydrido", "-H", or "hydrogen", denote a single
hydrogen atom (H). This hydrido radical may be attached, for example, to
an oxygen atom to form a hydroxyl radical, or two hydrido radicals may be
attached to a carbon atom to form a methylene (-CH2 -) radical.
[0070] The term "halo" means halogens such as fluorine, chlorine,
and bromine or iodine atoms. The term "haloalkyl" embraces radicals
wherein any one or more of the alkyl carbon atoms is substituted with halo
as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl,
and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may
have a bromo, chloro, or a fluoro atom within the radical. Dihalo alkyl
radicals may have two or more of the same halo atoms or a combination of
different halo radicals and polyhaloalkyl radicals may have more than two
of the same halo atoms or a combination of different halo radicals.
[0071] The term "hydroxyalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may be
substituted with one or more hydroxyl radicals.
16
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[0072] The terms "alkoxy" and "alkoxyalkyl" embrace linear or
branched oxy-containing radicals each having alkyl portions of one to
about ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl"
also embraces alkyl radicals having two or more alkoxy radicals attached
to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl
radicals. The "alkoxy" or "alkoxyalkyl" radicals may be further substituted
with one or more halo atoms, such as fluoro, chloro, or bromo, to provide
"haloalkoxy" or "haloalkoxyalkyl" radicals. Examples of "alkoxy" radicals
include methoxy, butoxy, and trifluoromethoxy.
[0073] The term "aryl", whether used alone or with other terms,
means a carbocyclic aromatic system containing one, two, or three rings
wherein such rings may be attached together in a pendent manner, or may
be fused. The term "aryl" embraces aromatic radicals such as phenyl,
naphthyl, tetrahydronapthyl, indane, and biphenyl. The term "heterocyclyl"
means a saturated or unsaturated mono- or multi-ring carbocycle wherein
one or more carbon atoms are replaced by N, S, P, or O. This includes,
for example, structures such as:
Z ~Z3
\Z3 ,or I
Z~ ~:Z2
Z Z Z
where Z, Z~, Z2, or Z3 is C, S, P, O, or N, with the proviso that one
of Z, Z~, Z2, or Z3 is other than carbon, but is not O or S when attached to
another Z atom by a double bond or when attached to another O or S
atom. Furthermore, the optional substituents are understood to be
attached to Z, Z~, Z2, or Z3 only when each is C. The term "heterocycle"
also includes fully saturated ring structures, such as piperazinyl, dioxanyl,
tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl,
piperidinyl,
thiazolidinyl, and others.
[0074] The term "heteroaryl" embraces unsaturated heterocyclic
rad icals. Examples of unsaturated heterocyclic radicals include thienyl,
pyrryl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl,
isoxazolyl,
imidazolyl, thiazolyl, pyranyl, and tetrazolyl. The term also embraces
17
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rad icals where heterocyclic radicals are fused with aryl radicals. Examples
of such fused bicyclic radicals include benzofuran, benzothiophene, and
the like.
[0075] The term "sulfonyl", whether used alone or linked to other
ternns such as alkylsulfonyl, denotes respectively divalent radicals -SO2-.
"Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical,
where alkyl is defined as above. The term "arylsulfonyl" embraces sulfonyl
radicals substituted with an aryl radical. The term "aminosulfonyl" denotes
a sulfonyl radical substituted with an amine radical, forming a sulfonamide
(-S02-NH2).
(0076] The terms "carboxy" or "carboxyl", whether used alone or
with other terms, such as "carboxyalkyl", denotes -C02-H. The term
"carboxyalkyl" embraces radicals having a carboxyradical as defined
above, attached to an alkyl radical. The term "carbonyl", whether used
alone or with other terms, such as "alkylcarbonyl", denotes - (C=O) -. The
term "alkylcarbonyl" embraces radicals having a carbonyl radical
substituted with an alkyl radical. An example of an "alkylcarbonyl" radical
is CH3 - (CO) -. The term "alkoxycarbonyl" means a radical containing an
alkoxy radical, as defined above, attached via an oxygen atom to a
carbonyl (C=O) radical. Examples of such "alkoxycarbonyl" radicals
include (CH3)3-C-O-C=O) - and - (O=)C- OCH3. The term "amino",
whether used alone or with other terms, such as "aminocarbonyl", denotes
-N H2.
(0077] The term "heterocycloalkyl" embraces heterocyclic-
substituted alkyl radicals such as pyridylmethyl and thienylmethyl. The
terms "aralkyl", or "arylalkyl" embrace aryl-substituted alkyl radicals such
as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
The terms benzyl and phenylmethyl are interchangeable. The term
"cycloalkyl" embraces radicals having three to ten carbon atoms, such as
cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term
"cycloalkenyl" embraces unsaturated radicals having three to ten carbon
18
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atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,
and cycloheptenyl.
[0078] The term "alkylthio" embraces radicals containing a linear or
branched alkyl radical, of one to ten carbon atoms, attached to a divalent
sulfur atom. An example of "alkylthio" is methylthio, (CH3 -S-). The term
"alkylsulfinyl" embraces radicals containing a linear or branched alkyl
radical, of one to ten carbon atoms, attached to a divalent -S(-O) - atom.
The term "acyl", whether used alone, or within a term such as "acylamino",
denotes a radical provided by the residue after removal of hydroxyl from
an organic acid.
[0079] The term "cyano", used either alone or with other terms, such
as "cyanoalkyl", refers to C=N. The term "nitro" denotes -N02.
[0080] In one embodiment of the invention the Cox-2 selective
inhibitor is of the chromene/chroman structural class, which encompasses
substituted benzopyrans or substituted benzopyran analogs, as well as
substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes
having the structure of any one of the general Formulas I, II, III, IV, V, and
VI, shown below, and including, by way of non-limiting example, the
structures disclosed in Table 1, and the diastereomers, enantiomers,
racemates, tautomers, salts, esters, amides and prodrugs thereof.
[0081 ] Benzopyrans that can serve as a Cox-2 selective inhibitor of
the present invention include substituted benzopyran derivatives that are
described in U.S. Patent Nos. 6,271,253 and 6,492,390. One such class
of compounds is defined by the general formula shown below in formula I:
R~
1
A2,A1 \ R
R4
3 ~
A~ 4 1I \ 3
A X R
wherein X' is selected from O, S, CR° R'~ and NRa ;
19
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wherein Ra is selected from hydrido, C~ -C3 -alkyl, (optionally
substituted phenyl)-C~ -C3 -alkyl, acyl and carboxy-C~ -C6 -alkyl;
wherein each of Rb and R~ is independently selected from hydrido,
C~ -C3 -alkyl, phenyl-C~ -C3 -alkyl, C~ -C3 -perfluoroalkyl, chloro, C~ -C6
-alkylthio, C~ -C6 -alkoxy, vitro, cyano and cyano-C~ -C3 -alkyl; or
wherein CR'~ R° forms a 3-6 membered cycloalkyl ring;
wherein R~ is selected from carboxyl, aminocarbonyl, C~ -C6 -
alkylsulfonylaminocarbonyl and C~ -C6 -alkoxycarbonyl;
wherein R2 is selected from hydrido, phenyl, thienyl, C~ -C6 -alkyl
and C2 -C6 -alkenyl;
wherein R3 is selected from C~ -C3 -perfluoroalkyl, chloro, C~ -C6 -
alkylthio, C~ -C6 -alkoxy, vitro, cyano and cyano-C~ -C3 -alkyl;
wherein R4 is one or more radicals independently selected from
hydrido, halo, C~ -C6 -alkyl, C2 -C6 -alkenyl, C2 -C6 -alkynyl, halo-C2 -C6
-alkynyl, aryl-C~ -C3 -alkyl, aryl-C2 -C6 -alkynyl, aryl-C2 -C6 -alkenyl, C~
-C6 -alkoxy, methylenedioxy, C~ -C6 -alkylthio, C~ -C6 -alkylsulfinyl,
aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C~ -C6 -alkoxy-C~ -C6 -alkyl,
aryl-C~ -C6 -alkyloxy, heteroaryl-C~ -C6 -alkyloxy, aryl-C~ -C6 -alkoxy-C~
-C6 -alkyl, C~ -C6 -haloalkyl, C~ -C6 -haloalkoxy, C~ -C6 -haloalkylthio,
C~ -C6 -haloalkylsulfinyl, C~ -C6 -haloalkylsulfonyl, C~ -C3 -(haloalkyl-~ -
C3 -hydroxyalkyl, C~ -C6 -hydroxyalkyl, hydroxyimino-C~ -C6 -alkyl, C~ -
C6 -alkylamino, arylamino, aryl-C~ -C6 -alkylamino, heteroarylamino,
heteroaryl-C~ -C6 -alkylamino, vitro, cyano, amino, aminosulfonyl, C~ -C6
-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C~ -
C6 -alkylaminosulfonyl, heteroaryl-C~ -C6 -alkylaminosulfonyl,
heterocyclylsulfonyl, C~ -C6 -alkylsulfonyl, aryl-C~ -C6 -alkylsulfonyl,
optionally substituted aryl, optionally substituted heteroaryl, aryl-C~ -C6 -
alkylcarbonyl, heteroaryl-C~ -C6 -alkylcarbonyl, heteroarylcarbonyl,
arylcarbonyl, aminocarbonyl, C~ -C~ -alkoxycarbonyl, formyl, C~ -C6 -
haloalkylcarbonyl and C~ -C6 -alkylcarbonyl; and
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wherein the A ring atoms A1, A2, A3 and A4 are independently
selected from carbon and nitrogen with the proviso that at least two of A1,
A2, A3 and A4 are carbon;
or wherein R4 together with ring A forms a radical selected from
naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl,
or an isomer or pharmaceutically acceptable salt thereof.
[0082 Another class of benzopyran derivatives that can serve as
the Cox-2 selective inhibitor of the present invention includes compounds
having the structure of formula II:
R6
1 R5
6 :~ 4~
R8 ~ D n
D~ $4 ~ j2' \ 7
D X R
wherein X~ is selected from O, S, CR° R'~ and NRa ;
wherein Ra is selected from hydrido, C1 -C3 -alkyl, (optionally
substituted phenyl)-C1 -C3 -alkyl, alkylsulfonyl, phenylsulfonyl,
benzylsulfonyl, acyl and carboxy-C1 -C6 -alkyl;
wherein each of Rb and R° is independently selected from hydrido,
C1 -C3 -alkyl, phenyl-C1 -C3 -alkyl, C1 -C3 -perfluoroalkyl, chloro, C1 -C6
-alkylthio, C1-C6 -alkoxy, nitro, cyano and cyano-C1 -C3 -alkyl;
or wherein CRS Rb form a cyclopropyl ring;
wherein R5 is selected from carboxyl, aminocarbonyl, C1 -C6 -
alkylsulfonylaminocarbonyl and C1 -C6 -alkoxycarbonyl;
wherein R6 is selected from hydrido, phenyl, thienyl, C2 -C6 -alkynyl and
C2 -C6 -alkenyl;
wherein R' is selected from C1 -C3 -perfluoroalkyl, chloro, C1 -C6 -
alkylthio, C1 -C6 -alkoxy, nitro, cyano and cyano-C1 -C3 -alkyl;
wherein R$ is one or more radicals independently selected from hydrido,
halo, C1 -C6 -alkyl, C2 -C6 -alkenyl, C2 -C6 -alkynyl, halo-C2 -C6 -
alkynyl, aryl-C1 -C3 -alkyl, aryl-C2 -C6 -alkynyl, aryl-C2 -C6 -alkenyl, C1 -
C6 -alkoxy, methylenedioxy, C1 -C6 -alkylthio, C1 -C6 -alkylsulfinyl, -
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O(CF2)2 O-, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C1 -C6 -alkoxy-
C1 -C6 -alkyl, aryl-C1 -C6 -alkyloxy, heteroaryl-C1 -C6 -alkyloxy, aryl-C1-
C6 -alkoxy-C1 -C6 -alkyl, C1 -C6 -haloalkyl, C1 -C6 -haloalkoxy, C1 -C6 -
haloalkylthio, C1-C~ -haloalkylsulfinyl, C1-C6 -haloalkylsulfonyl, C1 -C3 -
(haloalkyl-C1 -C3 -hydroxyalkyl), C1 -C6 -hydroxyalkyl, hydroxyimino-C1 -
C6 -alkyl, C1 -C6 -alkylamino, arylamino, aryl-C1 -C6 -alkylamino,
heteroarylamino, heteroaryl-C1 -C6 -alkylamino, nitro, cyano, amino,
aminosulfonyl, C1-C6 -alkylaminosulfonyl, arylaminosulfonyl,
heteroarylaminosulfonyl, aryl-C1 -C6 -alkylaminosulfonyl, heteroaryl-C1 -
C6 -alkylaminosulfonyl, heterocyclylsulfonyl, C1 -C6 -alkylsulfonyl, aryl-C1
-C6 -alkylsulfonyl, optionally substituted aryl, optionally substituted
heteroaryl, aryl-C1 -C6 -alkyl carbonyl, heteroaryl-C1 -C6 -alkylcarbonyl,
heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C1 -C6 -alkoxycarbonyl,
formyl, C1-C6 -haloalkylcarbonyl and C1 -C6 -alkylcarbonyl; and
wherein the D ring atoms D1, D2, D3 and D4 are independently
selected from carbon and nitrogen with the proviso that at least two of D1,
D2, D3 and D4 are carbon; or
wherein R$ together with ring D forms a radical selected from
naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl;
or an isomer or pharmaceutically acceptable salt thereof.
[0083] Other benzopyran Cox-2 selective inhibitors useful in the
practice of the present invention are described in U.S. Patent Nos.
6,034,256 and 6,077,850. The general formula for these compounds is
shown in formula III:
~5
R9
R10
R1~ ~ E ~~ ~ III
X3' ~R11
22
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WO 2005/084654 PCT/US2005/006818
wherein X3 is selected from the group consisting of O or S or NRa;
wherein Ra is alkyl;
wherein R9 is selected from the group consisting of H and aryl;
wherein R1° is selected from the group consisting of carboxyl,
aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
wherein R11 is selected from the group consisting of haloalkyl, alkyl,
aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals
selected from alkylthio, nitro and alkylsulfonyl; and
wherein R12 is selected from the group consisting of one or more
radicals selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy,
heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy,
alkylamino, arylamino, aralkylamino, heteroarylamino,
heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl,
arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl,
heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl,
hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally
substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl,
aminocarbonyl, and alkylcarbonyl; or
wherein R12 together with ring E forms a naphthyl radical; or an
isomer or pharmaceutically acceptable salt thereof; and
including the diastereomers, enantiomers, racemates, tautomers, salts,
esters, amides and prod rugs thereof.
[0084] A related class of compounds useful as Cox-2 selective
inhibitors in the present invention is described by Formulas IV and V
below:
R13
IV
R15
~4 R14
wherein X4 is selected from O or S or NRa ;
23
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WO 2005/084654 PCT/US2005/006818
wherein Ra is alkyl;
wherein R13 is selected from carboxyl, aminocarbonyl,
alkylsulfonylaminocarbonyl and alkoxycarbonyl;
wherein R14 is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and
aryl optionally substituted with one or more radicals selected from
alkylthio, vitro and alkylsulfonyl; and
wherein R15 is one or more radicals selected from hydrido, halo,
alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy,
haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino,
heteroarylamino, heteroarylalkylamino, vitro, amino, aminosulfonyl,
alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl,
aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl,
alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl,
aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and
alkylcarbonyl;
or wherein R15 together with ring G forms a naphthyl radical;
or an isomer or pharmaceutically acceptable salt thereof.
[0085] Formula V is:
R16
R1$ AI V
~5 R17
wherein:
X5 is selected from the group consisting of O or S or NRb;
Rb is alkyl;
R16 is selected from the group consisting of carboxyl,
aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R1' is selected from the group consisting of haloalkyl, alkyl, aralkyl,
cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl
each is independently optionally substituted with one or more radicals
selected from the group consisting of alkylthio, vitro and alkylsulfonyl; and
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WO 2005/084654 PCT/US2005/006818
R~$ is one or more radicals selected from the group consisting of
hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino,
aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino,
aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl,
heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl,
heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally
substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl,
aminocarbonyl, and alkylcarbonyl; or wherein R~$ together with ring A
forms a naphthyl radical;
or an isomer or pharmaceutically acceptable salt thereof.
[0086] The Cox-2 selective inhibitor rnay also be a compound of
Formula V, wherein:
X5 is selected from the group consisting of oxygen and sulfur;
R~6 is selected from the group consisting of carboxyl, lower alkyl,
lower aralkyl and lower alkoxycarbonyl;
R~' is selected from the group consisting of lower haloalkyl, tower
cycloalkyl and phenyl; and
R'$ is one or more radicals selected from the group of consisting of
hydrido, halo, lower alkyl, lower alkoxy, louver haloalkyl, lower haloalkoxy,
lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-
membered heteroarylalkylaminosulfonyl, 6-membered
heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered
nitrogen-containing heterocyclosulfonyl, 6-membered nitrogen-containing
heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl,
lower aralkylcarbonyl, and lower alkylcarb~nyl; or
wherein R~$ together with ring A forms a naphthyl radical;
or an isomer or pharmaceutically acceptable salt thereof.
[0087] The Cox-2 selective inhibitor may also be a compound of
Formula V, wherein:
X5 is selected from the group consisting of oxygen and sulfur;
R~6 is carboxyl;
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R~' is lower haloalkyl; and
R'$ is one or more radicals selected from the group consisting of
hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower
alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered
heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl,
lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-
containing heterocyclosulfonyl, optionally substituted phenyl, lower
aralkylcarbonyl, and lower alkylcarbonyl; or wherein R~$ together with ring
A forms a naphthyl radical;
or an isomer or pharmaceutically acceptable salt thereof.
[0088 The Cox-2 selective inhibitor may also be a compound of
Formula V, wherein:
X5 is selected from the group consisting of oxygen and sulfur;
R~6 is selected from the group consisting of carboxyl, lower alkyl,
lower aralkyl and lower alkoxycarbonyl;
R" is selected from the group consisting of fluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl,
dichloropropyl, difluoromethyl, and trifluoromethyl; and
R~$ is one or more radicals selected from the group consisting of
hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tart-butyl,
butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy,
trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N-
dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl, N-
phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro, N,N-
dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N-
ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N,N-dimethylaminosulfonyl,
N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl,
benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or
wherein R2 together with ring A forms a naphthyl radical;
or an isomer or pharmaceutically acceptable salt thereof.
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[0089] The Cox-2 selective inhibitor may also be a compound of
Formula V, wherein:
X5 is selected from the group consisting of oxygen and sulfur;
R~6 is selected from the group consisting of carboxyl, lower alkyl,
lower aralkyl and lower alkoxycarbonyl;
R~' is selected from the group consisting trifluoromethyl and
pentafluoroethyl; and
R~$ is one or more radicals selected from the grou p consisting of
hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl,
methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl,
N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N-
dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2-
dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, 2-
methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl,
benzylcarbonyl, and phenyl; or wherein R~$ together with ring A forms a ,.
naphthyl radical;
or an isomer or prodrug thereof.
[0090] The Cox-2 selective inhibitor of the present invention can
also be a compound having the structure of Formula VI:
R2o
VI
wherein:
X6 is selected from the group consisting of O and S;
R~9 is lower haloalkyl;
R2° is selected from the group consisting of hydrido, and halo;
R2~ is selected from the group consisting of hydrido, halo, lower
alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower
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dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl,
lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing
heterocyclosulfonyl, and 6- membered nitrogen-containing
heterocyclosulfonyl;
Rz2 is selected from the group consisting of hydrido, lower alkyl,
halo, lower alkoxy, and aryl; and
R23 is selected from the group consisting of the group consisting of
hydrido, halo, lower alkyl, lower alkoxy, and aryl;
or an isomer or prodrug thereof.
[0091] The Cox-2 selective inhibitor can also be a compound of
having the structure of Formula VI, wherein:
X6 is selected from the group consisting of O and S;
R~9 is selected from the group consisting of trifluoromethyl and
pentafluoroethyl;
R2° is selected from the group consisting of hydrido, chloro, and
fluoro;
R2~ is selected from the group consisting of hydrido, chloro,, bromo,
fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl,
dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl,
benzylaminosulfonyl, phenylethylaminosulfonyl,
methylpropylaminosulfonyl, methylsulfonyl, and morpholinosulfonyl;
R22 is selected from the group consisting of hydrido, methyl, ethyl,
isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl; and
R23 is selected from the group consisting of hydrido, chloro, bromo,
fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl;
or an isomer or prodrug thereof.
28
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Table 1. Examples of Chromene Cox-2 Selective Inhibitors
Compound Structural Formula
Number
B-3 °
OZN \ \ OH
s ~
O' -CF
3
6-Nitro-2-trifluoromethyl-2H-1-benzopyran
3-carboxylic acid
B-4 °
C1 \ \
-OH
/ O CF3
CH3
6-Chloro-8-methyl-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid
Cl \ \
~OH
/ 0 CF3
((S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl-2H-1
benzopyran-3-carboxylic acid
B_6 0
\ \ \ ~oH
/ / ° CF3
2-Trifluoromethyl-2H-naphtho[2,3-b]pyran-3
carboxylic acid
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Compound Structural Formula
Number
B_7 0
\ \
~OH
O / O~CF
3
6-Chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3
carboxylic acid
o
C1 \
~OH
O CF3
Cl
((S)-6,8-Dichloro-2-(trifluoromethyl)-2H-1-benzopyran-
3-carboxylic acid
B_g I \
i
~O H
O~CF3
6-Chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-
3-carboxylic acid
B-10 0 0
\ ~ \ \ ~oH
HO / / O CF3
6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)-2H-1
benzopyran-3-carboxylic acid
CA 02556380 2006-08-14
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Compound Structural Formula
Number
B-11 °
s
F3C~ ~ ~ ~ \OH
/ S CF3
2-(Trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-
3-carboxylic acid
B-12 °
C1
-OH
S CF3
C1
6,8-Dichloro-2-trifluoromethyl-2H-1-benzothiopyran
3-carboxylic acid
i
B-13 ~ °
~oH
S CF3
6-(1,1-Dimethylethyl)-2-(trifluoromethyl)-2H-1-
benzothiopyran-3-carboxylic acid
B-14 °
F
~OH
F ~ H CFa
6,7-Difluoro-1,2-dihydro-2-(trifluoromethyl)-3
quinolinecarboxylic acid
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Compound Structural Formula
Number
B-15 °
cl
~OH
CF3
CH3
6-Chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3
quinolinecarboxylic acid
B-16 °
cl
~OH
N H CF3
6-Chloro-2-(trifluoromethyl)-1,2-dihydro[1, 8]naphthyridine-
3-carboxylic acid
B-17 °
cl
-OH
CF3
((S)-6-Chloro-1,2-dihydro-2-(trifluoromethyl)-3-
quinolinecarboxylic acid
O
B-18
i I ~ ~oH
O F
F
(2S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene
3-carboxylic acid
32
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Compound Structural Formula
Number
B-19 0
F3Ci0 I ~ ~ OH
O~CF3
(2S)-8-ethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)
2H-chromene-3-carboxylic acid
B-20 0
ci I w w o_H
/ O~F
'\F
F
(2S)-6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H
chromene-3-carbox lic acid
[0092] In preferred embodiments the chromene Cox-2 inhibitor is
selected from (S)-6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-
benzopyran-3-carboxylic acid, (2S)-6,8-dimethyl-2-(trifluoromethyl)-2H-
chromene-3-carboxylic acid, (2S)-6-chloro-8-methyl-2-(trifluoromethyl)-2H-
chromene-3-carboxylic acid, (2S)-8-ethyl-6-(trifluoromethoxy)-2-
(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6,8-dichloro-2-
(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, (2S)-6-chloro-5,7-
dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and mixtures
thereof.
[0093] In a preferred embodiment of the invention the Cox-2
inhibitor can be selected from the class of tricyclic Cox-2 selective
inhibitors represented by the general structure of formula VII:
33
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WO 2005/084654 PCT/US2005/006818
p R24
VII
25 ~ ~ 26
R R
wherein:
Z~ is selected from the group consisting of partially unsaturated or
unsaturated heterocyclyl and partially unsaturated or unsaturated
carbocyclic rings;
R24 is selected from the group consisting of heterocyclyl, cycloalkyl,
cycloalkenyl and aryl, wherein R24 is optionally substituted at a
substitutable position with one or more radicals selected from alkyl,
. haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl,
haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl,
halo, alkoxy and alkylthio;
R25 is selected from the group consisting of methyl or amino; and
R26 is selected from the group consisting of a radical selected from
H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl,
heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl,
haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl,
alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl,
aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,
aminocarbonylalkyl, alkylaminocarbonyl, N- arylaminocarbonyl, N-alkyl-N-
arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-
arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino,
aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-
N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio,
aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-
arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl;
or a prodrug thereof.
34
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[0094] In a preferred embodiment of the invention the tricyclic Cox-2
selective inhibitor represented by the above Formula VII is selected from
the group of compounds, illustrated in Table 2, which includes celecoxib
(B-21 ), valdecoxib (B-22), deracoxib (B-23), rofecoxib (B-24), etoricoxib
(MK-663; B-25), JTE-522 (B-26), or prodrugs thereof.
(0095] Additional information about selected examples of the
tricyclic Cox-2 selective inhibitors discussed above can be found as
follows: celecoxib (CAS RN 169590-42-5, C-2779, SC-58653, and in U.S.
Patent No. 5,466,823); deracoxib (CAS RN 169590-41-4); rofecoxib (CAS
RN 162011-90-7); compound B-24 (U.S. Patent No. 5,840,924);
compound B-26 (WO 00/25779); and etoricoxib (CAS RN 202409-33-4,
MK-663, SC-86218, and in WO 98/03484).
[0096] Table 2. Examples of Tricyclic Cox-2 Selective Inhibitors
Compound Structural Formula
Number
o~ so
B-21
HzNiS ~ / CH3
~ N ~
N~
CF3
o~s~o
B-22
H2Ni I ~ / I
\N
H C~o'~
3
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WO 2005/084654 PCT/US2005/006818
Compound Structural Formula
Number
B-23 0 0
~s° ocH
N, ~ ~ / ~ a
/ N
N~
CHFz
o~s~o
B-24
H3C/
/
O o
B-25 °vs~° CH
H C/ ~ /~ 3
~N
\N
cl'
o~s~o
B-26
HaN ~
/
p' ' N
~CH3
[0097] In a more preferred embodiment of the invention, the Cox-2
selective inhibitor is selected from the group consisting of celecoxib,
rofecoxib and etoricoxib.
36
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[0098] In a preferred embodiment, parecoxib (See, U.S. Patent No.
5,932,598), having the structure shown in B-27, and which is a
therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor
valdecoxib, B-22, (See, U.S. Patent No. 5,633,272), may be
advantageously employed as the Cox-2 inhibitor of the present invention.
o S/o
HN~ ~ \
\ B-27
0 1 / ~ _
N
H3C O
[0100] A preferred form of parecoxib is sodium parecoxib.
[0101] Another tricyclic Cox-2 selective inhibitor useful in the
present invention is the compound ABT-963, having the formula B-28
shown below, that has been previously described in International
Publication Number WO 00/24719.
F
N \ F
N
H3C
B-28
[0102] In a further embodiment of the invention, the Cox-2 inhibitor
can be selected from the class of phenylacetic acid derivative Cox-2
selective inhibitors represented by the general structure of formula VIII:
37
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Rz~ O
OH
VIII
Rze Rsz
Rzs Rs~
wherein:
R2' is methyl, ethyl, or propyl;
R2$ is chloro or fluoro;
R~9 is hydrogen, fluoro, or methyl;
R3° is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or
hydroxyl;
R3' is hydrogen, fluoro, or methyl; and
R32 is chloro, fluoro, trifluoromethyl, methyl, or ethyl,
provided that R28, R29, R3° and R3~ are not all fluoro when R2' is
ethyl and
s
R3° is H.
[0103] An exemplary phenylacetic acid derivative Cox-2 selective
inhibitor that is described in WO 99/11605 is a compound that has the
structure shown in formula VIII,
wherein:
R2' is ethyl;
R2$ and R3° are chloro;
R29 and R3~ are hydrogen; and
R32 is methyl.
[0104] Another phenylacetic acid derivative Cox-2 selective inhibitor
is a compound that has the structure shown in formula VIII,
wherein:
R2' is propyl;
R~$ and R3° are chloro;
38
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WO 2005/084654 PCT/US2005/006818
R29 and R3' are methyl; and
R32 is ethyl.
[0105] Another phenylacetic acid derivative Cox-2 selective inhibitor
that is disclosed in WO 02/20090 is a compound that is referred to as
COX-189 (also termed lumiracoxib; CAS Reg. No. 220991-20-8), having
the structure shown in formula VIII,
wherein:
R2' is methyl;
R2$ is fluoro;
R32 is chloro; and
R29, R3°, and R3~ are hydrogen.
[0106] Compounds having a structure similar to that shown in
formula VIII, that can serve as the Cox-2 selective inhibitor of the present
invention, are described in U.S. Patent Nos. 6,451,858, 6,310,099,
6,291,523, and 5,958,978.
[0107] Other Cox-2 selective inhibitors that can be used in the
present invention have the general structure shown in formula IX, where
the J group is a carbocycle or a heterocycle. Preferred embodiments have
the structure:
R33 x7
Ix
/~ I
R°'" I
2o R35
r
wherein:
X' is O; J is 1-phenyl; R33 is 2-NHS02CH3; R34 is 4-N02; and there is no
R35 group, (nimesulide), or
X7 is O; J is 1-oxo-inden-5-yl; R33 is 2-F; R34 is 4-F; and R35 is 6-
NHSO2CH3, (flosulide); or
X' is O; J is cyclohexyl; R33 is 2-NHS02CH3; R34 is 5-N02; and there is no
R35 group, (NS-398); or
39
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X7 is S; J is 1-oxo-inden-5-yl; R33 is 2-F; R34 is 4-F; and R35 is 6-N-S02CH3
Na+, (L-745337); or
X~ is S; J is thiophen-2-yl; R33 is 4-F; there is no R34 group; and R35 is 5-
NHS02CH3, (RWJ-63556); or
X~ is O; J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)furan-(5H)-3-yl; R33
is
3-F; R34 is 4-F; and R35 is 4-(p-S02CH3)C6H4, (L-784512).
[0108] The Cox-2 selective inhibitor NS-398, also known as N-(2-
cyclohexyloxynitrophenyl) methane sulfonamide (CAS RN 123653-11-2),
having a structure as shown below in formula B-29, has been described in,
for example, Yoshimi, N. et al., in Japanese J. Cancer Res., 90(4):406 -
412 (1999).
H ~ /S02CH3
N
\ O\
B-29
NO~
[0109] An evaluation of the anti-inflammatory activity of the Cox-2
selective inhibitor, RWJ 63556, in a canine model of inflammation, was
described by Kirchner et al., in J Pharmacol Exp Ther 282, 1094-1101
(1997).
[0110] Materials that can serve as the Cox-2 selective inhibitor of
the present invention include diarylmethylidenefuran derivatives that are
described in U.S. Patent No. 6,180,651. Such diarylmethylidenefuran
derivatives have the general formula shown below in formula X:
CA 02556380 2006-08-14
WO 2005/084654 PCT/US2005/006818
Q1
R39
R38
X
L.~ ,
L2
wherein:
the rings T and M independently are a phenyl radical, a naphthyl radical, a
radical derived from a heterocycle comprising 5 to 6 members and
possessing from 1 to 4 heteroatoms, or a radical derived from a saturated
hydrocarbon ring having from 3 to 7 carbon atoms;
at least one of the substituents Q1, Q2, L1 or L2 is an -S(O)n -R group, in
which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having
1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms,
or an -S02NH2 group;
and is located in the para position,
the others independently being a hydrogen atom, a halogen atom, a lower
alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or
a lower O-alkyl radical having 1 to 6 carbon atoms, or Q1 and Q2 or L1 and
L2 are a methylenedioxy group; and
R36, R3', R3$ and R39 independently are a hydrogen atom, a halogen atom,
a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical
having 1 to 6 carbon atoms, or an aromatic radical selected from the group
consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or,
R36, R3' or R38, R39 are an oxygen atom; or
R36, R3' or R38, R39, together with the carbon atom to which they are
attached, form a saturated hydrocarbon ring having from 3 to 7 carbon
atoms;
or an isomer or prodrug thereof.
41
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[0111] Particular diarylmethylidenefuran derivatives that can serve
as the Cox-2 selective inhibitor of the present invention include, for
example, N-(2-cyclohexyloxynitrophenyl)methane sulfonamide, and (E)-4-
[(4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene)
methyl]benzenesulfonamide.
[0112] Other Cox-2 selective inhibitors that are useful in the present
invention include darbufelone (Pfizer), CS-502 (Sankyo), LAS 34475
(Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516
(Servier), SD 8381 (Pharmacia, described in U.S. Patent No. 6,034,256),
BMS-347070 (Bristol Myers Squibb, described in U.S. Patent No.
6,180,651 ), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1367
(Chiroscience), L-748731 (Merck), CT3 (Atlantic Pharmaceutical), CGP-
28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome),
6-dioxo-9H-purin-8-yl-cinnamic acid (Glaxo Wellcome), and S-2474
(Shionogi).
[0113] Compounds that may act as Cox-2 selective inhibitors of the
present invention include multibinding compounds containing from 2 to 10
ligands covanlently attached to one or more linkers, as described in U.S.
Patent No. 6,395,724.
[0114] Conjugated linoleic, as described in U.S. Patent No.
6,077,868, is useful as a Cox-2 selective inhibitor in the present invention.
[0115] Compounds that can serve as a Cox-2 selective inhibitor of
the present invention include heterocyclic aromatic oxazole compounds
that are described in U.S. Patents 5,994,381 and 6,362,209. Such
heterocyclic aromatic oxazole compounds have the formula shown below
in formula XI:
R4o
N
XI
W R42
R4~ z2
wherein:
42
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WO 2005/084654 PCT/US2005/006818
ZZ is an oxygen atom;
one of R4° and R4' is a group of the formula
R4
R43 02S t47
R4n
wherein;
R43 is lower alkyl, amino or lower alkylamino; and
R44, R45~ R4s and R47 are the same or different and each is
hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl,
hydroxyl or amino, provided that at least one of R44, R45, R4s and R47 is not
hydrogen atom, and the other is an optionally substituted cycloalkyl, an
optionally substituted heterocyclic group or an optionally substituted aryl;
and
R3° is a lower alkyl or a halogenated lower alkyl,
and a pharmaceutically acceptable salt thereof.
[0116] Cox-2 selective inhibitors that are useful in the method and
compositions of the present invention include compounds that are
described in U.S. Patent Nos. 6,080,876 and 6,133,292, and described by
formula XII:
0
XII
Rso
R48o2S
wherein:
43
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WO 2005/084654 PCT/US2005/006818
Z3 is selected from the group consisting of linear or branched C1 -
C6 alkyl, linear or branched C1 -C6 alkoxy, unsubstituted, mono-, di- or tri-
substituted phenyl or naphthyl wherein the substituents are selected from
the group consisting of hydrogen, halo, C1 -C3 alkoxy, CN, C1 -C3
fluoroalkyl C1 -C3 alkyl, and -C02 H;
R4$ is selected from the group consisting of NH2 and CH3,
R49 is selected from the group consisting of C1 -C6 alkyl
unsubstituted or substituted with C3 -C6 cycloalkyl, and C3 -C6 cycloalkyl;
R5° is selected from the group consisting of C1 -C6 alkyl
unsubstituted or substituted with one, two or three fluoro atoms, and C3
C6 cycloalkyl; with the proviso that R49 and R5° are not the same.
[0117] Pyridines that are described in U.S. Patent Nos. 6,596,736,
6,369,275, 6,127,545, 6,130,334, 6,204,387, 6,071,936, 6,001,843 and
6,040,450, and can seve as Cox-2 selective inhibitors of the present
invention, have the general formula described by formula XIII:
S02R51
R5
XIII
wherein:
R51 is selected from the group consisting of CH3, NH2, NHC(O)CF3,
and NHCH3;
Z4 is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-
oxide thereof), wherein the substituents are selected from the group
consisting of hydrogen, halo, C1 -C6 alkoxy, C1 -C6 alkylthio, CN, C1-C6
alkyl, C1 -C6 fluoroalkyl, N3, -CO2R53, hydroxyl, -C(R54)(R55)-OH, - C1 -
C6 alkyl-C02-R56, C1 -C6 fluoroalkoxy;
R52 is selected from the group consisting of halo, C1 -C6 alkoxy, C1
-C6 alkylthio, CN, C1 -C6 alkyl, C1 -C6 fluoroalkyl, N3, -CO2R5', hydroxyl,
44
N L'
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-C(R5$)(R59)-OH, - C~ -C6 alkyl-C02-R6°, C~ -C6 fluoroalkoxy, N02,
NR6~R62, and NHCOR6s;
R53, R54, R55, R56, R5', R58, R59, R6°, R6~, R62, and R63, are
each
independently selected from the group consisting of hydrogen andC~ -C6
alkyl;
or R54 and R55, R5$ and R59, or R6~ and R62 together with the atom
to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6,
or 7 atoms.
[0118] Materials that can serve as the Cox-2 selective inhibitor of
the present invention include diarylbenzopyran derivatives that are
described in U.S. Patent No. 6,340,694. Such diarylbenzopyran
derivatives have the general formula shown below in formula XIV:
x$
XIV
R66
wherein:
X$ is an oxygen atom or a sulfur atom;
R64 and R65, identical to or different from each other, are independently a
hydrogen atom, a halogen atom, a C~ -C6 lower alkyl group, a
trifluoromethyl group, an alkoxy group, a hydroxyl group, a nitro group, a
nitrite group, or a carboxyl group;
R66 is a group of a formula: S(O)nR6$ wherein n is an integer of 0~2, R6$ is
a hydrogen atom, a C~ -C6 lower alkyl group, or a group of a formula: NR69
R'° wherein R69 and R'°, identical to or different from
each other, are
independently a hydrogen atom, or a C~ -C6 lower alkyl group; and
R6' is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl,
indolyl,
pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a C~ -C6 lower
CA 02556380 2006-08-14
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alkyl group, indanyl, pyrazinyl, or a substituted group represented by the
following structures:
R71
R72 N
,75 ~ R73
R76
R74
N N
R76
R76
wherein:
R'~ through R75, identical to or different from one another, are
independently a hydrogen atom, a halogen atom, a C~ -C6 lower alkyl
group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a
hydroxyalkyl group, a nitro group, a group of a formula: S(O)nR68, a group
of a formula: NR69 R'°, a trifluoromethoxy group, a nitrite group a
carboxyl
group, an acetyl group, or a formyl group,
wherein n, R68, R69 and R'° have the same meaning as defined by
R66 above; and
R'6 is a hydrogen atom, a halogen atom, a C~ -C6 lower alkyl
group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a
trifluoromethoxy group, a carboxyl group, or an acetyl group.
[0119] Materials that can serve as the Cox-2 selective inhibitor of
the present invention include 1-(4-sulfamylaryl)-3-substituted-5-aryl-2-
pyrazolines that are described in U.S. Patent No. 6,376,519. Such 1-(4-
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sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines have the formula shown
below in formula XV:
X9
N
Z5 N~ XV
S02NH2
wherein:
X9 is selected from the group consisting of C~ -C6 trihalomethyl, preferably
trifluoromethyl; C~ -C6 alkyl; and an optionally substituted or di-substituted
phenyl group of formula XVI:
R~~
XVI
~/
7a
R
wherein:
R" and R'8 are independently selected from the group consisting of
hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl;
nitro; C~ -C6 alkyl, preferably C~ -C3 alkyl; C~ -C6 alkoxy, preferably C~ -
C3 alkoxy; carboxy; C~ -C6 trihaloalkyl, preferably trihalomethyl, most
preferably trifluoromethyl; and cyano;
Z5 is selected from the group consisting of substituted and unsubstituted
aryl.
47
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[0120] Compounds useful as Cox-2 selective inhibitors of the
present invention include heterocycles that are described in U.S. Patent
No. 6,153,787. Such heterocycles have the general formulas shown
below in formulas XVII and XVIII:
R~9
O
R$°S(O)2
XVI I
wherein:
R'9 is a mono-, di-, or tri-substituted C~ -C~~ alkyl, or a mono-, or an
unsubstituted or mono-, di- or tri-substituted linear or branched C2 -
C~°
alkenyl, or an unsubstituted or mono-, di- or tri-substituted linear or
branched C2 -C~° alkynyl, or an unsubstituted or mono-, di- or tri-
substituted C3 -C~2 cycloalkenyl, or an unsubstituted or mono-, di- or tri-
substituted C5 -C~2 cycloalkynyl, wherein the substituents are selected
from the group consisting of halo selected from F, CI, Br, and I, OH, CF3,
C3 -C6 cycloalkyl, =O,dioxolane, CN;
R$° is selected from the group consisting of CH3, NH2, NHC(O)CF3,
and NHCH3;
R8~ and R82 are independently selected from the group consisting of
hydrogen and C~ -C~° alkyl; or
R8~ and R82 together with the carbon to which they are attached
form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
[0121] Formula XVIII is:
48
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WO 2005/084654 PCT/US2005/006818
(O)2SH3C
XVIII
wherein X~° is fluoro or chloro.
[0122] Materials that can serve as the Cox-2 selective inhibitor of
the present invention include 2,3,5-trisubstituted pyridines that are
described in U.S. Patent No. 6,046,217. Such pyridines have the general
formula shown below in formula XIX:
S02R83
R84
\ XIX
Rs5 Rs~
Rs9
~1~- ~ - ~ OR9~
( I )n R90
Rss Rss
or a pharmaceutically acceptable salt thereof,
wherein:
X'~ is selected from the group consisting of O, S, and a bond;
nis0or1;
R83 is selected from the group consisting of CH3, NH2, and
NHC(O)CF3;
R84 is selected from the group consisting of halo, C~ -C6 alkoxy, C~
-C6 alkylthio, CN, C~ -C6 alkyl, C~ -C6 fluoroalkyl, N3, -C02 R92,
49
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hydroxyl, -C(R93)(R94)-OH, -C1 -C6 alkyl-CO2 -R95, C1-C6
fluoroalkoxy, N02, NR96 R9', and NHCOR98;
R85 to R89 are independently selected from the group consisting of
hydrogen and C1 -C6 alkyl; or
R85 and R89, or R89 and R9° together with the atoms to which they
are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R85 and R$'
are joined to form a bond.
[0123] Compounds that are useful as the Cox-2 selective inhibitor of
the present invention include diaryl bicyclic heterocycles that are described
in U.S. Patent No. 6,329,421. Such diaryl bicyclic heterocycles have the
general formula shown below in formula XX:
R99
8101 A6=~A5
A\~ ~ ~\ Rloo
8102 ~A$
X12
and pharmaceutically acceptable salts thereof wherein:
-A5=A6-A'=A$- is selected from the group consisting of
(a) -CH=CH-CH=CH-,
(b) -CH2 -CH2 -CH2 -C(O)-, -CH2 -CH2 -C(O)-CH2 -, -CH2
-C(O)-CH2 -CH2, -C(O)-CH2 -CH2 -CH2,
(c) -CH2 -CH2 -C(O)-, -CH2 -C(O)-CH2 -, -C(O)-CH2 -CH2
-
(d) -CH2 -CH2 -O-C(O)-, CH2 -O-C(O)-CH2 -, -O-C(O)-
CH2 -CH2 -,
(e) -CH2 -CH2 -C(O)-O-, -CH2 -C(O)-OCH2 -, -C(O)-O-
CH2 -CH2 -,
(f) -C(R105)2 -O-C(O)-, -C(O)-O-C(RloS)2 -, -O-C(O)-
C(R105)2 -~ -C(R105)2 -~(O)-O-
(g) -N=CH-CH=CH-,
CA 02556380 2006-08-14
WO 2005/084654 PCT/US2005/006818
(h) -CH=N-CH=CH-,
(i) -CH=CH-N=CH-,
Q) -CH=CH-CH=N-,
(k) -N=CH-CH=N-,
(I) -N=CH-N=CH-,
(m) -CH=N-CH=N-,
(n) -S-CH=N-,
(o) -S-N=CH-,
(p) -N=N-NH-,
(q) -CH=N-S-, and
(r) -N=CH-S-;
R99 is selected from the group consisting of S(O)2CH3, S(O)2NH2,
S(O)2NHCOCF3, S(O)(NH)CH3, S(O)(NH)NH2, S(O)(NH)NHCOCF3,
P(O)(CH3)OH, and P(O)(CH3)NH2;
R~oo is selected from the group consisting of
(a) C~ -C6 alkyl, ,
(b) C3 -C7 cycloalkyl,
(c) mono- or di-substituted phenyl or naphthyl wherein the substituent is
selected from the group consisting of
(1 ) hydrogen,
(2) halo, including F, CI, Br, I,
(3) C~ -C6 alkoxy,
(4) C~ -C6 alkylthio,
(5) CN,
(6) CF3,
(7) C~ -C6 alkyl,
(8) Ns,
(9) -CO~ H,
(10) -C02 -C~ -C4 alkyl,
(11 ) -C(R~°3)(R~o4)-OH,
(12) -C(R~03)(R104)-~-C1 -C4 alkyl, and
(13) -C~ -C6 alkyl-CO2 -R~o6;
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(d) mono- or di-substituted heteroaryl wherein the heteroaryl is a
monocyclic aromatic ring of 5 atoms, said ring having one hetero atom
which is S, O, or N, and optionally 1, 2, or 3 additional N atoms; or the
heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero
atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said
substituents are selected from the group consisting of
(1 ) hydrogen,
(2) halo, including fluoro, chloro, bromo and iodo,
(3) C~ -C6 alkyl,
(4) C~ -C6 alkoxy,
(5) C~ -C6 alkylthio,
(6) CN,
(7) CF3,
($) Ns~
(9) -C~R~03)(R104)-OH, and
(10) -C(R~°3)(R104)-O-C~ -C4 alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R~o~ and R~°2 are the substituents residing on any position of -
A5=A6-
A'=A$- and are selected independently from the group consisting of
(a) hydrogen,
(b) CF3,
(c) CN,
(d) C~ -C6 alkyl,
(e) -Q3 wherein Q3 is Q4, C02 H, C(R'o3)(R~o4)OH,
(f) -O-Q4,
(g) -S-Q4, and
(h) optionally substituted:
(1 ) -C~ -C5 alkyl-Q3,
(2) -O-C~ -C5 alkyl-Q3,
(3) -S-C~ -C5 alkyl-Q3,
(4) -C~ -C3 alkyl-O-C~_3 alkyl-Q3,
(5) -C~ -C3 alkyl-S-C~_3 alkyl-Q3,
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(6) -C1 -C5 alkyl-O-Q4,
(7) -C1-C5 alkyl-S-Q4,
wherein the substituent resides on the alkyl chain and the substituent is C1
-C3 alkyl, and Q3 is Q4, C02 H, C(Rlo3)(Rloa.)OH Q4 is CO2 -C1-C4 alkyl,
tetrazolyl-5-yl, or C(R~ °3)(Rloa.)O-C1 -C4 alkyl;
R103~ Rloa. and R1°5 are each independently selected from the
group
consisting of hydrogen and C1 -C6 alkyl; or
R1°3 and Rloa. together with the carbon to which they are attached
form a
saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms, or two 8105
groups on the same carbon form a saturated monocyclic carbon ring of 3,
4, 5, 6 or 7 atoms;
R1°6 is hydrogen or C-, -C6 alkyl;
R1°' is hydrogen, C1-C6 alkyl or aryl;
X' is O, S, NRloy CO, C(R107)2, C(Rlo~)(OH)~ -C(Rlo~)_C(Rlo~)-; -
C(R1°')=N-; or-N=C(R1o')-
[0124 Compounds that may act as Cox-2 selective inhibitors
include salts of 5-amino or a substituted amino 1,2,3-triazole compound
that are described in U.S. Patent No. 6,239,137. The salts are of a class
of compounds of formula XXI:
8110
N
~~N xxl
Rlos N
~ 1os
wherein:
R1°s is:
_ (R112)n
X13-
-(CH2)p
~(R111)m
53
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wherein:
pisOto2;misOto4;andnisOtoS;
X13 is O, S, SO, S02, CO, CHCN, CHI or C=NR113 where 8113 IS
hydrogen, loweralkyl, hydroxyl, loweralkoxy, amino, loweralkylamino,
diloweralkylamino or cyano;
8111 and R1'2 are independently halogen, cyano, trifluoromethyl,
loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy,
trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl,
loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio,
trifluoromethylsulfinyl,
or trifluoromethylsulfonyl;
R1°9 is amino, mono or diloweralkyl amino, acetamido, acetimido,
ureido, formamido, or guanidino; and
R11° is carbamoyl, cyano, carbazoyl, amidino or N
hydroxycarbamoyl; wherein the loweralkyl, loweralkyl containing,
loweralkoxy and loweralkanoyl groups contain from 1 to 3 carbon atoms.
[0125] Pyrazole derivatives such as those described in U.S. Patent
6,136,831 can serve as a Cox-2 selective inhibitor of the present invention.
Such pyrazole derivatives have the formula shown below in formula XXII:
R1' 4.
~i N
8115 ~ 117
I ,R
~ 14
11'6\ X /N XXII
R N
Z6
wherein:
8114 IS hydrogen or halogen;
8115 and 8116 are each independently hydrogen, halogen, lower alkyl,
lower alkoxy, hydroxyl or lower alkanoyloxy;
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R11' is lower haloalkyl or lower alkyl;
X14 is sulfur, oxygen or NH; and
Z6 is lower alkylthio, lower alkylsulfonyl or sulfamoyl;
or a pharmaceutically acceptable salt thereof.
[0126] Materials that can serve as a Cox-2 selective inhibitor of the
present invention include substituted derivatives of benzosulphonamides
that are described in U.S. Patent 6,297,282. Such benzosulphonamide
derivatives have the formula shown below in formula XXIII:
8118
X15 S(o)m 8119
0 0 ~ ~N/ XXIII
\\ll ~ I
120
/S\ \ \ R
8123 NH
8124
wherein:
X15 denotes oxygen, sulphur or NH;
5
R11$ is an optionally unsaturated alkyl or alkyloxyalkyl group, optionally
mono- or polysubstituted or mixed substituted by halogen, alkoxy, oxo or
cyano, a cycloalkyl, aryl or fleteroaryl group optionally mono- or
polysubstituted or mixed su bstituted by halogen, alkyl, CF3, cyano or
alkoxy;
8119 and 8120, independently from one another, denote hydrogen, an
optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or
a
group (CH2)~ -X16; or
8119 and R12°, together with the N- atom, denote a 3 to 7-membered,
saturated, partially or completely unsaturated heterocycle with one or more
heteroatoms N, O or S, which can optionally be substituted by oxo, an
alkyl, alkylaryl or aryl group, or a group (CH2)n X16;
X16 denotes halogen, N02, -OR121, -COR121, -C02 8121, -OC02 8121,
-CN, -CONR121 OR122, -CONR121 8122, -SR121, -S(O)R121, -S(O)2
R121~ -NR121 R122~ -NHC(O)R121, -NHS(O)2 8121;
n denotes a whole number from 0 to 6;
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8123 denotes a straight-chained or branched alkyl group with 1-10 C-
atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, aralkyl
group, a heteroaryl or heteroaralkyl group which can optionally be mono-
or polysubstituted or mixed substituted by halogen or alkoxy;
8124 denotes halogen, hydroxyl, a straight-chained or branched alkyl,
alkoxy, acyloxy or alkyloxycarbonyl group with 1 to 6 carbon atoms, which
can optionally be mono- or polysubstituted by halogen, N02, -OR121, -
C~1~121, -CO2 R121~ -oC~2 8121 ~ -CN, -CONR121 OR122, -CONR121
R122~ -SR121~ -S(~)R121~ -S(O)2 R121~ -NR121 R122~ -NHC(O)R121, -
NHS(O)2 1121, or a polyfluoroalkyl group;
8121 and 8122, independently from one another, denote hydrogen, alkyl,
aralkyl or aryl; and '
m denotes a whole number from 0 to 2;
and the pharmaceutically-acceptable salts thereof.
[0127] Compounds that are useful as Cox-2 selective inhibitors of
the present invention include phenyl heterocycles that are described in
U.S. Patent Nos. 5,474,995 and 6,239,173. Such phenyl heterocyclic
compounds have the formula shown below in formula XXIV:
XXIV
8126 n~' '~Z7
e'
a X17--Y1
or pharmaceutically acceptable salts thereof wherein:
X1'-Y1-Z'-is selected from the group consisting of
(a) -CH2 CH2 CH2 -,
(b) -C(O)CH2 CH2 -,
(c) -CH2 CH2 C(O)-,
56
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(d) -CR~29 (R129')-O-C(O)-
(e) -C(O)-O-CR129 (R129')-~
(f) -CHZ -NR~z~ -CHZ -,
(g) -CR~29 (R~as')-NR~27 -C(O)-,
(h) -CR~z$=CR~z8~ -S-,
(i) -S-CR'2$=CR~28' -,
(j) -S-N=CH-,
(k) -CH=N-S-,
(I) -N=CR~zs -O-s
(m) -O-CR'2$ =N- ,
(n) -N=CR~2$ -NH-,
(o) -N=CR'2$ -S-, and
(p) -S-CR~za=N-
(q) -C(O)-NR~27 -CR~29 (R129')-
(r) -R~2' N-CH=CH- provided R~ ~2 is not -S(O)2CH3,
(s) -CH=CH-NR~2' - provided R'25 is not -S(O)2CH3;
when side b is a double bond, and sides a and c are single bonds; and
X~'-Y'-Z'-is selected from the group consisting of
(a) =CH-O-CH=, and
(b) =CH-NR~2' -CH=,
(c) =N-S-CH=,
(d) =CH-S-N=,
(e) =N-O-CH=,
(f) =CH-O-N=,
(g) =N-S-N=,
(h) =N-O-N=,
when sides a and c are double bonds and side b is a single bond;
R'25 is selected from the group consisting of
(a) S(O)2 CH3,
(b) S(O)2 NH2,
(c) S(O)2 NHC(O)CF3,
(d) S(O)(NH)CH3,
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(e) S(O)(NH)NH2,
(f) S(O)(NH)NHC(O)CF3,
(g) P(O)(CH3)OH, and
(h) P(O)(CH3)NH2;
R~26 is selected from the group consisting of
(a) C~ -C6 alkyl,
(b) C3, C4, C5, C6, and C~, cycloalkyl, ,
(c) mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituent
is selected from the group consisting of
(1 ) hydrogen,
(2) halo,
(3) C~ -C6 alkoxy,
(4) C~ -C6 alkylthio,
(5) CN,
(6) CF3,
(7) C~ -C6 alkyl,
(8) Ns~
(9) -C02 H,
(10) -C02 -C~ -C4 alkyl,
(11 ) -C(R~29)(R~so)-OH,
(12) -C(R~29)(R~30)-O-C~ -C4 alkyl, and
(13) -C~ -C6 alkyl-CO~ -R~29
(d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a
monocyclic aromatic ring of 5 atoms, said ring having one hetero atom
which is S, O, or N, and optionally 1, 2, or 3 add itionally N atoms; or the
heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero
atom which is N, and optionally 1, 2, 3, or 4 add itional N atoms; said
substituents are selected from the group consisting of
(1 ) hydrogen,
(2) halo, including fluoro, chloro, bromo and iodo,
(3) C~ -C6 alkyl,
(4) C~ -C6 alkoxy,
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(5) C~ -C6 alkylthlo,
(6) CN,
(7) CF3,
($) Ns~
(9) -C(R129)(R130)-~H, and
(10) -C(R~29)(R130)-O-C~ -C4 alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R'~' is selected from the group consisting of
(a) hydrogen,
(b) CF3,
(c) CN,
(d) C~ -C6 alkyl,
(e) hydroxyl C~ -C6 alkyl,
(f) -C(O)- C~ -C6 alkyl,
(g) optionally substituted:
(1 ) -C~ -C5 alkyl-Q5,
(2) -C~ -C5 alkyl-O-C~ -C3 alkyl-Q5,
(3) -C~ -C3 alkyl-S-C~ -C3 alkyl-Q5,
(4) -C~ -C5 alkyl-O-Q5, or
(5) -C~ -C5 alkyl-S-Q5,
wherein the substituent resides on the alkyl and the substituent is C~ -
C3 alkyl;
(h) -Q5~
R~~$ and R'28~ are each independently selected from the group consisting
of
(a) hydrogen,
(b) CF3,
(c) CN,
(d) C~ -C6 alkyl,
(e) -Q5,
(f) -O-Q5~
(g) -S-Q5, and
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(h) optionally substituted:
(1 ) -C1 -C5 alkyl-Q5,
(2) -O-C1 -C5 alkyl-Q5,
(3) -S-C1 -C5 alkyl-Q5,
(4) -C1-C3 alkyl-O-C1-C3 alkyl-Q5,
(5) -C1 -C3 alkyl-S-C1 -C3 alkyl-Q5,
(6) -C1 -C5 alkyl-O-Q5,
(7) -C1 -C5 alkyl-S-Q5,
wherein the substituent resides on the alkyl and the su bstituent is C1 -
C3 alkyl, and
Rl2s, R129', R130~ 8131 and 8132 are each independently selected from the
group consisting of
(a) hydrogen,
(b) C1 -C6 alkyl;
or 8129 and R13° or 8131 and 8132 together with the carbon to which
they
are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7
atoms;
Q5 is C02 H, C02-C1 -C4 alkyl, tetrazolyl-5-yl, C(Rla1)(Rla2)(OH), or
C(R131)(R132)(O-C1 -C4 alkyl);
provided that when X-Y-Z is -S-CR12$=CR128~, then R12$ and R128~ are
other than CF3.
(0128] An exemplary phenyl heterocycle that is disclosed in U.S.
Patent No. 6,239,173 is 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(2H)-
furanone.
(0129] Bicycliccarbonyl indole compounds such as those described
in U.S. Patent No. 6,303,628 are useful as Cox-2 selective inhibitors of the
present invention. Such bicycliccarbonyl indole compounds have the
formula shown below in formula XXV:
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Z$
9
A
O
(X19)n ~ ~ XXV
Z9 ~ (CH2)q
\Z10
"." , , .(CH2)m
or the pharmaceutically acceptable salts thereof wherein:
A9 is C1 -C6 alkylene or-NR133 -;
Z$ IS C(=L3)R134, Or SO2 8135 ;
Z9 is CH or N;
Z1° and Y~ are independently selected from -CH2 -, O, S and -N-
8133;
m is 1, 2 or 3;
q and r are independently 0, 1 or 2;
X1$ is independently selected from halogen, C1 -C4 alkyl, halo-substituted ,
C1 -C4 alkyl, hydroxyl, C1 -C4 alkoxy, halo-substituted C1-C4 alkoxy, C1 -
C4 alkylthio, vitro, amino, mono- or di-(C1 -C4 alkyl)amino and cyano;
n is 0, 1, 2, 3 or 4;
L3 is oxygen or sulfur;
8133 iS hydrogen or C1 -C4 alkyl;
8134 is hydroxyl, C1 -C6 alkyl, halo-substituted C1 -C6 alkyl, C1 -C6 alkoxy,
halo-substituted C1 -C6 alkoxy, C3 -C7 cycloalkoxy, C1-C4 alkyl(C3 -C7
cycloalkoxy), -NRl3s R13', C1 -C4 alkylphenyl-O- or phenyl-O-, said
phenyl being optionally substituted with one to five substituents
independently selected from halogen, C1 -C4 alkyl, hydroxyl, C1 -C4
alkoxy and vitro;
8135 iS C1 -C6 alkyl or halo-substituted C1-C6 alkyl; and
Rl3s and R13' are independently selected from hydrogen, C1_6 alkyl and
halo-substituted C1 -C6 alkyl.
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[0130] Materials that can serve as a Cox-2 selective inhibitor of the
present invention include benzimidazole compounds that are described in
U.S. Patent No. 6,310,079. Such benzimidazole compounds have the
formula shown below in formula XXVI:
N
~X21)n ~ ~ CR140~-CR139~R138 XXV~
N
10-(X20~m
or a pharmaceutically acceptable salt thereof, wherein:
A1° is heteroaryl selected from:
a 5-membered monocyclic aromatic ring having one hetero atom
selected from O, S and N and optionally containing one to three N atoms)
in addition to said hetero atom, or
a 6-membered monocyclic aromatic ring having one N atom and
optionally containing one to four N atoms) in addition to said N atom; and
said heteroaryl being connected to the nitrogen atom on the benzirnidazole
through a carbon atom on the heteroaryl ring;
X2° is independently selected from halo, C1 -C4 alkyl, hydroxyl,
C1 -
C4 alkoxy, halo-substituted C1 -C4 alkyl, hydroxyl-substituted C1 -C4 alkyl,
(C1 -C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, N-(C1
-C4 alkyl)amino, N, N-di(C1-C4 alkyl)amino, [N-(C1 -C4 alkyl)amino]C1-
C4 alkyl, [N, N-di(C1-C4 alkyl)amino]C1-C4 alkyl, N-(C1 -C4
alkanoyl)amonio, N-(C1-C4 alkyl)(C1 -C4 alkanoyl)amino, N-((C1 -C4
alkyl)sulfonyl]amino, N-[(halo-substituted C1 -C4 alkyl)sulfonyl]amino, C1 -
C4 alkanoyl, carboxy, (C1 -C4 alkoxy)carbonyl, carbamoyl, (N-(C1 -C4
alkyl)amino]carbonyl, [N, N-di(C1 -C4 alkyl)amino]carbonyl, cyano, nitro,
mercapto, (C1 -C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1 -C4 alkyl)sulfonyl,
aminosulfonyl, [N-(C1 -C4 alkyl)amino]sulfonyl and (N, N-di(C1 -C4
alkyl)amino]sulfonyl;
X21 is independently selected from halo, C1-C4 alkyl, hydroxyl, C1 -
C4 alkoxy, halo-substituted C1 -C4 alkyl, hydroxyl-substituted C1 -G4 alkyl,
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(C~ -C4 alkoxy)C~ -C4 alkyl, halo-substituted C~ -C4 alkoxy, amino, N-(C~
-C4 alkyl)amino, N, N-di(C~ -C4 alkyl)amino, [N-(C~ -C4 alkyl)amino]C~ -
C4 alkyl, [N, N-di(C~ -C4 alkyl)arni no]C~ -C4 alkyl, N-(C~ -C4
alkanoyl)amino, N-(C~ -C4 alkyl)-N-(C~ -C4 alkanoyl) amino, N-[(C~ -C4
alkyl)sulfonyl]amino, N-[(halo-substituted C~ -C4 alkyl)sulfonyl]amino, C~ -
C4 alkanoyl, carboxy, (C~ -C4 alkoxy)hydroxyl, cabamoyl, [N-(C~ -C4 alkyl)
amino]carbonyl, [N, N-di(C~ -C4 alkyl)amino]carbonyl, N-carbomoylamino,
cyano, vitro, mercapto, (C~ -C4 al kyl)thio, (C~ -C4 alkyl)sulfinyl, (C~ -C4
alkyl)sulfonyl, aminosulfonyl, [N-(C~ -C4 alkyl)amino]sulfonyl and [N, N-
di(C~ -C4 alkyl)amino]sulfonyl;
R~3$ is selected from hydrogen; straight or branched C~ -C4 alkyl
optionally substituted with one to three substituent(s) wherein said
substituents are independently selected from halo, hydroxyl, C~ -C4
alkoxy, amino, N-(C~ -C4 alkyl)amino and N, N-di(C~ -C4 alkyl)amino; C3
-C$ cycloalkyl optionally substituted with one to three su.bstituent(s)
wherein said substituents are indepently selected from halo, ~C~ -C4 alkyl,
hydroxyl, C~ -C4 alkoxy, amino, N-(C~ -C4 alkyl)amino and N, N-di(C~ -C4
alkyl)amino; C4 -C$ cycloalkenyl optionally substituted with one to three
substituent(s) wherein said substituents are independently selected from
halo, C~ -C4 alkyl, hydroxyl, C~ -C~. alkoxy, amino, N-(C~ -C4 alkyl)amino
and N, N-di(C~ -C4 alkyl)amino; phenyl optionally substituted with one to
three substituent(s) wherein said substituents are independently selected
from halo, C~ -C4 alkyl, hydroxyl, C~ -C4 alkoxy, halo-substituted C~ -C4
alkyl, hydroxyl-substituted C~ -C4 alkyl, (C~ -C~. alkoxy)C~ -C4 alkyl, halo-
substifiuted C~ -C4 alkoxy, amino, N-(C~ -C4 alkyl)amino, N, N-di(C~ -C4
alkyl)amino, [N-(C~ -Ca alkyl)arni no]C~ -C4 alkyl, [N, N-di(C~ -C4
alkyl)amino]C~ -C4 alkyl, N-(C~ -C4 alkanoyl)amino, N-[C~ -C4 alkyl)(C~ -
C4 alkanoyl)]amino, N-[(C~ -C4 alkyl)sulfony]amino, N-[(halo-substituted C-,
-C4 alkyl)sulfonyl]amino, C~ -C4 alkanoyl, carboxy, (C~ -C4
alkoxy)carbonyl, carbomoyl, [N-(C~ -C4 alky)amino]carbonyl, [N, N-di(C~ -
C4 alkyl)amino]carbonyl, cyano, vitro, mercapto, (C~ -C4 alkyl)thio, (C~ -C~.
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alkyl)sulfinyl, (C~ -C4 alkyl)sulfonyl, aminosulfonyl, [N-(C~ -C4
alkyl)amino]sulfonyl and [N, N-di(C~ -C4 alkyl)amino]sulfonyl; and
heteroaryl selected from: a 5-membered monocyclic aromatic ring having
one hetero atom selected from O, S and N and optionally containing one
to three N atoms) in addition to said hetero atom; or a 6-membered
monocyclic aromatic ring having one N atom and optionally containing one
to four N atoms) in addition to said N atom; and said heteroaryl being
optionally substituted with one to three substituent(s) selected from
X2° ;
R~39 and R~4o are independently selected from: hydrogen; halo; C~ -
C4 alkyl; phenyl optionally substituted with one to three substituent(s)
wherein said substituents are independently selected from halo, C~ -C4
alkyl, hydroxyl, C~ -C4 alkoxy, amino, N-(C~ -C4 alkyl)amino and N, N-
di(C~ -C4 alkyl)amino; or R~3$ and R'39 can form, together with the carbon
atom to which they are attached, a C3 -C7 cycloalkyl ring;
m is 0, 1, 2, 3, 4 or 5; and
nis0,1,2,3or4.
[0131] Compounds that may be employed as a Cox-2 selective
inhibitor of the present invention include indole compounds that are
described in U.S. Patent No. 6,300,363. Such indole compounds have the
formula shown below in formula XXVII:
_4
XXVII
~X22)n-
~3-Q6
and the pharmaceutically acceptable salts thereof, wherein:
L4 is oxygen or sulfur;
Y3 is a direct bond or C~ -C4 alkylidene;
Q6 is:
64
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(a) C~ -C6 alkyl or halosubstituted C~ -C6 alkyl, said alkyl being optionally
substituted with up to three substituents independently selected from
hydroxyl, C~ -C4 alkoxy, amino and mono- or di-( C~ -C4 alkyl)amino,
(b) C3 -C~ cycloalkyl optionally substituted with up to three substituents
independently selected from hydroxyl, C~ -C4 alkyl and C~ -C4 alkoxy,
(c) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted
with up to four substituents independently selected from:
(c-1 ) halo, C~ -C4 alkyl, halosubstituted C~ -C4 alkyl, hydroxyl, C~ -C4
alkoxy, halosubstituted C~ -C4 alkoxy, S(O)m R~43, SO2 NH2, S02 N(C~
-C4 alkyl)2, amino, mono- or di-( C~ -C4 alkyl)amino, NHS02 R~43,
NHC(O)R'43, CN, C02 H, C02 (C~ -C4 alkyl), C~ -C4 alkyl-OH, C~ -C4
alkyl-OR~43, CONH2, CONH(C~ -C4 alkyl), CON(C~ -C4 alkyl)2 and -
O-Y-phenyl, said phenyl being optionally substituted with one or two
substituents independently selected from halo, C~ -C4 alkyl, CF3,
hydroxyl, OR~43, S(O)mR143~ amino, mono- or di-( C~ -C4 alkyl)amino
and CN;
(d) a monocyclic aromatic group of 5 atoms, said aromatic group Having
one heteroatom selected from O, S and N and optionally containing up to
three N atoms in addition to said heteroatom, and said aromatic group
being substituted with up to three substitutents independently selected
from:
(d-1 ) halo, C~ -C4 alkyl, halosubstituted C~ -C4 alkyl, hydroxyl, C~ -C4
alkoxy, halosubstituted C~ -C4 alkoxy, C~ -C4 alkyl-OH, S(O)m R~43,
S02 NH2, SO~ N(C~ -C4 alkyl)2, amino, mono- or di-( C~ -C4
alkyl)amino, NHS02 R~43, NHC(O)R~43, CN, C02 H, CO~ (C~ -C4 alkyl),
C~ -C4 alkyl-OR''~3, CONH2, CONH(C~ -C4 alkyl), CON(C~ -C4 alkyl)2,
phenyl, and mono-, di- or tri-substituted phenyl wherein the substituent
is independently selected from halo, CF3, C~ -C4 alkyl, hydroxyl, C~ -
C4 alkoxy, OCF3, SR~43, S02 CH3, S02 NH2, amino, C~_4 alkylamino
and NHS02 R~43;
(e) a monocyclic aromatic group of 6 atoms, said aromatic group having
one heteroatom which is N and optionally containing up to three atoms in
CA 02556380 2006-08-14
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addition to said heteroatom, and said aromatic group being substituted
with up to three substituents independently selected from the above group
(d-1 );
8141 IS hydrogen or C1-C6 alkyl optionally substituted with a substituent
selected independently from hydroxyl, ORl4s, vitro, amino, mono- or di-( C1
-C4 alkyl)amino, C02 H, C02 (C1 -C4 alkyl), CONH2, CONH(C1-C4 alkyl)
and CON(C1 -C4 alkyl)2 ;
8142 jS:
(a) hydrogen,
(b) C1 -C4 alkyl,
(c) C(O)R145~
wherein 8145 is selected from:
(c-1 ) C1 -C22 alkyl or C2 -C22 alkenyl, said alkyl or alkenyl being
optionally substituted with up to four substituents independently
selected from:
(c-1-1 ) halo, hydroxyl, OR143, S(O)m 8143, vitro, amino, mono- or di-
C1 -C4 alkyl)amino, NHS02 8143, C02 H, CO2 (C1 -C4 alkyl), CONH2,
CONH(C1 -C4 alkyl), CON(C1 -C4 alkyl)2, OC(O)Rl4a, thienyl,
naphthyl and groups of the following formulas:
66
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(X22)n
NHS02 ~ NHS02
(X22)n
(X22)n ~ (X22)n
S ' ~ '
O
O
N/(CH2)p N/(CH2)P
> >
O
(CH2)q (CH2)q
N~ ~Z~~ and N~ ~Z11
(c-2) C~ -C22 alkyl or C2 -C22 alkenyl, said alkyl or alkenyl being
optionally substituted with five to forty-five halogen atoms,
(c-3) -Y5-C3 -C~ cycloalkyl or -Y5-C3 -C7 cycloalkenyl, said
cycloalkyl or cycloalkenyl being optionally substituted with up to three
substituent independently selected from:
(c-3-1 ) C~ -C4 alkyl, hydroxyl, OR~43, S(O)m R143~ amino, mono- or di-
( C~ -C4 alkyl)amino, CONH2, CONH(C~ -C4 alkyl) and CON(C~ -C4
alkyl)2,
(c-4) phenyl or naphthyl, said phenyl or naphthyl being optionally
substituted with up to seven (preferably up to seven) substituents
independently selected from:
67
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(c-4-1 ) halo, C1-C$ alkyl, C1-C4 alkyl-OH, hydroxyl, C1 -C$ alkoxy,
halosubstituted C1 -C$ alkyl, halosubstituted C1 -C$ alkoxy, CN, nitro,
S(O)", R143~ S02 NH2, S02 NH(C1 -C4 alkyl), S02 N(C1-C4 alkyl)2,
amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, CONH2, CONH(C1
-C4 alkyl), CON(C1 -C4 alkyl), OC(O)R143' and phenyl optionally
substituted with up to three substituents independently selected from
halo, C1-C4 alkyl, hydroxyl, OCH3, CF3, OCF3, CN, nitro, amino,
mono- or di-(C1 -C4 alkyl)amino, C02 H, C02 (C1 -C4 al kyl) and
CONH2,
(c-5) a monocyclic aromatic group as defined in (d) and (e) above, said
aromatic group being optionally substituted with up to three
substituents independently selected from:
(c-5-1 ) halo, C1-C$ alkyl, C1 -C4 alkyl-OH, hydroxyl, C1 -C$ alkoxy,
CF3, OCF3, CN, nitro, S(O)m 8143, amino, mono- or di-( C1 -C4
alkyl)amino, CONH~, CONH(C1 -C4 alkyl), CON(C1-Cø alkyl)2, C02
H and C02 (C1 -C4 alkyl), and -Y-phenyl, said phenyl being
optionally substituted with up to three substituents independently
selected halogen, C1 -C4 alkyl, hydroxyl, C1 -C4 alkoxy', CF3, OCF3,
CN, nitro, S(O)m 1143, amino, mono- or di-( C1 -C4 alkyd )amino, C02
H, C02 (C1-C4 alkyl), CONH2, CONH(C1-C4 alkyl) and CON(C1 -C4
alkyl)2,
(c-6) a group of the following formula:
(CH\2)e
\Z11
(CH2)n
X22 is halo, C1-C4 alkyl, hydroxyl, C1 -C4 alkoxy, halosubstitutued C1 -C4
alkoxy, S(O)m 1143, amino, mono- or di-(C1 -C4 alkyl)amino, NHS02 8143'
nitro, halosubstitutued C1 -C4 alkyl, CN, C02 H, C02 (C1 -Cue. alkyl), C1 -C4
alkyl-OH, C1 -C4 alkylOR143, CONH2, CONH(C1 -C4 alkyl) o r CON(C1 -C4
alkyl)2 ;
8143 is C1 -C4 alkyl or halosubstituted C1 -C4 alkyl;
m is 0, 1 or 2; n is 0, 1, 2 or 3; p is 1, 2, 3, 4 or 5; q is 2 or 3;
68
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Z'~ is oxygen, sulfur or NR~44 ; and
R~44 Is hydrogen, C~ -C6 alkyl, halosubstitutued C~ -C4 alkyl or-Y5-
phenyl, said phenyl being optionally substituted with up to two substituents
independently selected from halo, C~ -C4 alkyl, hydroxyl, C~ -C4 alkoxy,
S(O)m R~43, amino, mono- or di-(C~ -C4 alkyl)amino, CF3, OCF3, CN and
nitro;
with the proviso that a group of formula -Y5-Q is not methyl or ethyl when
X22 is hydrogen;
L4 is oxygen;
1O 1~~41 IS hydrogen; and
R'42 is acetyl.
[0132] Aryl phenylhydrazides that are described in U.S. Patent No.
6,077,869 can serve as Cox-2 selective inhibitors of the present invention.
Such aryl phenylhydrazides have the formula shown below in formula
XXVIII: ,
H
~N ~ ,
XXVIII
~~i
X23 ~r6
wherein:
X23 and Y6 are selected from hydrogen, halogen, alkyl, nitro, amino,
hydroxy, methoxy and methylsulfonyl;
or a pharmaceutically acceptable salt thereof,.
[0133] Materials that can serve as a Cox-2 selective inhibitor of the
present invention include 2-aryloxy, 4-aryl furan-2-ones that are described
in U.S. Patent No. 6,140,515. Such 2-aryloxy, 4-aryl furan-2-ones have
the formula shown below in formula XXIX:
69
CA 02556380 2006-08-14
WO 2005/084654 PCT/US2005/006818
8146
8149
8148
lllllan
O
8147
O
or a pharmaceutical salt thereof, wherein:
8146 is selected from the group consisting of SCH3, -S(O)2 CH3 and -
S(O)S NH2 ;
8147 is selected from the group consisting of OR15°, mono or di-
substituted
phenyl or pyridyl wherein the substituents are selected from the group
consisting of methyl, chloro and F;
RlSO is unsubstituted or mono or di-substituted phenyl or pyridyl wherein
the substituents are selected from the group consisting of methyl, chloro
and F;
R14$ is H, C1 -C4 alkyl optionally substituted with 1 to 3 groups of F, CI or
Br; and
8149 Is H, C1 -C4 alkyl optionally substituted with 1 to 3 groups of F, CI or
Br, with the proviso that R14$ and 8149 are not the same.
[0134] Materials that can serve as a Cox-2 selective inhibitor of the
present invention include bisaryl compounds that are described in U.S.
Patent No. 5,994,379. Such bisaryl compounds have the formula shown
below in formula XXX:
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(R151 )0_1
1 13 8152
A
W
8153
8154 ~CO2H
XXX
or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein:
Z13 is C or N;
when Z13 IS N, 8151 represents H or is absent, or is taken in conjunction
with 8152 as described below:
when Z13 IS C, 8151 represents H and 8152 is a moiety which has the ,
following characteristics:
(a) it is a linear chain of 3-4 atoms containing 0-2 double bonds, which can
adopt an energetically stable transoid configuration and if a double bond is
present, the bond is in the trans configuration,
(b) it is lipophilic except for the atom bonded directly to ring A, which is
either lipophilic or non-lipophilic, and
(c) there exists an energetically stable configuration planar with ring A to
within about 15 degrees;
or 8151 and 8152 are taken in combination and represent a 5- or 6-
membered aromatic or non-aromatic ring D fused to ring A, said ring D
containing 0-3 heteroatoms selected from O, S and N;
said ring D being lipophilic except for the atoms attached directly to ring A,
which are lipophilic or non-lipophilic, and said ring D having available an
71
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energetically stable configuration planar with ring A to within about 15
degrees;
said ring D further being substituted with 1 Ra group selected from the
group consisting of C1-C2 alkyl, -OC1 -C2 alkyl, -NHC1-C2 alkyl, -
N(C1 -C2 alkyl)2, -C(O) C1 -C2 alkyl, -S-C1 -C2 alkyl and -C(S) C1 -
C2 alkyl;
Y7 represents N, CH or C-OC1 -C3 alkyl, and when Z13 is N, Y~ can also
represent a carbonyl group;
8153 represents H, Br, CI or F; and
8154 represents H or CH3.
[0135] Compounds useful as Cox-2 selective inhibitors of the
present invention include 1,5-diarylpyrazoles that are described in U.S.
Patent No. 6,028,202. Such 1,5-diarylpyrazoles have the formula shown
below in formula XXXI:
8158
8160
R15 ~~
N N ~ R161
N
R1 WC
O
8159
R' ~~
wherein:
R155~ R156~ R157~ and R15$ are independently selected from the groups
consisting of hydrogen, C1-C5 alkyl, C1 -C5 alkoxy, phenyl, halo, hydroxyl,
C1 -C5 alkylsulfonyl, C1 -C5 alkylthio, trihaloCl -C5 alkyl, amino, vitro and
2-quinolinylmethoxy;
8159 Is hydrogen, C1 -C5 alkyl, trihaloCl -C5 alkyl, phenyl, substituted
phenyl where the phenyl substitutents are halogen, C1 -C5 alkoxy,
72
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trihaloC~ -C5 alkyl or vitro or R~59 IS heteroaryl of 5-7 ring members where
at least one of the ring members is nitrogen, sulfur or oxygen;
8160 jS hydrogen, C~ -C5 alkyl, phenyl C~ -C5 alkyl, substituted phenyl C~ -
C5 alkyl where the phenyl substitutents are halogen, C~ -C5 alkoxy,
trihaloC~ -C5 alkyl or vitro, or R~60 is C~ -C5 alkoxycarbonyl,
phenoxycarbonyl, substituted phenoxycarbonyl where the phenyl
substitutents are halogen, C~ -C5 alkoxy, trihaloC~ -C5 alkyl or vitro;
8161 jS C~ -C~o alkyl, substituted C~ -Coo alkyl where the substituents are
halogen, trihaloC~ -C5 alkyl, C~ -C5 alkoxy, carboxy, C~ -C5
alkoxycarbonyl, amino, C~ -C5 alkylamino, diC~ -C5 alkylamino, diC~ -C5
alkylaminoC~ -C5 alkylamino, C~ -C5 alkylaminoC~ -C5 alkylamino or a
heterocycle containing 4-8 ring atoms where one more of the ring atoms is
nitrogen, oxygen or sulfur, where said heterocycle may be optionally
substituted with C~ -C5 alkyl; or R~61 Is phenyl, substituted phenyl (where
the phenyl substitutents are one or more of C~ -C5 alkyl, halogen, C~ -C5
alkoxy, trihaloC~ -C5 alkyl or vitro), or R'61 Is heteroaryl having 5-7 ring
atoms where one or more atoms are nitrogen, oxygen or sulfur, fused
heteroaryl where one or more 5-7 membered aromatic rings are fused to
the heteroaryl; or
2O R~61 Is NR~63 8164 where R~63 and R'64 are independently selected from
hydrogen and C~_5 alkyl or R~63 and R~64 may be taken together with the
depicted nitrogen to form a heteroaryl ring of 5-7 ring members where one
or more of the ring members is nitrogen, sulfur or oxygen where said
heteroaryl ring may be optionally substituted with C~ -C5 alkyl; R'62 is
hydrogen, C~ -C5 alkyl, vitro, amino, and halogen;
and pharmaceutically acceptable salts thereof.
(0136 Materials that can serve as a Cox-2 selective inhibitor of the
present invention include 2-substituted imidazoles that are described in
U.S. Patent No. 6,040,320. Such 2-substituted imidazoles have the
formula shown below in formula XXXII:
73
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WO 2005/084654 PCT/US2005/006818
8166
8165
N
8167
8164 N
wherein:
8164 is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring
atoms, or
substituted phenyl;
wherein the substituents are independently selected from one or members
of the group consisting of C1_5 alkyl, halogen, nitro, trifluoromethyl and
nitrite;
8165 is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring
atoms,
substituted heteroaryl;
wherein the substituents are independently selected from one or more
members of the group consisting of C1-C5 alkyl and halogen, or
substituted phenyl,
wherein the substituents are independently selected from one or members
of the group consisting of C1 -C5 alkyl, halogen, nitro, trifluoromethyl and
nitrite;
8166 Is hydrogen, 2-(trimethylsilyl)ethoxymethyl), C1 -C5 alkoxycarbonyl,
aryloxycarbonyl, arylCl -C5 alkyloxycarbonyl, arylCl -C5 alkyl,
phthalimidoCl -C5 alkyl, aminoCl -C5 alkyl, diaminoCl -C5 alkyl,
succinimidoCl -C5 alkyl, C1 -C5 alkylcarbonyl, arylcarbonyl, C1 -C5
alkylcarbonylCl -C5 alkyl, aryloxycarbonylCl -C5 alkyl, heteroarylCl -C5
alkyl where the heteroaryl contains 5 to 6 ring atoms, or
substituted arylCl -C5 alkyl,
wherein the aryl substituents are independently selected from one or more
members of the group consisting of C1 -C5 alkyl, C1 -C5 alkoxy, halogen,
amino, C1 -C5 alkylamino, and diC1 -C5 alkylamino;
8167 IS (A11 )" -(CH165)g -~2a. wherein:
74
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WO 2005/084654 PCT/US2005/006818
A~~ is sulfur or carbonyl;
nis0or1;
q is 0-9;
Xa4 is selected from the group consisting of hydrogen, hydroxyl, halogen,
vinyl, ethynyl, C~ -C5 alkyl, C3 -C~ cycloalkyl, C~ -C5 alkoxy, phenoxy,
phenyl, arylC~ -C5 alkyl, amino, C~ -C5 alkylamino, nitrite, phthalimido,
amido, phenylcarbonyl, C~ -C5 alkylaminocarbonyl, phenylaminocarbonyl,
arylC~ -C5 alkylaminocarbonyl, C~ -C5 alkylthio, C~ -C5 alkylsulfonyl,
phenylsulfonyl,
substituted sulfonamido,
wherein the sulfonyl substituent is selected from the group consisting of C~
-C5 alkyl, phenyl, araC~ -C5 alkyl, thienyl, furanyl, and naphthyl;
substituted vinyl,
wherein the substituents are independently selected from one or members
of the group consisting of fluorine, bromine, chlorine and iodine,
substituted ethynyl,
wherein the substituents are independently selected from one or more
members of the group consisting of fluorine, bromine chlorine and iodine,
substituted C~ -C5 alkyl,
wherein the substituents are selected from the group consisting of one or
more C~ -C5 alkoxy, trihaloalkyl, phthalimido and amino,
substituted phenyl,
wherein the phenyl substituents are independently selected from one or
more members of the group consisting of C~ -C5 alkyl, halogen and C~ -C5
alkoxy,
substituted phenoxy,
wherein the phenyl substituents are independently selected from one or
more members of the group consisting of C~ -C5 alkyl, halogen and C~ -C5
alkoxy,
substituted C~ -C5 alkoxy,
wherein the alkyl substituent is selected from the group consisting of
phthalimido and amino,
CA 02556380 2006-08-14
WO 2005/084654 PCT/US2005/006818
substituted arylC~ -C5 alkyl,
wherein the alkyl substituent is hydroxyl,
substituted arylC~ -C5 alkyl,
wherein the phenyl substituents are independently selected from one or
more members of the group consisting of C~ -C5 alkyl, halogen and C~ -C5
al koxy,
substituted amido,
wherein the carbonyl substituent is selected from the group consisting of
C~ -C5 alkyl, phenyl, arylC~ -C5 alkyl, thienyl, furanyl, and naphthyl,
substituted phenylcarbonyl,
wherein the phenyl substituents are independently selected from one or
members of the group consisting of C~ -C5 alkyl, halogen and C~ -C5
alkoxy,
substituted C~ -C5 alkylthio,
wherein the alkyl substituent is selected from the group consisting of
hydroxyl and phthalimido,
substituted C~ -C5 alkylsulfonyl,
wherein the alkyl substituent is selected from the group consisting of
hydroxyl and phthalimido,
substituted phenylsulfonyl,
wherein the phenyl substituents are independently selected from one or
members of the group consisting of bromine, fluorine, chlorine, C~ -C5
alkoxy and trifluoromethyl,
with the proviso:
if A~~ is sulfur and X24 is other than hydrogen, C~ -C5 alkylaminocarbonyl,
phenylaminocarbonyl, arylC~ -C5 alkylaminocarbonyl, C~ -C5 alkylsulfonyl
or phenylsulfonyl, then q must be equal to or greater than 1;
if A~~ is sulfur and q is 1, then X24 cannot be C~ -C2 alkyl;
if A~~ is carbonyl and q is 0, then X24 cannot be vinyl, ethynyl, C~ -C5
alkylaminocarbonyl, phenylaminocarbonyl, arylC~ -C5 alkylaminocarbonyl,
C~ -C5 alkylsulfonyl or phenylsulfonyl;
76
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if A11 is carbonyl, q is 0 and X~4 is H, then Rls6 is not 2-
(trimethylsilyl)ethoxymethyl;
if n is 0 and q is 0, then X24 cannot be hydrogen;
and pharmaceutically acceptable salts thereof.
[0137] Materials that can serve as a Cox-2 selective inhibitor of the
present invention include 1,3- and 2,3-diarylcycloalkano and cycloalkeno
pyrazoles that are described in U.S. Patent No. 6,083,969. Such 1,3- and
2,3-diarylpyrazole compounds have the general formulas shown below in
formulas XXXIII and XXXIV:
8169
XXXI I I
8168
8169
XXXIV
8168
wherein:
R16$ and 8169 are independently selected from the group consisting of
hydrogen, halogen, (C1 -C6)alkyl, (C1 -C6)alkoxy, nitro, amino Oydroxyl,
77
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trifluoro, -S(C1 -C6)alkyl, -SO(C1 -C6)alkyl and -S02 (C1-C6)alkyl;
and
the fused moiety M is a group selected from the group consisting of an
optionally substituted cyclohexyl and cycloheptyl group having the
formulae:
.173
8172
,or
Rl7o
172
R17° is selected from the group consisting of hydrogen, halogen,
hydroxyl
and carbonyl;
or R17° and 8171 taken together form a moiety selected from the group
consisting of -OCOCH2 -, -ONH(CH3)COCH2 -, -OCOCH= and -
O-;
8171 and 8172 are independently selected from the group consisting of
hydrogen, halogen, hydroxyl, carbonyl, amino, (C1 -C6)alkyl, (C1 -
C6)alkoxy, =NOH, -NR174 8175, -OCH3, -OCH2 CH3, -OS02 NHC02
CH3, =CHC02 CH2 CH3, -CH2 C02 H, -CH2 C02 CH3, -CH2 C02 CH2
CH3, -CH2 CON(CH3)2, -CH2 C02 NHCH3, -CHCHC02 CH2 CH3, -
OCON(CH3)OH, -C(COCH3)2, di(C1 -C6)alkyl and di(C1 -C6)alkoxy;
8173 is selected from the group consisting of hydrogen, halogen, hydroxyl,
carbonyl, amino, (C1 -C6)alkyl, (C1 -C6)alkoxy and optionally substituted
carboxyphenyl, wherein substituents on the carboxyphenyl group are
selected from the group consisting of halogen, hydroxyl, amino, (C1 -
C6)alkyl and (C1 -C6)alkoxy;
or 8172 and 8173 taken together form a moiety selected from the group
consisting of -O-and
78
wherein:
CA 02556380 2006-08-14
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F
8174 is selected from the group consisting of hydrogen, OH, -OCOCH3,
-COCH3 and (C1 -C6)alkyl; and
8175 is selected from the group consisting of hydrogen, OH, -OCOCH3,
-COCH3, (C1 -C6)alkyl, -CONH2 and -S02 CH3 ;
with the proviso that
if M is a cyclohexyl group, then 8170 through 8173 may not all be hydrogen;
and
pharmaceutically acceptable salts, esters and pro-drug forms thereof.
[0138] Esters derived from indolealkanols and novel amides derived
from indolealkylamides that are described in U.S. Patent No. 6,306,890
can serve as Cox-2 selective inhibitors of the present invention. Such
compounds have the general formula shown below in formula XXXV:
0
8176
~CH2)n-X25
8177 ~XV
~ R178
N/
179
wherein:
8176 is C1 -C6 alkyl, C1 -C6 branched alkyl, C4 -C$ cycloalkyl, C1-C6
hydroxyalkyl, branched C1 -C6 hydroxyalkyl, hydroxyl substituted C4 -C$
79
CA 02556380 2006-08-14
WO 2005/084654 PCT/US2005/006818
aryl, primary, secondary or tertiary C1-C6 alkylamino, primary, secondary
or tertiary branched C1-C6 alkylamino, primary, secondary or tertiary C4 -
C$ arylamino, C1 -C6 alkylcarboxylic acid, branched C1 -C6 alkylcarboxylic
acid, C1 -C6 alkylester, branched C1 -C6 alkylester, C4 -C$ aryl, C4 -C$
arylcarboxylic acid, C4 -C$ arylester, C4 -C$ aryl substituted C1 -C6 alkyl,
C4 -C$ heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-
substituted
or aryl-substituted C4 -C$ heterocyclic alkyl or aryl with O, N or S in the
ring, or halo-substituted versions thereof, where halo is chloro, bromo,
fluoro or iodo;
R1" is C1 -C6 alkyl, C1-C6 branched alkyl, C4 -C$ cycloalkyl, C4 -C$ aryl,
C4 -C$ aryl-substituted C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C6 branched
alkoxy, C4 -C$ aryloxy, or halo-substituted versions thereof or R1" is halo
where halo is chloro, fluoro, bromo, or iodo;
R1'8 is hydrogen, C1 -C6 alkyl or C1-C6 branched alkyl;
R1'9 is C1 -C6 alkyl, C4 -C$ aroyl, C4 -C$ aryl, C4 -C$ heterocyclic alkyl or
aryl with O, N or S in the ring, C4 -C$ aryl-substituted C1 -C6 alkyl, .alkyl-
substituted or aryl-substituted C4 -C$ hetero~yclic alkyl or aryl with~0, N or
S in the ring, alkyl-substituted C4 -C$ aroyl, or alkyl-substituted C4 -C$
aryl, or halo-substituted versions thereof where halo is chloro, bromo, or
iodo;
n is 1, 2, 3, or 4; and
X25 is O, NH, or N-R1$°, where R1$° is C1 -C6 or C1 -C6
branched alkyl.
[0139] Materials that can serve as a Cox-2 selective inhibitor of the
present invention include pyridazinone compounds that are described in
U.S. Patent No. 6,307,047. Such pyridazinone compounds have the
formula shown below in formula XXXVI:
8184 N X181
~N~
XXXVI
Rls3
8182
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:
CA 02556380 2006-08-14
WO 2005/084654 PCT/US2005/006818
X26 is selected from the group consisting of O, S, -NRls5, -NORa, and -
N N Rb R~ ;
RIBS is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl,
cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic,
and
heterocyclic alkyl;
Ra, Rb, and R° are independently selected from the group
consisting of
alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;
Rla1 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl,
alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl,
aryl,
arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl,
arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl,
arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl,
haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic, heterocyclic
alkoxy, heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl,
hydroxyiminoalkoxy, -(CH2)n C(O)RlBS, -(CH2)n CH(OH)R186, -(CH2)n
C(NORd)Rls6, -(CH2)n CH(NORd)Rls6, -(CH~)~ CH(NRd Re)Rls6, -8187
188 188 26' 188
R , -(CH2)" C=CR , -(CH2)n (CH(CX s)]m (CH2)p R , -(CH2)n
(CX26~2)m (CH2)p Rlsa~ and -(CH2)" (CHX26~)m (CH2)m Rlss ;
RIBS is selected from the group consisting of hydrogen, alkenyl, alkyl,
alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl,
haloalkynyl, heterocyclic, and heterocyclic alkyl;
R1s' is selected from the group consisting of alkenylene, alkylene, halo-
substituted alkenylene, and halo-substituted alkylene;
RlsB is selected from the group consisting of hydrogen, alkenyl, alkyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic,
and
heterocyclic alkyl;
Rd and Re are independently selected from the group consisting of
hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl,
haloalkyl, heterocyclic, and heterocyclic alkyl;
X26 is halogen;
m is an integer from 0-5;
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n is an integer from 0-10;
p is an integer from 0-10;
R182~ R183~ and 8184 are independently selected from the group consisting
of hydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy, alkoxyiminoalkyl,
alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbonylamino,
alkylcarbonylaminoalkyl, aminoalkoxy, aminoalkylcarbonyloxyalkoxy
aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl,
carboxyalkylcarbonyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl,
cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen,
heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl,
mercaptoalkoxy, nitro, phosphonatoalkoxy, Y8, and Z14;
provided that one of 8182, 8183, or 8184 must be Z14, and further provided
that only one of 8182, 8183, or 8184 is X14;
Z14 is selected from the group consisting of
x28
x28
--
x27-8190 and
x27-8190
S
X27 is selected from the group consisting of S(O)2, S(O)(NR191), S(Q),
Se(O)2, P(O)(OR192), and P(O)(NR193 8194);
X28 is selected from the group consisting of hydrogen, alkenyl, alkyl,
alkynyl and halogen;
R19° is selected from the group consisting of alkenyl, alkoxy,
alkyl,
alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl,
dialkylamino, -NHNH2, and -NCHN(R191)R192 ;
8191, 8192, 8193, and 8194 are independently selected from the group
consisting of hydrogen, alkyl, and cycloalkyl, or 8193 and 8194 can be taken
together, with the nitrogen to which they are attached, to form a 3-6
membered ring containing 1 or 2 heteroatoms selected from the group
consisting of O, S, and NR188 ;
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Y$ is selected from the group consisting of -OR~95, -SR~95, -
C~R197~~R198~R195~ -C~O~R195~ _C~O~~R195~ -N~R197~C~~~R195~ -
N'C(R~9/,')R~95, and -Nl(RI~9')R~95 ' l ' I;
R~95 is selected from the group consisting of hydrogen, alkenyl,
alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocyclic
alkyl,
hydroxyalkyl, and NR'99 R2oo ; and
R~9', R'98, R~99, and R2°° are independently selected from
the group
consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl,
aryl,
arylalkyl, heterocyclic, and heterocyclic alkyl.
[0140] Benzosulphonamide derivatives that are described in U.S.
Patent No. 6,004,948 are useful as Cox-2 selective inhibitors of the
present invention. Such benzosulphonamide derivatives have the formula
shown below in formula XXXVII:
8201
A12
5 XXXV I I
~S~
8206/
wherein:
A~2 denotes oxygen, sulphur or NH;
8201 denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or
polysubstituted by halogen, alkyl, CF3 or alkoxy;
D5 denotes a group of formula XXXVIII or XXXIX:
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S(o)m
\ ~ R2o2
XXXVIII
\ R2oa
or
S(o)m
/N R2o2~ XXXIX
\ X15
R2°2 and R2°3 independently of each other denote hydrogen,
an
optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl
radical
or a radical (CH2)" -X29; or
R2°2 and R2°3 together with the N-atom denote a three- to
seven-
membered, saturated, partially or totally unsaturated heterocycle with one
or more heteroatoms N, O, or S, which may optionally be substituted by
oxo, an alkyl, alkylaryl or aryl group or a group (CH2)~ -X29, R2°2'
denotes
x
hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or a
heteroaryl group or a group (CH2)n -X29,
wherein:
X29 denotes halogen, N02, -OR2°4, -COR2°4, -C02
R2°4, -
O~O2 R204~ -~N~ -CONR2°4 OR205~ -CONR2°4 R205~ -SR204~ -
S~O)R204~ -S(~)2 R204~ -NR204 R205~ -NHC(O)R2°4, -NHS(O)2 8204;
X15 denotes -CH2 -, -CH2 -CH2 -, -CH2 -CH2 -CH2 -, -CH2
-CH=CH-, -CH=CH -CH2 -CH2 -CO-, -CO-CH2 -, -
-,
NHCO-, CONH-, -NHCH2 -, -CH2 NH-, -N=CH-, -NHCH-,
-
-CH2-CH2 -NH-, CH=CH- , >N-R23, >C=O, >S(O)m;
-
R2o4 and R2°5 independently of each other denote hydrogen, alkyl,
aralkyl or aryl;
n is an integer from .0 to 6;
R2°6 is a straight-chained or branched C1 -C4 alkyl group which
may
optionally be mono- or polysubstituted by halogen or alkoxy, or R2°s
d enotes CF3; and
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m denotes an integer from 0 to 2;
with the proviso that A~2 does not represent O if R2os denotes CF3;
and the pharmaceutically acceptable salts thereof.
[0141] Materials that can serve as Cox-2 selective inhibitors of the
present invention include methanesulfonyl-biphenyl derivatives that are
described in U.S. Patent No. 6,583,321. Such methanesulfonyl-biphenyl
derivatives have the formula shown below in formula XXXX:
XXXX
OR2°$
wherein:
R2°' and R2°$ are respectively a hydrogen;
C~ -C4-alkyl substituted or not substituted by halogens;
C3 -C~-cycloalkyl;
C~ -C5-alkyl containing 1-3 ether bonds and/or an aryl substitute;
substituted or not substituted phenyl;
or substituted or not substituted five or six ring-cycled heteroaryl
containing more than one hetero atoms selected from a group consisting
of nitrogen, sulfur, and oxygen (wherein phenyl or heteroaryl can be one-
or multi-substituted by a substituent selected from a group consisting of
hydrogen, methyl, ethyl, and isopropyl).
OR~m
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[0142] Cox-2 selective inhibitors such as 1 H-indole derivatives
described in U.S. Patent No. 6,599,929 are useful in the present invention.
Such 1 H-indole derivatives have the formula shown below in formula
XXXXI:
X30
N
XXXXI
wherein:
X3° is -NHS02R2°9 wherein R2°9 represents hydrogen
or C1 -C3-
alkyl;
Y9 is hydrogen, halogen, C1 -C3-alkyl substituted or not substituted
by halogen, N02, NH2, OH, OMe, C02H, or CN; and
Q' is C=O, C=S, or CH2.
[0143] Compounds that are useful as Cox-2 selective inhibitors of
the present invention include prodrugs of Cox-2 inhibitors that are
described in U.S. Patent Nos. 6,436,967 and 6,613,790. Such prodrugs of
Cox-2 in hibitors have the formula shown below in formula XXXXII:
A13
8211 ~ R210
XXXXII
N
8212/
0213
wherein
A13 is a ring substituent selected from partially unsaturated
heterocyclic, heteroaryl, cycloalkenyl and aryl, wherein A13 is unsubstituted
or substituted with one or more radicals selected from alkylcarbonyl,
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formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy,
aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl,
haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl,
cycloalkylalkyl, alkenyl, alkynyl, heterocycloxy, alkylthio, cycloalkyl, aryl,
heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl,
arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl,
aryloxyalkyl, aralkylthioalkyl, araalkoxyalkyl, alkoxycarbonylalkyl,
aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-
arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, -arylamino, N-
aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl,
alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-
arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl,
alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl, and N-alkyl-N-arylaminosulfonyl;
R~~° is selected from heterocyclyl, cycloal.kyl, cycloalkenyl, and
aryl,
wherein R2~o is unsubstituted or substituted with one or more radicals
selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl,
alkylsulfinyl, halo, alkoxy, and alkylthio;
R2'~ is selected from hydrido and alkoxycarbonylalkyl;
R2'~ is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl,
heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl,
amino acid residue, and alkylcarbonylaminoalkylcarbonyl;
provided A~3 is not tetrazolium, or pyridinium; and further provided
A~3 is not indanone when R2~2 is alkyl or carboxyalkyl; further provided A~3
is not thienyl, when R2~° is 4-fluorophenyl, when 8211 IS hydrido, and
when
R2~2 is methyl or aryl; and
R2~3 IS hydrido;
or a pharmaceutically-acceptable salt thereof.
[0144] Specific non-limiting examples of substituted sulfonamide
prodrugs of Cox-2 inhibitors disclosed in U.S. Patent No. 6,436,967 that
are useful in the present invention include:
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N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1-
yl]phen yl]sulfonyl]propanamide;
N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1-
yl]phen yl]sulfonyl]butanamide;
N-[[4-[1,5-dimethyl)-3-phenyl-1 H-pyrazol-4-yl]phenyl]sulfonyl]acetamide;
N-[[4-(2-(3-pyridinyl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl)phenyl]sulfonyl]acetamide;
N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]phenyl]sulfonyl]butanamide;
N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]phenyl]sulfonyl]butanamide;
N-[[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]phenyl]sulfonyl]acetamide;
N-[[4-[3-(3-fluorophenyl)-5-methylisoxazol-4-yl]phenyl]sulfonyl]acetamide;
2-methyl-N-[[4-(5-methyl-3-phenylisoxazol-4-
yl)phenyl]sulfonyl]propanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]benzamide;
2,2-dimethyl-N-[[4-(5-methyl-3-phenylisoxazol-4-
yl)phenyl]sulfonyl]propanamide;
N-[[4-5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]butanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]pentanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]hexanamide;
3-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-
yl)phenyl]sulfonyl]propanamide ;
2-ethoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide;
N-[[4-[5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide;
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N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H pyrazol-1-
yl]phenyl]sulfonyl]pro panamide;
N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]phenyl]sulfonyl]butanamide;
N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]phenyl]sulfonyl]acetamide;
N-[[4-[3-(difluoromethyl)-6-fluoro-1,5-dihydro-7-methoxy-
[2]benzothiopyrano [4,3-c]pyrazol-1-yl)phenyl]sulfonyl]acetamide;
N-[[4-[6-fluoro-1,5-dihydro-7-methoxy-3-(trifluoromethyl)-[2]benzothiopyran
0[4,3-c]pyrazol-1-yl]phenyl]sulfonyl]acetamide;
N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1-
yl]phenyl]sulfonyl]acetamide;
N-[[4-(2-methyl-4-phenyloxazol-5-yl)phenyl]sulfonyl]acetamide;
methyl[[[4-(5-methyl-3-phenylisoxazol-4-
yl)phenyl]sulfonyl]amino]oxoacetate;
2-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-
yl)phenyl]sulfonyl]acetamide;
N-[[4-[5-(difluoromethyl)-3-phenylisoxazol-4-
yl]phenyl]sulfonyl]propanamide;
N-[[4-[5-(difluoromethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]butanamide;
N-[[4-(5-methyl-3-ph enylisoxazol-4-yl)phenyl]sulfonyl]formamide;
1,1-dimethylethyl-N-[[4-(5-methyl-.3-phenylisoxazol-4-
yl)phenyl]sulfonyl]ca rbamate;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine;
2-amino-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide;
2-(acetylamino)-N-[[4-(5-methyl-3-phenylisoxazol-4-
yl)phenyl]sulfonyl]acetamide;
methyl 4-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-4-
oxobutanoate;
methyl N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]carbamate;
N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine,
ethyl ester;
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N-[[4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl)phenyl]sulfonyl]acetamide;
methyl 3-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-3-
oxopropanoate;
4-[5-(3-bromo-5-fluoro-4-methoxyphenyl)-2-(trifluoromethyl)oxazol-4-yl]-N-
methylbenezenesulfonamide;
N-(1,1-dimethylethyl)-4-(5-methyl-3-phenylisoxazol-4-
yl)benzenesulfonamide;
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]-N-
methylbenzenesulfonamide;
N-methyl-4-(5-methyl-3-phenylisoxazol-4-yl)benezenesulfonamide;
N-[[4-[5-(hydroxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide:
N-[[4-[5-(acetoxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-
yl)phenyl]sulfonyl]acetamide;
4-[2-(4-fluorophenyl)-1 H-pyrrol-1-yl]-N-methylbenzenesulfonamide;
N-[[4-(3,4-dimethyl-1-phenyl-1 H-pyrazol-5-yl]phenyl]sulfonyl]propanamide;
N-[[4-[2-(2-methylpyridin-3-yl)-4-trifluoromethylimidazol-1-
yl]phenyl]sulfonyl]propanamide;
4-[2-(4-fluorophenyl)cyclopenten-1-yl]-N-methylbenezenesulfonamide; and
N-[[4-(3-phenyl-2,3-dihydro-2-oxofuran-4-yl)phenyl]sulfonyl]propanamide.
[0145] Those prodrugs disclosed in U.S. Patent No. 6,613,790 have
the general formula shown above in formula XXXXII wherein:
A~3 is a pyrazole group_optionally substituted at a substitutable
position with one or more radicals independently selected at each
occurrence from the group consisting of alkylcarbonyl, formyl, halo, alkyl,
haloalkyl, oxo, cyano, intro, carboxyl, alkoxy, aminocarbonyl,
alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl,
haloalkylsulonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, alkenyl,
alkynyl, alkylthio, alkylthioalkyl, alkoxyalkyl, alkoxycarbonylalkyl,
aminocarbonylalkyl, alkylaminocarbonyl, alkylaminocarbonylalkyl,
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alkylamino, aminoalkyl, alkylaminoalkyl, alkylsutfinyl, alkylsulfonyl,
aminosulfonyl, and alkylaminosulfonyl;
R~~° is a phenyl group optionally substituted at a substitutable
position with one or more radicals independently selected at each
occurrence from the group consisting of alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino,
nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio;
R2'~ and R2'2 are independently selected from the group consisting
of hydroxyalkyl and hydrido but at least one of R2~~ and R2~2 is other than
hydrido; and
R2~3 is selected from the group consisting of hydrido and fluoro.
[0146] Examples of prodrug compounds disclosed in U.S.
6,613,790 that are useful as Cox-2 inhibitors of the present invention
include, but are not limited to, N-(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-
(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide, N,N-bis(2-
hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyraz ol-1-
yl]benzenesulfonamide, or pharmaceuticaly-acceptable salts thereof.
[0147] Cox-2 selective inhibitors such as sulfamoylheleroaryl
pyrazole compounds that are described in U.S. Patent No. 6,583,321 may
serve as Cox-2 inhibitors of the present invention. Such
sulfamoylheleroaryl pyrazole compounds have the formula shown below in
formula XXXXIII:
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O
H2N~ ~ N
., ~N
CF3 XXXXI II
X3L
wherein:
8214 Is furyl, thiazolyl or oxazolyl;
8215 IS hydrogen, fluoro or ethyl; and
X31 and X32 are independently hydrogen or chloro.
[0148] Heteroaryl substituted amidinyl and imidazolyl compounds
such as those described in U.S. Patent No. 6,555,563 are useful as Cox-2
selective inhibitors of the present invention. Such heteroaryl substituted
amidinyl and imidaZOlyl compounds have the formula shown below in
formula XXXXIV:
/ 8219
N
N ~ R2ls
N/ ~ N~ XXXXIV
~Z16 ~ 217
8216
wherein:
Z16 is O or S,
8216 is optionally substituted aryl,
R21~ is aryl optionally substituted with aminosulfonyl, and
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R21$ and 8219 cooperate to form an optionally substituted 5-
membered ring.
[0149] Materials that can serve as Cox-2 selective inhibitors of the
present invention include substituted hydroxamic acid derivatives that are
described in U.S. Patent Nos. 6,432,999, 6,512,121, and 6,515,014.
These compounds also act as inhibitors of the lipoxygenase-5 enzyme.
Such substituted hydroxamic acid derivatives have the general formulas
shown below in formulas XXX:7CV and XXXXVI:
0
8220
O
8221 XXXXV
14-~r10 N OH
222
O 8223 OH O H
8224 /
15-Y11 ~ ~ ~ Ne XXXXVI
A
O 8225
[0150] Pyrazole substituted hydroxamic acid derivatives described
in U.S. Patent No. 6,432,999 have the formula shown above in formula
XXXXV, wherein:
A14 is pyrazolyl optionally substituted with a substituent selected
from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro,
carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower
carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y1° is selected from lower alkenylene and lower alkynylene;
R22° is a substituent selected from 5- and 6-membered heterocyclo,
lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl,
biphenyl and naphthyl, wherein R22° is optionally substituted at a
substitutable position with one or more substituents selected from lower
alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl,
lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,
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phenylmino, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy
and lower alkylthio;
R22~ is selected from lower alkyl and amino; and
8222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-
membered heterocyclo and lower cycloalkyl; or a pharmaceutically-
acceptable salt thereof.
[0151] Pyrazole substituted hydroxamic acid derivatives described
in U.S. Patent No. 6,432,999 may also have the formula shown above in
formula XXXXVI, wherein:
A~5 is pyrazolyl optionally substituted with a substituent selected
from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, vitro,
carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower
carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y~' is selected from lower alkylene, lower alkenylene and lower
alkynylene;
8223 is a substituent selected from 5- and 6-membered heterocyclo,
lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl,
biphenyl and naphthyl, wherein 8223 is optionally substituted at a
substitutable position with one or more substituents selected from lower
alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl,
lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,
phenylmino, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy
and lower alkylthio;
8224 is selected from lower alkyl and amino; and
8225 is selected from hydrido, lower alkyl;
or a pharmaceutically-acceptable salt thereof.
[0152] Heterocyclo substituted hydroxamic acid derivatives
described in U.S. Patent No. 6,512,121 have the formula shown above in
formula XXXXV, wherein:
A~4 is a ring substiuent selected from oxazolyl, furyl, pyrrolyl,
thiazolyl, imidazolyl, isochiazolyl, isoxazolyl, cyclopentenyl, phenyl, and
pyridyl; wherein A~4 is optionally substituted with a substituent selected
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from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, vitro,
carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower
carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y~° is lower alkylene, lower alkenylene, and lower alkynylene;
R22° is a substituent selected from 5- and 6-membered heterocyclo,
lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl,
biphenyl and naphthyl, wherein R22° is otionallv substituted at a
substitutable position with one or more substituents selected from lower
alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl,
lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,
phenylamino, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy
and lower alkylthio;
R2a~ is selected from lower alkyl and amino; and
8222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-
membered heterocyclo and lower cycloalkyl; or a pharmaceutically-
acceptable salt thereof. ;
[0153) Heterocyclo substituted hydroxamic acid derivatives
described in U.S. Patent No. 6,512,121 may also have the formula shown
above in formula XXXXVI, wherein:
A~5 is a ring substituent selected from oxazolyl, furyl, pyrrolyl,
thia~olyl, imidazolyl, isothiazolyl, isoxazolyl, cyclopentenyl, phenyl, and
pyridyl; wherein A is optionally substituted with a substituent selected from
acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, vitro,
carboxyl,
lower alkoxy, aminocarbonyl, lower alkoxycarboryl, lower carboxyalkyl,
lower cyanoalkyl, and lower hydroxyalkyl;
Y~~ is selected from lower alkyl, lower alkenyl and lower alkynyl;
8223 is a substituent selected from 5- and 6-membered heterocyclo,
lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl,
biphenyl and naphthyl, wherein 8223 is optionally substituted at a
substitutable position with one or more substituents selected from lower
alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl,
lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,
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phenylamino, nitto, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy
and lower alkylthio;
R22a. is selected from lower alkyl and amino; and
8225 is selected from hydrido and alkyl; or a pharmaceutically-
acceptable salt thereof.
[0154] Thiophene substituted hydroxamic acid derivatives described
in U.S. Patent No. 6,515,014 have the formula shown above in formula
XXXXV, wherein:
A~4 is thienyl optionally substituted with a substituent selected from
acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, vitro,
carboxyl,
lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl,
lower cyanoalkyl, and lower hydroxyalkyl;
Y~° is ethylene, isopropylene, propylene, butylene, lower
alkenylene, and lower alkynylene;
R22° is a substituent selected from 5- and 6-membered heterocyclo,
lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl,
biphenyl and naphthyl, wherein R22° is optionally substituted at a
substitutable position with one or more substituents selected from lower
alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl,
lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,
phenylamino, vitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy
and lower alkylthio;
R22' is selected from lower alkyl and amino; and
8222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-
membered heterocyclo and lower cycloalkyl; or a pharmaceutically-
acceptable salt thereof.
[0155] Thiophene substituted hydroxamic acid derivatives described
in U.S. Patent No. 6,515,014 may also have the formula shown above in
formula XXXXV, wherein:
A~5 is thienyl optionally substituted with a substituent selected from
acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, vitro,
carboxyl,
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lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl,
lower cyanoalkyl, and lower hydroxyalkyl;
Y~ ~ is selected from lower alkyl, lower alkenyl and lower alkynyl;
8223 is a substituent selected from 5- and 6-membered heterocyclo,
lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl,
biphenyl and naphthyl, wherein 8223 is optionally substituted at a
substitutable position with one or more substituents selected from lower
alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl,
lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino,
phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy
and lower alkylthio;
8224 is selected from lower alkyl and amino; and
8225 is selected from hydrido and alkyl; or a pharmaceutically-
acceptable salt thereof.
[0156] Compounds that are useful as Cox-2 selective inhibitors of
the present invention include pyrazolopyridine compounds that are
described in U.S. Patent No. 6,498,166. Such pyrazolopyridine
compounds have the formula shown below in formula XXXXVII:
8229
R22s
,,, XXXXVI I
8226
wherein:
8226 and R22~ are independently selected from the group consisting
of H, halogen, C~ -C6 alkyl, C~ -C6 alkoxy, and C~ -C6 alkoxy substituted
by one or more fluorine atoms;
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R22$ is halogen, CN, CON R23° (~231~ C02 H, C02 C~ -C6 alkyl, or
NHS02R23o;
8229 is C~ -C6 alkyl or NH2 ; and
8225 and 8225 are independently selected from the group consisting
of H, C~ -C6 alkyl, phenyl, phenyl substituted by one or more atoms or
groups selected from the group consisting of halogen, C~ -C6 alkyl, C~ -C6
alkoxy, and C~ -C6 alkoxy substituted by one or more fluorine atoms,
or a pharmaceutically acceptable salt, solvate, ester, or salt or solvate of
such ester thereof.
[0157] Materials that are useful as Cox-2 selective inhibitors of the
present invention include 4,5-diaryl-3(2H)-furanone derivatives that are
described in U.S. Patent No. 6,492,416. Such 4,5-diaryl-3(2H)-furanone
derivatives have the formula shown below in formula XXXXVIII:
y12
XXXXV~~~
wherein:
X33 represents halo, hydrido, or alkyl;
Y~2 represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N-
acylamino)-sulfonyl, (N-alkylamino)sulfonyl, or alkylthio;
Z~~ represents oxygen or sulfur atom;
8233 and 8234 are selected independently from louver alkyl radicals;
and
8232 represents a substituted or non-substituted aromatic group of 5
to 10 atoms; ,
or a pharmaceutically-acceptable salt thereof.
9~
RL3;i RL;54
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(0158] Cox-2 selective inhibitors that can be used in the present
invention include 2-phenyl-1,2-benzisoselenazol-3(2H)-one derivatives
and 2-phenylcarbomyl-phenylselenyl derivatives that are described in U.S.
Patent No. 6,492,416. Such 2-phenyl-1,2-benzisoselenazol-3(2H)-one
derivatives and 2-phenylcarbomyl-phenylselenyl derivatives have the
formulas shown below in formulas XXXXIX or XXXXIX':
8237
N
XXXXIX
235
KGJJ
236
R
8237
XXXXIX'
8235
~GJJ VG
2
wherein:
8235 is a hydrogen atom or an alkyl group having 1-3 carbon atoms;
8236 is a hydrogen atom, a hydroxyl group, an organothiol group
that is bound to the selenium atom by its sulfur atom, or 8235 and R23s are
joined to each other by a single bond;
8237 is a hydrogen atom, a halogen atom, an alkyl group having 1-3
carbon atoms, an alkoxyl group having 1-3 carbon atoms, a trifluoromethyl
group, or a nitro group;
R23$ and 8239 are identical to or different from each other, and each
is a hydrogen atom, a halogen atom, an alkoxyl group having 1-4 carbon
atoms, a trifluoromethyl group, or R23$ and 8239 are joined to each other to
form a methylenedioxy group,
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a salt thereof, or a hydrate thereof.
[0159] Pyrones such as those disclosed in U.S. Patent No.
6,465,509 are also useful as Cox-2 inhibitors of the present invention.
These pyrone compounds have the general formula shown below in
formula XXXXX:
1
R2'
XXXXX
O
wherein:
X34 is selected from the group consisting of
(a) a bond,
(b) --(CH2)m --, wherein m 1 or 2,
(c) --C(O)--,
(d) __~__,
(e) --S--, and
(f) --N(R244)--;
R24° is selected from the group consisting of
(a) C1 -C1° alkyl, optionally substituted with 1-3 substituents
independently selected from the group consisting of hydroxy, halo, C1 -
C1°
alkoxy, C1 -C1° alkylthio, and CN,
(b) phenyl or naphthyl, and
(c) heteroaryl, which is comprised of a monocyclic aromatic ring of 5
atoms having one hetero atom which is S, O or N, and optionally 1, 2, or 3
additional N atoms; or
a monocyclic ring of 6 atoms having one hetero atom which is N,
and optionally 1, 2, or 3 additional N atoms, wherein groups (b) and (c)
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above are each optionally substituted with 'I-3 substituents independently
selected from the group consisting of halo, C~ -Coo alkoxy, C~ -Coo
alkylthio, CN, C~ -Coo alkyl, optionally substituted to its maximum with
halo, and N3 ;
R24' is selected from the group consisting of
(a) C~ -C6 alkyl, optionally substituted to its maximum with halo,
(b) NH2, and
(c) NHC(O)C~ -Coo alkyl, optionally substituted to its maximum with
halo;
8242 and 8243 are each independently selected from the group
consisting of hydrogen, halo, and C~ -Cs alkyl, optionally substituted to its
maximum with halo; and
8244 is selected from the group consisting of hydrogen and C~ -C6
alkyl, optionally substituted to its maximum with halo.
[0160] Examples of pyrone compou nds that are useful as Cox-2
selective inhibitors of the present invention include, but are not limited to:
4-(4-Methylsulfonyl)phenyl-3-phenyl-pyran-2-one,
3-(4-Fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one,
3-(3-Fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one,
6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one,
6-Difluoromethyl-4-(4-methylsulfonyl)phen yl-3-phenyl-pyran-2-one,
6-Fluoromethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one,
6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenylthio-pyran-2-one,
6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenoxy-pyran-2-one,
6-Methyl-4-(4-methylsulfonyl)phenyl-3-pyr-idin-3-yl-pyran-2-one,
3-Isopropylthio-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one,
4-(4-Methylsulfonyl)phenyl)-3-phenylthio-6-trifluoromethyl-pyran-2-one,
3-Isopropylthio-4-(4-methylsulfonyl)phenyl-6-trifluoromethyl-pyran-2-one,
4-(4-Methylsulfonyl)phenyl-3-phenyl-6-(2,2,2-trifluoroethyl)-pyran-2-one,
and
3-(3-Hydroxy-3-methylbutyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-
one.
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[0161] Organically synthesized or purified from plant sources, free-
B-ring flavanoids such as those described in U.S. Published Application
No. 2003/0165588, are useful as Cox-2 selective inhibitors of the present
invention. Such free-B-ring flavanoids have the general structure shown in
formula XXXXXI:
8246
R24~ R25o
XXXXXI
8248 ~ 0
B
8249
wherein:
R246~ R247~ R248~ R24s~ and R25° are independently selected from
the
group consisting of --H, --OH, --SH, --OR, --SR, --NH2, --NHR245, --
N~R245~2~
--N(R245)3+X35-, a carbon, oxygen, nitrogen or sulfur, glycoside of a
single or a combination of multiple sugars including, aldopentoses, methyl-
aldopentose, aldohexoses, ketohexose and their chemical derivatives
thereof; wherein 8245 is an alkyl group having between 1-10 carbon atoms;
and X35 is selected from the group of pharmaceutically acceptable counter
anions including, hydroxyl, chloride, iodide, sulfate, phosphate, acetate,
fluoride and carbonate.
[0162] Heterocyclo-alkylsulfonyl pyrazoles such as those described
in European Patent Application No. EP 1312367 are useful as Cox-2
selective inhibitors of the present invention. Such heterocyclo-alkylsulfonyl
pyrazoles have the general formula shown below in formula XXXXXII:
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N XXXXXII
8251
N,
\\a
8253 8252
or a pharmaceutically acceptable salt thereof, wherein the ring of the
formula (R255)-A-(SOmR254) is selected from the group consisting of
SOmR~54 SOmR254 SOmR254
R25\ ~ i a
\I
X~3s / N RzsS ~ N
SO,i,R254 gpmR2s4 SOmR254
R2ss
N ~ N ~\ N a N
N ~ R255
R2ss
' , '~~.,.' , and 'M'v'
m is 0, 1 or 2;
1 O X35 IS >CR255 Or >N;
8251 is a radical selected from the group consisting of H,
N02, CN, (C1 -C6)alkyl, (C1 -C6)alkyl-S02-, (C6 -C1o)aryl-S02-, H-(C=O)-,
(C1 -C6)alkyl-(C=O)-, (C1 -C6)alkyl-)-(C=O)-, (C1 -C9)heteroaryl-(C=O)-,
(C1 -C9)heterocyclyl-(C=O)-, H2N-(C=O)-, (C1 -C6)alkyl-NH-(C=O)-, [(C1 -
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Cs)alkyl]2-N-(C=O)-~ [(Cs -C1o)aryl]2-NH-(C=O)-, [(C1-Cs)alkyl]-[((Cs -
C1o)aryl-N]-(C=O)-, HO-NH-(C=O)-, and (C1 -Cs)alkyl-O-NH-(C=O)-;
8252 is a radical selected from the group consisting of H, -N02, -CN, (C2-
Cs)alkenyl, (C2-Cs)alkynyl, (C3-C7)cycloalkyl, (Cs-C1o)aryl, (C1-
C9)heteroaryl, (C1-C9)heterocyclyl, (C1-Cs)alkyl-O-, (C3-C7)cycloalkyl-O-,
(Cs-C1o)aryl-O-, (C1-C9)heteroaryl-O-, (Cs -C9)heterocyclyl-O-, H-(C=O)-,
(C1-Cs)alkyl-(C=O)-, (C3-C7)cycloalkyl-(C=O)-, (Cs-C1o)aryl-(C=O)-, (C1-
C9)heteroaryl-(C=O)-, (C1-C9)heterocyclyl-(C=O)-, (C1-Cs)alkyl-O-(C=O)-,
(C3-C~)cycloalkyl-O-(C=O)-, (Cs-C1o)aryl-O-(C=O)-, (C1-C9)heteroaryl-O-
(C=O)-, (C1-C9)heterocyclyl-O-(C=O)-, (C1-C6)alkyl-(C=O)-O-, (C3-
C~)cycloalkyl-(C=O)-O-, (Cs-C1o)aryl-(C=O)-O-, (C1-C9)heteroaryl-(C=O)-
O-, (C1-C9)heterocyclyl-(C=O)-O-, (C1-Cs)alkyl-(C=O)-NH-, (C3-
C~)cycloalkyl-(C=0)-NH-, (Cs-Cloaryl-(C=O)-NH-. (C1-C9)heteroaryl-(C=O)-
NH-, (C1-C9)heterocyclyl-(C=O)-NH-, (C1-Cs)alkyl-O-(C=O)-NH-, (C1-
Cs)alkyl-NH, [(C1-Cs)alkyl]2-N-, (C3-C7)cycloalkyl-NH-. [(C3-C7)cycloalkyl]2-
N-~ [(Cs-C1o)aryl]-Nhi-~ [(Cs-C1 o)arYl]2-N-~ [(C1-Cs)alkyl]-[((Cs-C1o)aryl)-
N]-~
[(C1-C9)heteroaryl]-NH-, [(C1-C9)heteroaryl]2-N-, [(C1-C9)heterocycly]-NH-,
[(C1-C9)heterocyclyl]2-N-, H2N-(C=O)-, HO-NH-(C=O)-, (C1-Cs)alkyl-O-NH-
(C=O)-a [(C1-Cs)alkyl]-NH-(C=O)-~ [(C1-Cs)alkyl]2-N-(C=O)-~ [(Cs-
C7)cycloalkyl]-NH-(C=O)-, [(C3-C~)cycloalkyl]2-N-(C=O)-, [(Cs-C1o)aryl]-NH-
(C=O)-~ [(Cs-CloarYl]2-N-(C-O)-~ [(C1-C s)alkyl]-[((Cs-C1o)arYl)-N]-(C=O)-~
[(C1-C9)heteroaryl]-NH-(C=O)-, [(C1-C9)heferoaryl]2-N-(O=O)-, [(C1-
C9)heterocyclyl]-NH-(C=O)-, (C1-Cs)alkyl-S- and (C1-Cs)alkyl optionally
substituted by one -OH substituent or by one to four fluoro substituents;
RzSS is a saturated (3- to 4-membered)-heterocyclyl ring
radical; or a saturated, partially saturated or aromatic (7- to 9-membered)-
heterocyclyl ring radical;
wherein said saturated (3- to 4-membered)-heterocyclyl ring
radical orsaid saturated, partially saturated or aromatic (7- to 9-
membered)-heterocyclyl ring radical; may optionally contain one to four
ring heteroatoms independently selected Irom the groups consisting of -
N=, -NH-, -O-, and -S-;
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wherein said saturated (3- to 4-membered)-heterooyclyl ring
radical; or said saturated, partially saturated or aromatic (7- to 9-
nembered)-heterocyclyl ring radical; may optionally be substituted on any
ring carbon atom by one to three substituents per ring independently
selected from the group consisting of halo, -OH, -CN, -N02, (C2-
C6)alkenyl, (C2-C6)alkynyl, (C3-C~)cycloalkyl, (C6-C~o)aryl, (C2-
C9)hetorocyclyl, (C~ -C6)alkyl-O-, H-(C=0)-, (C~-C6)alkyl-(C=O)-, HO-
(C=O)-, (C~-C6)alkyl-O-(C=O)-, -NH2, (C~-C6)alkyl-NH-, [(C~-C6) alkyl]2-N-,
(C3-C~)cycloalkyl-NH-, (C6-C~o)aryl-NH-, [(C~-C6)alkyl]-[((C6-C~o)aryl)-N]-,
(C~-C9)heteroaryl-NH-, H2N-(C=O)-[(C~-C6)alkyl]-NH-(C=O)-, [(C~-
C6)alkyl]2-N-(C=O)-, [(Cs-C~o)ar'YI]-NH-(C=O)-~ [(C~-Cs)alkyl]-[((Cs-
C~o)ai"YI)-
N]-(C=O)-, (C~-C6)alkyl-O-NH-(C=O)-, (C~-C6)alkyl-(C=O)-HN-, (C~-
C6)alkyl-(C=O)-[(C~-C6)alkyl-N]-, -SH, (C~-C6)alkyl-S-, (C~-C6)alkyl-(S=0)-,
(C~-C6)alkyl-S02- and (C~-C6)alkyl optionally substituted with one to
fourfluoro moieties;
wherein said saturated (3- to 4-membered)-heterocyclyl ring
radical; or said saturated, partially saturated or aromatic (7- to 9-
membered)-heterocyclyl ring radical; may also optionally be substituted on
any ring nitrogen atom by one to three substituents per ring independently
selected from the group consisting of (C3-C~)cyoloalkyl, (C6-C~o)aryl, (C2-
C9)heterocyclyl, H-(C=O)-, (C~-C6)alkyl-(C=O)-, (C~-C6)alkyl-O-(C=O)-,
HEN-(C=O)-, [(C~-C6)alkyl]-NH-(C=O)-, [(C~-C6)alkyl]2-N-(C=O)-, [(C6-
C~o)arYl]-NH-(C=O)-, [(C~-C6)alkyl]-[((C6-C~o)arYl)-N]-(C=O)-, (C~ -C6)alkyl-
O-NH-(C=O)-, and (C~-C6)alkyl optionally substituted with one to four
fluoro moieties;
8254 is an (C~-C6)alkyl radical optionally substituted by one to
four fluoro substituents; and
8255 is a radical selected from the group consisting of H,
halo, -OH, (C~-C6)alkyl-O-, (C~-C6)alkenyl, (CZ-C6) alkynyl, (C3-
C7)cycloalkyl, -CN, H-(C=O)-, (C~-C6)alkyl-(C=O)-, (C~-C6)alkyl-(C=O)-O-,
HO-(C=O)-, (C~-C6)alkyl-O-(C=O)-, (C~-C6)alkyl-NH-. [(C~-C6)alkyl]2-N-,
(C3-C7)cycloalkyl-NH-, (C6-C~o)aryl-NH-, [(C~-C6)alkyl]-[((C6-C~o)aryl)-N]-,
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(C~-C9)heteroaryl-NH-, H2N-(C=O)-, (C~-C6)alkyl-NH-(C=O)-. [(C~-
C6)alkyl]2-N-(C=O)-, (Cs-C~o)a~"YI-(C=O)-~ L(C~-Cs)alkyl]-[((Cs-C~o)arYl)-N]_
(C=O)-, (C~-C6)alkyl-O-NH-(C=O)-, (C~-C6)alkyl-S-, and (C~-C 6)alkyl
optionally substituted by one to four fluoro substituents.
[0163] 2-phenylpyran-4-one derivatives such as those described in
U.S. Patent No. 6,518,303 are also useful as Cox-2 selective inhibitors of
the present invention. Such 2-phenylpyran-4-one derivatives have the
general formula shown below in formula XX)CXXIII:
R256-
R25a
XXXXXI I I
0
wherein:
8256 represents an alkyl or -NR259 R2so group, wherein 8259 and R26°
each
independently represents a hydrogen atom or an alkyl group,
R25~ represents an alkyl, C3 -C~ cycloalkyl, naphthyl, tetrahydronaphthyl or
indanyl group, or a phenyl group which may be unsubstituted or
substituted by one or more halogen atoms or alkyl, trifluorom ethyl,
hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or
hydroxycarbonyl groups;
R25$ represents a methyl, hydroxymethyl, alkoxymethyl, C3 -C7
cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile~,
trifluoromethyl or difluoromethyl group or a CH2 -- R26~ group wherein 8261
represents an alkyl group; and
X36 represents a single bond, an oxygen atom, a sulfur atom or a
methylene group;
or a pharmaceutically acceptable salt thereof.
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[0164] Examples of 2-phenylpyran-4-one derivatives useful in the
present invention include, but are not limited to:
3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-bromophenyl)-2-(4-methylsulfonylphenyl)-6-methylpyran-4-one,
3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(3-chloro-4-methylphenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-
4-one ,
2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one,
3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy)pyran-4-one,
3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-
one,
3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methoxymethylpyran-4-
one,
3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonylphenyl)pyran-4-
one,
and pharmaceutically acceptable salts thereof.
[0165] Cox-2 selective inhibitors that are useful in the subject
method and compositions can include the compounds that are described
in U.S. Patent No. 6,472,416 (sulfonylphenylpyrazoles); U.S. Patent No.
6,451,794 (2,3-diaryl-pyrazolo[1,5-b]pyridazines); U.S. Patent Nos.
6,169,188, 6,020,343, and 5,981,576 ((methylsulfonyl)phenyl furanones);
U.S. Patent No. 6,222,048 (diaryl-2-(5H)-furanones); U.S. Patent No.
6,057,319 (3,4-diaryl-2-hydroxy-2,5-dihydrofurans); U.S. Patent No.
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6,046,236 (carbocyclic sulfonamides); U.S. Patent Nos. 6,002,014 and
5,945,539 (oxazole derivatives); and U.S. Patent Nos. 6,359,182 and
6,538,116 (C-nitroso compounds).
[0166] Examples of specific compounds that are useful as Cox-2
selective inhibitors include, without limitation:
a1 ) 8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo(1,2-
a)pyridine;
a2) 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone;
a3) 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-
(trifluoromethyl)pyrazole;
a4) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-
(trifluoromethyl)pyrazole;
a5) 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1 H-pyrazol-1-
yl)benzenesulfonamide;
a6) 4-(3,5-bis(4-methylphenyl)-1 H-pyrazol-1-yl)benzenesulfonamide;
a7) 4-(5-(4-chlorophenyl)-3-phenyl-1 H-pyrazol-1-
yl)benzenesulfonamide;
a8) 4-(3,5-bis(4-methoxyphenyl)-1 H-pyrazol-1-yl)benzenesulfonamide;
a9) 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1 H-pyrazol-1-
yl)benzenesulfonamide;
a10) 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1 H-pyrazol-1-
yl)benzenesulfonamide;
b1 ) 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1 H-pyrazol-1-
yl)benzenesulfonamide;
b2) 4-(4-chloro-3,5-diphenyl-1 H-pyrazol-1-yl)benzenesulfonamide
b3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
b4) 4-[5-phenyl-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
b5) 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
b6) 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
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b7) 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide;
b8) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
b9) 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
b10) 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
c1 ) 4-[3-(difluoromethyl)-5-phenyl-1 H-pyrazol-1-yl]benzenesulfonamide;
c2) 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
c3) 4-[3-cyano-5-(4-fluorophenyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
c4) 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
c5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
c6) 4-[4-chloro-5-phenyl-1 H-pyrazol-1-yl]benzenesulfonamide;
c7) 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
c8) 4-(5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1 H-pyrazol-
1-yl]benzenesulfonamide;
c9) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
c10) 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;
d1) 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene;
d2) 5-(3-chloro-4-methoxyphenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
d3) 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-
yl]benzenesulfonamide;
d4) 5-(3,5-dichloro-4-methoxyphenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
d5) 5-(3-chloro-4-fluorophenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
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d6) 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-
yl]benzenesulfonamide;
d7) 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-
methylsulfonylphenyl)thiazole;
d8) 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-
methylsulfonylphenyl)thiazole;
d9) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;
d10) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-
trifluoromethylthiazole;
e1 ) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;
e2) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-
benzylaminothiazole;
e3) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-
propylamino)thiazole;
e4) 2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]thiazole;
e5) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-
trifluoromethylthiazole;
e6) 1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-
dien-3-yl]benzene;
e7) 4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-
yl]benzenesulfonamide;
e8) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-
diene;
e9) 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-
yl]benzenesulfonamide;
e10) 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine-
3-carbonitrile;
f1 ) 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3-
carbonitrile;
f2) 6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3-
carbonitrile;
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f3) 4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide;
f4) 4-(2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide;
f5) 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide;
f6) 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazol-2-
yl]pyridine;
f7) 2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol-2-
yl]pyridine;
f8) 2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-
imidazol-2-yl]pyridine;
f9) 2-methyl-6-[1-(4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-
imidazol-2-yl]pyridine;
f10) 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide;
g1 ) 2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-
(trifluoromethyl)-1 H-imidazole;
g2) 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide;
g3) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1 H-
imidazole;
g4) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-~ H-
imidazole;
g5) 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-
1 H-imidazole;
g6) 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-
(trifluoromethyl)-1 H-imidazole;
g7) 1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1 H-
imidazole;
g8) 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-
1 H-imidazole;
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g9) 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide;
g10) 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-
(trifluoromethyl)-1 H-imidazole;
h1 ) 4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide;
h2) 2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-
1 H-imidazole;
h3) 4-[2-(3-methylphenyl)-4-trifluoromethyl-1 H-imidazol-1-
yl]benzenesulfonamide;
h4) 1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-
1 H-imidazole;
h5) 4-[2-(3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1-
yl]benzenesulfonamide;
h6) 4-[2-phenyl-4-trifluoromethyl-1 H-imidazol-1-yl]benzenesulfonamide;
h7) 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1-
yl]benzenesulfonamide;
h3) 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-
(trifluoromethyl)-1 H-pyrazole;
h9) 4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1 H-pyrazol-3-
yl]benzenesulfonamide;
i1 ) N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-
( trifluoromethyl)-1 H-pyrazol-1-yl]acetamide;
i2) ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-
(trifluoromethyl)-1 H-pyrazol-1-yl]acetate;
i3) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-
1 H-pyrazole;
i4) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5-
(trifluoromethyl)pyrazole;
i5) 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-
(trifluoromethyl)-1 H-pyrazole;
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i6) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1 H-
imidazole;
i7) 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1 H-
imidazole;
i8) 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-
(trifluoromethyl)pyridine; ,
i9) 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-
(trifluoromethyl)pyridine;
i10) 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-
(trifluoromethyl)pyridine;
j1 ) 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-
(trifluoromethyl)pyridine;
j2) 4-[2-(3-chloro-4-methoxyphenyl)-4,5-
difluorophenyl]benzenesulfonamide;
j3) 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
j4) 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole;
j5) 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide;
j6) 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
j7) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
j8) 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide;
j9) 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
j10) 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
k1 ) 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
k2) 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
k3) 1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
k4) 1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
k5) 1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
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k6) 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-
yl]benzenesulfonamide;
k7) 1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
k8) 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-
yl]benzenesulfonamide;
k9) 4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
k10) 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide;
11 ) 1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
12) 1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
13) 4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-
yl]benzenesulfonamide;
14) 1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene; °
15) 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
16) 4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide;
17) ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]oxazol-2-yl]-
2-benzyl-acetate;
18) 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]acetic
acid;
19) 2-(tent-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole;
110) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole;
m1 ) 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole;
and
m2) 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-
oxazolyl]benzenesulfonamide;
m3) 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
m4) 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
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m5) 8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
m6) 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic
acid;
m7) 6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic
acid;
m8) 2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid;
m9) 7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic
acid;
m10) 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
n1 ) 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
n2) 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
n3) 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
n4) 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
n5) 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
, a
n6) 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-berizopyran-3-
carboxylic
acid;
n7) 7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
n8) 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
n9) 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
n10) 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
01 ) 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
02) 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
03) 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
04) 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic
acid;
05) 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
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06) 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
07) 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
08) 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
09) 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
010) 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
p1 ) 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
p2) 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
p3) 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
p4) 6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid;
p5) 6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic acid;
p6) 6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic acid;
p7) 6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic acid;
p8) 6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid;
p9) 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid;
p10) 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
q1 ) 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid;
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q2) 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q3) 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q4) 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-
carboxylic acid;
q5) 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
q6) 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic
acid;
q7) 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid;
q8) 6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-
benzopyran-3-carboxylic acid;
q9) 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
q10) 7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-
carboxylic acid;
r1 ) 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulphonyl-2(5H)-
fluranone;
r2) 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;
r3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
r4) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
r5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1 H-pyrazol-1-
yl]benzenesulfonamide;
r6) 3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol-2-
yl]pyridine;
r7) 2-methyl-5-[1-(4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-
imidazol-2-yl]pyridine;
r8) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide;
r9) 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
r10) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
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s1 ) [2-trifluoromethyl-5-(3,4-difluorophenyl)-4-
oxazolyl]benzenesulfonamide;
s2) 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; or
s3) 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-
oxazolyl]benzenesulfonamide;
or a pharmaceutically acceptable salt or prodrug thereof.
[0167] Cox-2 inhibitors that are useful in the methods and
compositions of present invention can be supplied by any source as long
as the Cox-2 inhibitor is pharmaceutically acceptable. Likewise, Cox-2
inhibitors that are useful in the compositions and methods of present
invention can by synthesized, for example, according to the description in
Example 1. Several Cox-2 inhibitors that are suitable for use with the
compositions and methods of the present invention may be synthesized by
the methods described in, for example, U.S. Patent No. 5,466,823 to
Talley, et al. Cox-2 inhibitors can also be isolated and purified from
natural sources. Cox-2 inhibitors should be of a quality and purity that is
conventional in the trade for use in pharmaceutical products.
(0168] Preferred Cox-2 selective inhibitor compounds are those
compounds selected from the group consisting of celecoxib, parecoxib,
deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS
57067, T-614, BMS-347070 (Bristol Meyers Squibb, described in U.S.
Patent No. 6,180,651 ), JTE-522 (Japan Tabacco), S-2474 (Shionogi),
SVT-2016, CT-3 (Atlantic Pharmaceutical), ABT-963 (Abbott), SC-58125
(GD Searle), nimesulide, flosulide, NS-398 (Taisho Pharmaceutical), L-
745337 (Merck), RWJ-63556, L-784512 (Merck), darbufelone (Pfizer), CS-
502 (Sankyo), LAS-34475 (Almirall Prodesfarma), LAS-34555 (Almirall
Prodesfarma), S-33516 (Servier), SD-8381 (Pharmacia, described in U.S.
Patent No. 6,0340256), MK-966 (Merck), L-783003 (Merck), T-614
(Toyama), D-1376 (Chiroscience), L-748731 (Merck), CGP-28238
(Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome),
prodrugs of any of them, and mixtures thereof.
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[0169] More preferred is that the Cox-2 selective inhibitor is
selected from the group consisting of celecoxib, parecoxib, deracoxib,
valdecoxib, lumiracoxib, etoricoxib, rofecoxib, prodrugs of any of them,
and mixtures thereof.
[0170] Even more preferred still is that the Cox-2 selective inhibitor
is celecoxib.
[0171] Cox-2 inhibitors that are useful in the methods and
compositions and methods of present invention can be supplied by any
source as long as the Cox-2 inhibitor is pharmaceutically acceptable.
Likewise, Cox-2 inhibitors that are useful in the compositions and methods
of present invention can by synthesized, for example, according to the
description in Example 1. Several Cox-2 inhibitors that are suitable for use
with the compositions and methods of the present invention may be
synthesized by the methods described in, for example, U.S. Patent No.
5,466,823 to Talley, et. al.
[0172] Various classes of Cox-2 inhibitors useful in the present
invention can be prepared as follows. Pyrazoles can be prepared by
methods described in WO 95/15316. Pyrazoles can further be prepared
by methods described in WO 95/15315. Pyrazoles can also be prepared
by methods described in WO 96/03385.
[0173] Thiophene analogs useful in the present invention can be
prepared by methods described in WO 95/00501. Preparation of
thiophene analogs is also described in WO 94/15932.
[0174] Oxazoles useful in the present invention can be prepared by
the methods described in WO 95/00501. Preparation of oxazoles is also
described in WO 94/27980.
[0175] Isoxazoles useful in the present invention can be prepared
by the methods described in WO 96/25405.
[0176] Imidazoles useful in the present invention can be prepared
by the methods described in WO 96/03388. Preparation of imidazoles is
also described in WO 96/03387.
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[0177] Cyclopentene Cox-2 inhibitors useful in the present invention
can be prepared by the methods described in U.S. Patent No. 5,344,991.
Preparation of cyclopentene Cox-2 inhibitors is also described in WO
95/00501.
[0178] Terphenyl compounds useful in the present invention can be
prepared by the methods described in WO 96/16934.
[0179] Thiazole compounds useful in the present invention can be
prepared by the methods described in WO 96/03392.
[0180] Pyridine compounds useful in the present invention can be
prepared by the methods described in WO 96/03392. Preparation of
pyridine compounds is also described in WO 96/24585.
[0181] Benzopyranopyrazolyl compounds useful in the present
invention can be prepared by the methods described in WO 96/09304.
[0182] Chromene compounds useful in the present invention can be
prepared by the methods described in WO 98/47890. Preparation of
chromene compounds is also described in WO 00/23433. Chromene
compounds can further be prepared by the methods described in U.S.
Patent No. 6,077,850. Preparation of chromene compounds, is further
described in U.S. Patent No. 6,034,256.
[0183] Arylpyridazinones useful in the present invention can be
prepared by the methods described in WO 00/24719. Preparation of
arylpyridazinones is also described in WO 99/10332. Arylpyridazinones
can further be prepared by the methods described in WO 99/10331.
[0184] 5-Alkyl-2-arylaminophenylacetic acids and derivatives useful
in the present invention can be prepared by the methods described in WO
99/11605.
[0185] Diarylmethylidenefuran derivative Cox-2 selective inhibitors
useful in the present invention can be prepared by the methods described
in U.S. Patent No. 6,180,651.
[0186] The celecoxib used in the compositions and methods of the
present invention can be prepared in the manner set forth in U.S. Patent
No. 5,466,823.
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[0187] The valdecoxib used in the compositions and methods of the
present invention can be prepared in the manner set forth in U.S. Patent
No. 5,633,272.
[0188] The parecoxib used in the compositions and methods of the
present invention can be prepared in the manner set forth in U.S. Patent
No. 5,932,598.
[0189] The rofecoxib used in the compositions and methods of the
present invention can be prepared in the manner set forth in U.S. Patent
No. 5,474,995.
[0190] The deracoxib used in the compositions and methods of the
present invention can be prepared in the manner set forth in U.S. Patent
No. 5,521,207.
[0191] The etoricoxib used in the compositions and methods of the
present invention can be prepared in the manner set forth in WO
98/03484.
[0192] The meloxicam used in the compositions and methods of the
present invention can be prepared in the manner set forth in U.S. Patent
No. 4,233,299.
[0193] The compound 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-
fluorobenzenesulfonamide used in the compositions and methods of the
present invention can be prepared in the manner set forth in U.S. Patent
No. 5,994,381.
[0194] The compound 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-
methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone used in the
compositions and methods of the present invention can be prepared in the
manner set forth in WQ 00/24719.
[0195] The compound 2-(3,5-difluorophenyl)-3-[4-
(methylsulfonyl)phenyl]-2-cyclopenten-1-one used in the compositions and
methods of the present invention can be prepared in the manner set forth
in EP 863134.
121
CA 02556380 2006-08-14
WO 2005/084654 PCT/US2005/006818
[0196] The compound 2-[(2-chloro-6-fluorophenyl)amino]-5-methyl-
benzeneacetic acid used in the compositions and methods of the present
invention can be prepared in the manner set forth in WO 99/11605.
[0197] The compound N-[2-(cyclohexyloxy)-4-
nitrophenyl~methanesulfonamide used in the compositions and methods of
the present invention can be prepared in the manner set forth in U.S.
Patent No. 4,885,367.
[0198] The compound (3~)-3-[(4-chlorophenyl)[4-
(methylsulfonyl)phenyl]methylene]dihydro-2(3H)-furanone used in the
compositions and methods of the present invention can be prepared in the
manner set forth in U.S. Patent No. 6,180,651.
[0199] Cox-2 inhibitors can also be isolated and purified from
natural sources. Cox-2 inhibitors should be of a quality and purity that is
conventional in the trade for use in pharmaceutical products.
(0200] An optional component of the combination therapy
embodiments of the present invention is an antidepressant agent.
[0201 ] As used herein, the phrase "antidepressant agent" means an
agent or compound, or a combination of two or more of such agents or
compounds, which treat or prevent psychiatric disorders or symptoms of a
psychiatric disorder in a subject in need of such treatment.
[0202] Antidepressant agents display a wide range of chemical
structures. Some of the structural classes of antidepressant agents that
are encompassed by the present invention include tricyclics, tetracylics,
hydrazides/hydrazines, bicyclics, benzodiazepines, and pyrrolidones.
[0203] Antidepressant agents also perform a wide range of
functions within the subject's body. Some of the functional classes of
antidepressant agents that are encompassed by the present invention
include selective serotonin reuptake inhibitors, monoamine oxidase
inhibitors, noradrenaline reuptake inhibitors, selective serotonin and
noradrenaline reuptake inhibitors, dual-action serotonin norepinephrine
reuptake inhibitors, norepinephrine antagonist serotonin antagonists,
selective serotonin and noradrenaline reuptake inhibitors, serotonin
122
CA 02556380 2006-08-14
WO 2005/084654 PCT/US2005/006818
antagonist and reuptake inhibitors, norepinephrine dopamine reuptake
inhibitor, and serotonin reuptake accelerators.
[0204 In one embodiment, sertraline (Zoloft~), in particular, has
been found to be a preferred antidepressant agent. Sertraline was initially
introduced for the treatment of depression, but it is now used to treat a
wide variety of psychiatric disorders. See Khouzam H., et al., Compr Ther
29(1 ):47-53 (2003). Sertraline acts as a selective serotonin reuptake
inhibitor (SSRI) through oral administration. However, it is chemically
unrelated to other SSRIs, tricyclic, tetracyclic, or other available
antidepressant agents.
[0205] In another embodiment, the present invention encompasses
one or more of the antidepressant agents described in Table 3 below.
123
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[0206] In a preferred embodiment, the class of antidepressant that
is suitable for use with the methods and compositions of the present
invention is selected from the group consisting of tricyclics, tetracylics,
hydrazides/hydrazines, bicyclics, benzodiazepines, and pyrrolidones, and
mixtures thereof.
[0207] In a preferred embodiment, the tricyclic antidepressant that is
suitable for use with the methods and compositions of the present
invention is selected from the group consisting of amitriptyline,
desipramine, imipramine, nortriptyline, amineptine, clomipramine, doxepin,
amoxapine, trimipramine, protriptyline, tianeptine, adinazolam,
amitriptylinoxide, butriptyline, dibenzepin, dimetacrine, dothiepin,
fluacizine, imipramine N-oxide, iprindole, lofepramine, melitracen,
metapramine, noxiptilin, opipramol, pizotyline, propizepine, and
quinupramine, and mixtures thereof.
[0208] In a preferred embodiment, the tetracyclic antidepressant
that is suitable for use with the methods and compositions of the present
invention is selected from the group consisting of maprotiline, mirtazapine,
metralindole, and mianserin, and mixtures thereof.
[0209] In a preferred embodiment, the bicyclic antidepressant that is
suitable for use with the methods and compositions of the present
invention is selected from the group consisting of sertraline, citalopram,
paroxetine, trazodone, binodaline, caroxazone, dimethazan, fencamine,
indalpine, indeloxazine hydrochloride, nefopam, nomifensine, oxitriptan,
oxypertine, and thiazesim, and mixtures thereof.
[0210] In a preferred embodiment, the benzodiazepine
antidepressant that is suitable for use with the methods and compositions
of the present invention is selected from the group consisting ofalprazolam
and diazepam, and mixtures thereof.
[0211] In a preferred embodiment, the class of antidepressant that
is suitable for use with the methods and compositions of the present
invention is selected from the group consisting of selective serotonin
reuptake inhibitors, monoamine oxidase inhibitors, noradrenaline reuptake
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inhibitors, selective serotonin and noradrenaline reuptake inhibitors, dual-
action serotonin norepinephrine reuptake inhibitors, norepinephrine
antagonist serotonin antagonists, selective serotonin and noradrenaline
reuptake inhibitors, serotonin antagonist and reuptake inhibitors,
norepinephrine dopamine reuptake inhibitor, and serotonin reuptake
accelerators, and mixtures thereof.
[0212] In a preferred embodiment, the selective serotonin reuptake
inhibitor antidepressant that is suitable for use with the methods and
compositions of the present invention is selected from the group consisting
of sertraline, citalopram, escitalopram oxalate, fluvoxamine, paroxetine,
and fluoxetine, and mixtures thereof.
[0213] In a preferred embodiment, the selective serotonin reuptake
inhibitor antidepressant that is suitable for use with the methods and
compositions of the present invention is selected from the group consisting
of phenelzine, tranylcypromine, isocarboxazid, selegiline, caroxazone, and
amiflamine, and mixtures thereof.
[0214] In a preferred embodiment, the serotonin antagonist and
reuptake inhibitor antidepressant that is suitable 'for use with the methods
and compositions of the present invention is selected from the group
consisting of nefazodone and trazodone, and mixtures thereof.
[0215] In a preferred embodiment, the serotonin and noradrenaline
reuptake inhibitor antidepressant that is suitable for use with the methods
and compositions of the present invention is selected from the group
consisting of milnacipran and moclobemide, and mixtures thereof.
[0216] In a preferred embodiment, the antidepressant that is
suitable for use with the methods and compositions of the present
invention is selected from the group consisting of sertraline, citalopram,
escitalopram oxalate, fluvoxamine, paroxetine, fluoxetine, amitriptyline,
desipramine, imipramine, maprotiline, reboxetine, nortriptyline, amineptine,
zimelidine, venlafaxine, mirtazapine, milnacipran, phenelzine,
tranylcypromine, nefazodone, trazodone, bupropion, clomipramine,
tandospirone, isocarboxazid, lithium carbonate, lithium citrate, doxepin,
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amoxapine, moclobemide, trimipramine, selegiline, protriptyline,
viloxazine, alprazolam, pargyline, dextroamphetamine, methylphenidate,
diazepam, buspirone, tianeptine, binodaline, caroxazone, dimethazan,
fencamine, indalpine, indeloxazine hydrochloride, nefopam, nomifensine,
oxitriptan, oxypertine, thiazesim, benmoxine, iproclozide, iproniazid, L-
tryptophan, nialamide, octamoxin, toloxatone, cotinine, rolicyprine,
rolipram, metralindole, mianserin, adinazolam, amitriptylinoxide,
butriptyline, dibenzepin, dimetacrine, dothiepin, fluacizine, imipramine N-
oxide, iprindole, lofepramine, melitracen, metapramine, noxiptilin,
opipramol, pizotyline, propizepine, quinupramine, tofenacin, adrafinil,
benactyzine, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate,
femoxetine, fenpentadiol, hematoporphyrin, hypericin, levophacetoperane,
medifoxamine, minaprine, oxaflozane, piberaline, prolintane,
pyrisuccideanol, ritanserin, roxindole, rubdium chloride, sulpiride,
thozalinone, amantadine, amiflamine, amisulpride, amphetamine,
aprepitant, aripiprazole, atomoxetine, befloxatone, brofaromine,
brornocriptine, buprenorphine, cericlamine, ciclazindol, cimoxatone,
clorgyline, clovoxamine, dapoxetine, demexiptiline, dexmethylphenidate,
etryptamine, fengabine, flerobuterol, flesinoxan, flibanserin, fluparoxan,
gepirone, idazoxan, igmesine, incazane, ipsapirone, isradipine, levodopa,
lamotrigine, levoprotiline, liothyronine, litoxetine, mazindol, mebanazine,
mefexamide, memantine, mifepristone, modafinil, nemifitide, nisoxetine,
nitroxazepine, olanzapine, oxaprotiline, oxycodone, ziprasidone, pemoline,
pergolide, phenoxypropazine, phentermine, pindolol, piribedil, pirlindole or
pyrazidol, pramipexole, pregabalin, pyrovalerone, risperidone, ropinirole,
sibutramine, talipexole, tetrindole, thyroxine, tolcapone, vilazodone,
viqualine, asenapine, 1-pyrimidinylpiperazine, 6-hydroxy-buspirone, and
yohimbine, prodrugs of any of them, and mixtures thereof.
[02'17) Any combination that includes at least one of the Cox-2
inhibitors that are described alone and, optionally, at least one of the
antidepressant agents that are described above can be used in the novel
methods, compositions, pharmaceutical compositions and kits of the
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present invention. For example, a Cox-2 inhibitor such as celecoxib can
be combined with any of the aforementioned antidepressant agents
described in Table 3, including, for example, the antidepressant agent,
sertraline.
[0218] One of skill in the art will understand how to make the
antidepressant agents described above by following the teachings of the
corresponding references.
[0219] Cox-2 inhibitors and antidepressant agents that are useful in
the present invention can be of any purity or grade, as long as the
preparation is of a quality suitable for pharmaceutical use. The Cox-2
inhibitor or antidepressant agent can be provided in pure form, or it can be
accompanied with impurities or commonly associated compounds that do
not affect its physiological activity or safety.
[0220] The Cox-2 inhibitors and antidepressant agents can be
supplied in the form of a pharmaceutically active salt, a prodrug, an
isomer, a tautomer, a racemic mixture, or in any other chemical form or
combination that, under physiological conditions, still provides for
inhibition
of the Cox-2 enzyme and any physiological function that the
antidepressant agent may perform. The present invention includes all
possible diastereomers as well as their racemic and resolved,
enantiomerically pure forms.
[0221] The present invention also encompasses a novel therapuetic
composition comprising at least one Cox-2 inhibitor and one or more
antidepressant agents.
[0222] In the present invention, a composition comprising a Cox-2
inhibitor in combination with a antidepressant agent is administered to a
subject in need of such treatment according to standard routes of drug
delivery that are well known to one of ordinary skill in the art.
[0223] The present invention also encompasses a pharmaceutical
composition for preventing or treating a psychiatric disorder in a subject
that is in need of such prevention and treatment, the pharmaceutical
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composition comprising at least one Cox-2 inhibitor, at least one
antidepressant agent, and a pharmaceutically acceptable carrier.
Thus, the combination of a Cox-2 inhibitor and an antidepressant agent
can be provided in a pharmaceutically acceptable carrier or excipient to
form a pharmaceutical composition.
[0224] The pharmaceutical compositions of the present invention
comprise a Cox-2 inhibitor and an antidepressant agent as an active
ingredient or a pharmaceutically acceptable salt, thereof, and also contain
a pharmaceutically acceptable carrier and optionally other therapeutic
ingredients. When the Cox-2 inhibitor and an antidepressant agent
inhibitor are supplied along with a pharmaceutically acceptable carrier, a
pharmaceutical composition is formed. A pharmaceutical composition of
the present invention is directed to a composition suitable for the
prevention, treatment, or amelioration of a psychiatric disorder. The
pharmaceutical composition comprises a pharmaceutically acceptable
carrier, a Cox-2 inhibitor, and an antidepressant agent.
[0225] The term "pharmaceutically acceptable" is used herein to
mean that the modified noun is appropriate for use in a pharmaceutical
product.
[0226] Pharmaceutically acceptable carriers and excipients include,
but are not limited to, physiological saline, Ringer's solution, phosphate
solution or buffer, buffered saline and other carriers known in the art.
Pharmaceutical compositions may also include stabilizers, anti-oxidants,
colorants, and diluents. Pharmaceutically acceptable carriers and
additives are chosen such that side effects from the pharmaceutical
compound are minimized and the performance of the compound is not
canceled or inhibited to such an extent that treatment is ineffective. In one
embodiment the Cox-2 inhibitor alone or in combination with the
antidepressant agent are administered to a subject together in one
pharmaceutical carrier. In another embodiment, the Cox-2 inhibitor and
the antidepressant agent are administered separately.
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[0227] The pharmaceutically acceptable carrier can also be
selected on the basis of the desired route of administration of the
compound. For example, in a preferred embodiment the carrier is suitable
for oral administration. In a more preferred embodiment, the composition
includes a carrier or additional agent that is suitable for promoting delivery
of the compound to the brain. Carriers that can promote delivery of the
compound to the brain can include any carrier that promotes translocation
across the blood-brain barrier and any carrier that promotes uptake of the
compound by neural cells. Examples of such carriers include those
disclosed in U.S. Pat. Nos. 5,604,198 (issued to Poduslo, et al.),
5,827,819 (issued to Yatvin, et al.), 5,919,815 (issued to Bradley, et al.),
5,955,459 (issued to Bradley, et al.), and 5,977,174 (issued to Bradley, et
al. ).
[0228] The terms "pharmaceutically acceptable salts" refer to salts
prepared from pharmaceutically acceptable non-toxic bases including
inorganic bases and organic bases. Illustrative pharmaceutically
acceptable salts are prepared from formic, acetic, propionic, succinic,
glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic,
malefic,
fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, trifluoroacetic,
anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic,
mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,
benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic,
sulfanilic, cyclohexylaminosulfonic, algenic, a-hydroxybutyric, galactaric
and galacturonic acids.
[0229] Salts derived from inorganic bases include aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic
salts, manganous, potassium, sodium, zinc, and the like. Particularly
preferred are the ammonium, calcium, magnesium, potassium, and
sodium salts. Salts derived from pharmaceutically acceptable organic.
non-toxic bases include salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted amines, cyclic
amines, and basic ion exchange resins, such as arginine, betaine,
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caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-
diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
procaine, purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine and the like.
[0230] Pharmaceutically acceptable cations include metallic ions
and organic ions. More preferred metallic ions include, but are not limited
to, appropriate alkali metal salts, alkaline earth metal salts and other
physiological acceptable metal ions. Exemplary ions include aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc in their usual
valences.
[0231] Preferred organic ions include protonated tertiary amines
and quaternary ammonium cations, including in part,.trimethylamine,
diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglueamine) and
procaine. Exemplary pharmaceutically acceptable acids include, without
limitation, hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric
acid, sulfuric acid, rnethanesulfonic acid, acetic acid, formic acid, tartaric
acid, malefic acid, malic acid, citric acid, isocitric acid, succinic acid,
lactic
acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric
acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the
like.
[0232] All of the above salts and ions can be prepared by those
skilled in the art by conventional means from the corresponding compound
of the present invention.
[0233] In the present invention, a Cox-2 inhibitor and/or
antidepressant agent are administered to a patient in need of such
treatment or prevention according to standard routes of drug delivery that
are well known to one of ordinary skill in the art. The particular route and
dosage of the Cox-2 inhibitor and the antidepressant agent depend upon
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the needs of the subject being treated, the type of treatment or prevention,
the efficacy of the compound and the degree of disease severity in the
subject.
(0234] The pharmaceutical compositions may be administered
enterally and parenterally. Oral (intra-gastric) is a preferred route of
administration. Pharmaceutically acceptable carriers can be in solid
dosage forms for the methods of the present invention, which include
tablets, capsules, pills, and granules, which can be prepared with coatings
and shells, such as enteric coatings and others well known in the art.
Liquid dosage forms for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups, and elixirs.
(0235] Enteral administration includes solution, tablets, sustained
release capsules, enteric-coated capsules, and syrups. When
administered, the pharmaceutical composition may be at or near body
temperature.
(0236] Compositions intended for oral use may be prepared
according to any method known in the art for the manufacture of
pharmaceutical compositions and such compositions may contain one or
more agents selected from the group consisting of sweetening agents,
flavoring agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets contain the
active ingredient in admixture with non-toxic pharmaceutically acceptable
excipients, which are suitable for the manufacture of tablets. These
excipients may be, for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate,
granulating and disintegrating agents, for example, maize starch, or alginic
acid, binding agents, for example starch, gelatin or acacia, and lubricating
agents, for example magnesium stearate, stearic acid, or talc. The tablets
may be uncoated or they may be coated by known techniques to delay
disintegration and absorption in the gastrointestinal tract and thereby
provide a sustained action over a longer period. For example, a time
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delay material such as glyceryl monostearate or glyceryl distearate may be
employed.
[0237] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredients are mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or kaolin,
or as soft gelatin capsules wherein the active ingredients are present as
such, or mixed with water or an oil medium, for example, peanut oil, liquid
paraffin, or olive oil.
[0238] Aqueous suspensions can be produced that contain the
active materials in a mixture with excipients suitable for the manufacture of
aqueous suspensions. Such excipients are suspending agents, for
example, sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum
tragacanth and gum acacia; dispersing or wetting agents may be naturally-
occurring phosphatides, for example lecithin, or condensation products of
an alkylene oxide with fatty acids; for example polyoxyethylene stearate,
or condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty acids and
a hexitol such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty acids and
hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
The aqueous suspensions may also contain one or more preservatives, for
example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring
agents, one or more flavoring agents, or one or more sweetening agents,
such as sucrose or saccharin.
[0239] Oily suspensions may be formulated by suspending the
active ingredients in an omega-3 fatty acid, a vegetable oil, for example,
arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as
liquid paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol.
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[0240] Sweetening agents, such as those set forth above, and
flavoring agents may be added to provide a palatable oral preparation.
These compositions may be preserved by the addition of an antioxidant
such as ascorbic acid.
[0241] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent, a suspending
agent and one or more preservatives. Suitable dispersing or wetting
agents and suspending agents are exemplified by those already
mentioned above. Additional excipients, for example sweetening, flavoring
and coloring agents, may also be present.
[0100] Syrups and elixirs containing the Cox-2 inhibitor and/or
antidepressant agent may be formulated with sweetening agents, for
example glycerol, sorbitol, or sucrose. Such formulations may also
contain a demulcent, a preservative and flavoring and coloring agents.
[0242] The subject method of prescribing a Cox-2 inhibitor and/or
antidepressant agent and compositions comprising the same can also be
administered parenterally, either subcutaneously, or intravenously, or
intramuscularly, or intrasternally, or by infusion techniques, in the form of
sterile injectable aqueous or olagenous suspensions. Parenteral
administration includes subcutaneous, intramuscular, intradermal,
intramammary, intravenous, and other administrative methods known in
the art.
[0243] Administration of either one or both of the Cox-2 inhibitor and
antidepressant agents can also be by inhalation, in the form of aerosols or
solutions for nebulizers. Therefore, in one embodiment, the Cox-2
inhibitor and/or the antidepressant agent is administered by direct
inhalation into the respiratory system of a subject for delivery as a mist or
other aerosol or dry powder. Delivery of drugs or other active ingredients
directly to the subject's lungs provides numerous advantages including,
providing an extensive surface area for drug absorption, direct delivery of
therapeutic agents to the disease site in the case of regional drug therapy,
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eliminating the possibility of drug degradation in the subject's intestinal
tract (a risk associated with oral administration), and eliminating the need
for repeated subcutaneous injections.
[0244] Aerosols of liquid particles comprising the active materials
may be produced by any suitable means, such as inhalatory delivery
systems. Nebulizers are commercially available devices which transform
solutions or suspensions of the active ingredient into a therapeutic aerosol
mist either by means of acceleration of compressed gas, typically air or
oxygen, through a narrow venturi orifice or by means of ultrasonic
agitation. Suitable formulations for use in nebulizers consist of the active
ingredient in a liquid carrier. The carrier is typically water, and most
preferably sterile, pyrogen-free water, or a dilute aqueous alcoholic
solution, preferably made isotonic, but may be hypertonic with body fluids
by the addition of, for example, sodium chloride. Optional additives
include preservatives if the formulation is not made sterile, for example,
methyl hydroxybenzoate, as well as antioxidants, flavoring agents, volatile
oils, buffering agents and surfactants, which are normally used in the
preparation of pharmaceutical compositions.
[0245] Aerosols of solid particles comprising the active materials
may likewise be produced with any solid particulate medicament aerosol
generator. Aerosol generators for administering solid particulate
medicaments to a subject produce particles which are respirable, as
explained above, and generate a volume of aerosol containing a
predetermined metered dose of a medicament at a rate suitable for human
administration.
[0246] One type of solid particulate aerosol generator is an
insufflator. Suitable formulations for administration by insufflation include
finely comminuted powders which may be delivered by means of an
insufflator or taken into the nasal cavity in the manner of a snuff. In the
insufflator, the powder is contained in capsules or cartridges, typically
made of gelatin or plastic, which are either pierced or opened in situ and
the powder delivered by means of air drawn through the device upon
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inhalation.or by means of a manually-operated pump. The powder
employed in the insufflator consists either solely of the active ingredient or
of a powder blend comprising the active materials, a suitable powder
diluent, such as lactose, and an optional surfactant.
(0247] A second type of aerosol generator is a metered dose
inhaler. Metered dose inhalers are pressurized aerosol dispensers,
typically containing a suspension or solution formulation of the Cox-2
inhibitor and/or the antidepressant agent in a liquified propellant. During
use, the metered dose inhaler discharges the formulation through a valve,
adapted to deliver a metered volume, to produce a fine particle spray
containing the active materials. Any propellant may be used for aerosol
delivery, including both chlorofluorocarbon-containing propellants and non-
chlorofluorocarbon-containing propellants.
[0248] A third type of aerosol generator is a electrohydrodynamic
(EHD) aerosol generating device, which has the advantage of being
adjustable to create substantially monomodal~\aerosols having particles
more uniform in size than aerosols generated by other devices or
methods. Typical EHD devices include a spray nozzle in fluid
communication with a source of liquid to be aerosolized, at least one
discharge electrode, a first voltage source for maintaining the spray nozzle
at a negative (or positive) potential relative to the potential of the
discharge
electrode, and a second voltage source for maintaining the discharge
electrode at a positive (or negative) potential relative to the potential of
the
spray nozzle. Most EHD devices create aerosols by causing a liquid to
form droplets that enter a region of high electric field strength. The
electric
field then imparts a net electric charge to these droplets, and this net
electric charge tends to remain on the surface of the droplet. The repelling
force of the charge on the surface of the droplet balances against the
surface tension of the liquid in the droplet, thereby causing the droplet to
form a cone-like structure known as a Taylor Cone. In the tip of this cone-
like structure, the electric force exerted on the surface of the droplet
overcomes the surface tension of the I iquid, thereby generating a stream
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of liquid that disperses into a many smaller droplets of roughly the same
size. These smaller droplets form a mist which constitutes the aerosol
cloud that the user ultimately inhales.
[0249] Administration of the compositions of the present invention
can also be rectally, in the form of suppositories prepared by mixing the
drug with a suitable non-irritating excipient which is solid at ordinary
temperature, but liquid at the rectal temperature and will therefore, melt in
the rectum to release the drug. Such materials are cocoa butter and
polyethylene glycols.
[0250] Also encompassed by the present invention is buccal or
"sub-lingual" administration, which includes lozenges or a chewable gum
comprising the compounds, set forth herein. The compounds can be
deposited in a flavored base, usually sucrose, and acacia or tragacanth,
and pastilles comprising the compounds in an inert base such as gelatin
and glycerin or sucrose and acacia.
[0251] The prevent invention further encompasses intran'asal
administration comprising the compounds set forth herein. Intranasal
dosage forms include, but are not limited to, aerosols, drops, gels,
powders, and mixtures thereof.
[0252] Other methods for administration of the Cox-2 inhibitor
compound and/or the antidepressant agent include dermal patches that
release the medicaments directly into a subject's skin.
[0253] Topical delivery systems are also encompassed by the
present invention and include ointments, powders, sprays, creams, jellies,
collyriums, solutions or suspensions.
[0254] The compositions of the present invention can optionally be
supplemented with additional agents such as, for example, viscosity
enhancers, preservatives, surfactants and penetration enhancers.
[0255] Viscosity is an important attribute of many medications.
Drops that have a high viscosity tend to stay in the body for longer periods
and thus, increase absorption of the active compounds by the target
tissues or increase the retention time. Such viscosity-building agents
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include, for example, polyvinyl alcohol, polyvinyl pyrrolidone,
methylcellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose,
carboxymethyl cellulose, hydroxy propyl cellulose or other agents know to
those skilled in the art. Such agents are typically employed at a level of
from 0.01 % to 2% by weight.
Preservatives are optionally employed to prevent microbial contamination
during use. Suitable preservatives include polyquaternium-1,
benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl
paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other
agents known to those skilled in the art. The use of polyquaternium-1 as
the antimicrobial preservative is preferred. Typically, such preservatives
are employed at a level of from 0.001 % to 1.0% by weight.
(0256] The solubility of the components of the present compositions
may be enhanced by a surfactant or other appropriate co-solvent in the
composition. Such co-solvents include polysorbate 20, 60, and 80,
polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-68, F-84
and P-103), cyclodextrin, or other agents known to those skilled in the art.
Typically, such co-solvents are employed at a level of from 0.01 % to 2%
by weight.
[0257] A penetration enhancer is an agent used to increase the
permeability of the skin to an active agent to increase the rate at which the
drug diffuses through the skin and enters the tissues and bloodstream.
Thus, in one embodiment of the present invention, a penetration enhancer
may be added to a Cox-2 inhibitor topical composition or a Cox-2 inhibitor
and antidepressant agent or topical composition.
[0258] Examples of penetration enhancers suitable for use with the
compositions of the present invention include: alcohols, such as ethanol
and isopropanol; polyols, such as n-alkanols, limonene, terpenes,
dioxolane, propylene glycol, ethylene glycol, other glycols, and glycerol;
sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformamide, methyl
dodecyl sulfoxide, dimethylacetamide; esters, such as isopropyl
myristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate, and
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capric/caprylic triglycerides; ketones; amides, such as acetamides;
oleates, such as triolein; various surfactants, such as sodium lauryl sulfate;
various alkanoic acids, such as caprylic acid; lactam compounds, such as
azone; alkanols, such as oleyl alcohol; dialkylamino acetates, and
admixtures thereof.
[0259] Pharmaceutically acceptable excipients and carriers
encompass all the foregoing and the like. The above considerations
concerning effective formulations and administration procedures are well
known in the art and are described in standard textbooks. See e.g.
Gennaro, A. R., Remington: The Science and Practice of Pharmacy, 20th
Edition, (Lippincott, Williams and Wilkins), 2000; Hoover, John E.,
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage
Forms, Marcel Decker, New York, N.Y., 1980; and ICibbe, et al., Eds.,
Handbook of Pharmaceutical Excipients (3rd Ed.), American
Pharmaceutical Association, Washington, 1999.
[0260] For purposes of the present invention, it is preferred that the
amount of a Cox-2 inhibitor and the amount of an antidepressant agent
comprise an effective amount of each of the two treatment agents. In
another embodiment of the present invention, the amou nt of the
combination therapy with the Cox-2 inhibitor and antidepressant agent
together comprises a therapeutically effective amount of the combined
therapy.
[0261] As used herein, an "effective amount" means the dose or
amount to be administered to a subject and the frequency of
administration to the subject, which is readily determined by one having
ordinary skill in the art, by the use of known techniques and by observing
results obtained under analogous circumstances.
[0262] In determining the effective amount or dose, a number of
factors are considered by the attending diagnostician, including, but not
limited to, the potency and duration of action of the compounds used, the
nature and severity of the illness to be treated, as well as the sex, age,
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weight, general health and individual responsiveness of the patient to be
treated, and other relevant circumstances.
[0263] As used herein, the terms "therapeutically effective" are
intended to qualify the amount of an agent for use in therapy that will
achieve the goal of preventing or improving the severity of the disorder
being treated, while avoiding adverse side effects typically associated with
alternative therapies. A psychiatric disorder symptom is considered
ameliorated or improved if any benefit is achieved, no matter how slight.
[0264] As used herein, the terms "prophylactically effective" refer to
an amount of a Cox-2 inhibitor alone or in combination with at least one
antidepressant agents that causes a decrease in the frequency of
incidence of psychiatric disorders or psychiatric disorder-related
symptoms. The term "prophylactic" refers to the prevention of psychiatric
disorders or a psychiatric disorder-related symptom, whereas the term
"therapeutic" refers to the effective treatment of an existing disorder such
as psychiatric disorders or a psychiatric disorder-related symptom.
[0265] It will be appreciated that the amount of the Cox-2 inhibitor
alone or in combination with at least one antidepressant agent required for
use in the treatment or prevention of psychiatric disorders and psychiatric
disorder-related symptoms will vary within wide limits and will be adjusted
to the individual requirements in each particular case. In general, for
administration to adults, an appropriate daily dosage is described herein,
although the limits that are identified as being preferred may be exceeded
if expedient. The daily dosage can be administered as a single dosage or
in divided dosages.
[0266] The appropriate dosage level of a Cox-2 inhibifior will
generally be from about 0.01 mg per kg to about 140 mg per kg subject
body weight per day, which may be administered in single or multiple
doses. Preferably, the dosage level will be about 0.1 mg/kg to about 25
mg/kg per day; more preferably about 0.5 mg/kg to about 10 mg/kg per
day.
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[0267] In larger mammals, for example humans, a typical indicated
dose is about 0.5 mg to 7 grams orally per day. A Cox-2 inhibitor
compound may be administered on a regimen of several times per day, for
example 1 to 4 times per day, preferably once or twice per day.
[0268] The amount of the Cox-2 inhibitor that may be combined with
the carrier materials to produce a single dosage form will vary depending
upon the host treated and the particular mode of administration. For
example, a formulation intended for the oral administration of humans may
contain from 0.5 mg to 7 g of active agent compounded optionally with an
appropriate and convenient amount of carrier material, which may vary
from about 5 to about 95 percent of the total composition. Dosage unit
forms for the Cox-2 inhibitor will generally contain between from about 1
mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg ~ 100
mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
[0269] The dosage level of an antidepressant agent will necessarily
depend on the particular antidepressant agent that is used. The
appropriate dosage level of an antidepressant agent will generally be from
about 0.001 mg per kg to about 50 mg per kg subject body weight per day,
which may be administered in single or multiple doses. Preferably, the
dosage level will be about 0.1 mg/kg to about 25 mg/kg per day; more
preferably about 1.0 mg/kg to about 10 mg/kg per day.
[0270] In larger mammals, for example humans, a typical ind icated
dose of an antidepressant agent is about 0.1 mg to 2 grams orally per day.
An antidepressant agent may be administered on a regimen of several
times per day, for example 1 to 4 times per day, preferably once or twice
per day.
[0271] The exact dosage and regimen for administering a Cox-2
inhibitor alone or in combination with at least one antidepressant agent will
necessarily depend upon the potency and duration of action of the
compounds used, the nature and severity of the illness to be treated, as
well as the sex, age, weight, general health, and individual responsiveness
of the patient to be treated, and other relevant circumstances. Those
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skilled in the art will appreciate that dosages may also be determined with
guidance from Goodman & Goldman's The Pharmacological Basis of
Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711.
[0272] The effectiveness of a particular dosage of a Cox-2 inhibitor
alone or in combination with an antidepressant agent is determined by
monitoring the effect of a given dosage on the progress or prevention of a
particular psychiatric disorder. This monitoring may be done through out-
patient therapy or in a hospitalized setting.
[0273] For example, monitoring the effectiveness of the methods
and compositions of the present invention on a subject suffering from
depression may involve evaluating the subject under out-patient therapy.
In this setting, any changes in the subject's symptoms of depression are
monitored and evaluated by a therapist.
[0274] Still other methods for monitoring the effectiveness of the
methods and compositions of the present invention can include conducting
an evaluation of a subject's limbic-diencephalic function/dysfunction. Such
evaluation can be performed by utilizing such tests as the thyrotropin-
releasing hormone (TRH) stimulation test, the dexamethasone
suppression test (DST), and sleep EEG for rapid eye movement (REM)
latency test. See The Merck Manual of Diagnosis & Therapy, Beers &
Brakow, 17th edition, Published by Merck Research Labs, Sec. 15, Chap.
189, Psychiatric Disorders, Mood Disorders (1999).
[0275] As used herein, the term "subject" for purposes of treatment
includes any subject, and preferably is a subject who is in need of the
treatment of psychiatric disorders, or who needs treatment of a psychiatric
disorder-related symptom. For purposes of prevention, the subject is any
subject, and preferably is a subject that is at risk for, or is predisposed
to,
developing a psychiatric disorder or a psychiatric disorder-related
symptom. The subject is typically an animal, and yet more typically is a
mammal. "Mammal", as that term is used herein, refers to any animal
classified as a mammal, including humans, domestic and farm animals,
zoo, sports, or pet animals, such as dogs, horses, cats, cattle, etc.
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Preferably, the mammal is a human. For purposes of the present
invention, an adult human weighs approximately seventy kilograms.
[0276] As used herein, the terms "a subject who is predisposed to a
psychiatric disorder" and "a subject who is at risk for a psychiatric
disorder," both of which are used interchangeably herein, mean any
subject at risk for developing psychiatric disorders or any psychiatric
disorder-related symptoms. The subject may be a human subject who is
at risk for developing psychiatric disorders or any psychiatric disorder-
related symptoms. The subject may be at risk due to genetic
predisposition, diet, age, exposure to traumatic life events, exposure to a
separation such as death, and the like. The subject may also be at risk
due to physiological factors such as abnormalities in the brain.
[0277] As used herein, the terms "subject is in need of the
prevention or treatment of a psychiatric disorder or a psychiatric disorder-
related symptom" refer to any subject who is suffering from or is
predisposed to psychiatric disorders or any psychiatric disorder-related
symptoms described herein. The terms "subject is in need of the
prevention or treatment of a psychiatric disorder or a psychiatric disorder-
related symptom" also refer to any subject that requires a lower dose of
conventional antidepressant agents. In addition, the terms "subject is in
need of the prevention or treatment of a psychiatric disorder or a
psychiatric disorder-related symptom" mean any subject who requires a
reduction in the side effects of a conventional antidepressant agent.
Furthermore, the terms "subject is in need of the prevention or treatment of
a psychiatric disorder or a psychiatric disorder-related symptom" mean a ny
subject who requires improved tolerability to any conventional psychiatric
disorder treatment agent for psychiatric disorders therapy.
[0278] The present invention encompasses the prevention and/or
treatment of any pychiatric disorder including, but not limited to,
depression (uni-polar disorder or major depressive disorder), manic
depression (bipolar disorders), anxiety disorder, anxious depression, panic
disorder, attention deficit disorder, attention deficit/hyperactivity
disorder,
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melancholia (endogenous depression), depressive pseudodementia,
dysthymic disorder, cyclothymic disorder, somatization disorder,
conversion disorder, hypochondriasis, pain disorder, posttraumatic stress
disorder, acute stress disorder, obsessive compulsive disorder,
premenstrual dysphonic disorder, body dysmorphic disorder,
schizophrenia, autism, agoraphobia, specific phobias, social phobia, acute
stress disorder, dissociative amnesia, dissociative fugue, dissociative
identity disorder, depersonalization disorder, and any combination of the
above.
(0279] In one embodiment, the present invention encompasses the
treatment or prevention of depression.
[0280] In other embodiments, the present invention encompasses a
kit for preventing or treating psychiatric disorders or any psychiatric
disorder-related symptoms in a subject that is in need of such prevention
or treatment, the kit comprising one dose ge form comprising a Cox-2
inhibitor and a second dosage form comprising at least one antidepressant
agent.
(0281] The following examples describe embodiments of the
invention. Other embodiments within the scope of the claims herein will be
apparent to one skilled in the art from consideration of the specification or
practice of the invention as disclosed herein. It is intended that the
specification, together with the examples ~ be considered to be exemplary
only, with the scope and spirit of the invention being indicated by the
claims, which follow the examples. In the examples, all percentages are
given on a weight basis unless otherwise indicated.
EXAMPLE 1
[0282] This example shows the preparation of the Cox-2 inhibitor,
celecoxib.
[0283] Step 1: Preparation of 1-(4-methylphenyl)-4,4,4-
trifluorobutane-1,3-dione.
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[0284] Following the disclosure provided in U.S. Patent No.
5,760,068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in
25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide
in methanol (25%) was added. The mixture was stirred for 5 minutes and
5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24
hours, the mixture was cooled to room temperature and concentrated.
100 mL 10% HCI was added and the mixture extracted with 4 x 75 mL
ethyl acetate. The extracts were dried over MgS04, filtered and
concentrated to afford 8.47 g (94%) of a brown oil which was carried on
without further purification.
[0285] Step 2: Preparation of 4-[5-(4-methylphenyl)-3-
(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide.
[0286] To the dione from Step 1 (4.14 g, 18.0 mmol) in 75 mL
absolute ethanol, 4.26 g (19.0 mmol) 4-sulphonamidophenylhydrazine
hydrochloride was added. The reaction was refluxed under argon for 24
hours. After cooling to room temperature and filtering, the reaction mixture
was concentrated to afford 6.13 g of an orange solid. The solid was
recrystallized from methylene chloride/hexane to give 3.11 g (8.2 mmol,
46%) of the product as a pale yellow solid, having a melting point (mp) of
157°-159°C; and a calculated composition of C~7 H~4 N3 02 SF3 ;
C, 53.54;
H, 3.70; N, 11.02. The composition that was found by analysis was: C,
53.17; H, 3.81; N, 10.90.
EXAMPLE 2
[0287] This example illustrates the production of a composition
containing celecoxib and an antidepressant agent, and of a
pharmaceutical composition containing the combination.
[0288] An antidepressant such as sertraline may be supplied by any
one of several commercially available preparations. One such preparation
of sertraline is the trade name Zoloft~ 100mg (NDC: 00049-4910-66)
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available from the Roerig Division of Pfizer Inc, NY, NY. Each tablet of
Zoloft~ contains 100mg of sertraline.
[0289] Alternatively, one of skill in the art may synthesize sertraline
from a reading of the general synthesis outline disclosed in U.S. Patent
Numbers 4,536,518 and 4,556,676.
[0290] A therapeutic composition of the present invention can be
formed by intermixing sertraline, 100 g; and 4-[5-(4-methylphenyl)-3-
(trifluoromethyl)-1 H-pyrazol-1-ylJbenzenesulfonamide (200 g, as produced
in Example 1, or as available from Pharmacia Corporation, Peapack, NJ,
under the tradename Celebrex~), in a suspension or solution with a sterile
pharmaceutically acceptable liquid.
[0291] After mixing, the combination of sertraline and celecoxib
forms a therapeutic composition that is sufficient for the production of
about 1000 human single dose units. Each single dose unit contains
about 100 mg of sertraline and about 200 mg of celecoxib.
[0292] If desirable, a solid carrier and other materials may be
intermixed with the therapeutic composition to form a pharmaceutical
composition and the resulting pharmaceutical composition may be formed
into capsules for human consumption, for example, by conventional
capsule-forming equipment, where each capsule can contain about the
same amount of the active ingredients as each of the single dose units of
the liquid preparation described above.
[0293] Therapeutic and pharmaceutical compositions comprising a
combination of any of the Cox-2 inhibitors alone and in combination with
any of the sources of antidepressant agents that are described above can
be formed by similar methods.
[0294] All references cited in this specification, including without
limitation all papers, publications, patents, patent applications,
presentations, texts, reports, manuscripts, brochures, books, Internet
postings, journal articles, periodicals, and the like, are hereby incorporated
by reference into this specification in their entireties. The discussion of
the
references herein is intended merely to summarize the assertions made by
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their authors and no admission is made that any reference constitutes
prior art. Applicants reserve the right to challenge the accuracy and
pertinency of the cited references.
[0295] In view of the above, it will be seen that the several
advantages of the invention are achieved and other advantageous results
obtained.
[0296] As various changes could be made in the above methods
and compositions without departing from the scope of the invention, it is
intended that all matter contained in the above description shall be
interpreted as illustrative and not in a limiting sense. In addition, it
should
be understood that aspects of the various embodiments may be
interchanged both in whole or in part.
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