Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
  • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• 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.
• psychiatric disorders 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 (unipolar disorder or major depressive disorder) and manic depression (bipolar 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, 17 th edition, Published by Merck Research Labs, Sec. 15, Chap.
• 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, uncomfortable, 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.
• impaired limbic- diencephalic function is the final pathway causing mood disorders.
• 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.
• mood disorders can be stressors that 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.
• 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.
• antidepressant agents with varying functionalities have emerged over the years and are used as pharmaceutical therapies. See Abies, A., et al., Am. Fam. Physician 67(3):547-54 (2003). These 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.
• Sertraline 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.
• SSRI serotonin reuptake inhibitor
• 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.
• 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 4J0(6827):471-5 (2001).
• NSAIDS nonsteroidal anti-inflammatory drugs
• NSAIDS nonsteroidal anti-inflammatory drugs
• some NSAIDS are known to cause gastrointestinal (Gl) bleeding or ulcers in patients undergoing consistent long term regimens of NSAID therapy.
• Gl gastrointestinal bleeding or ulcers in patients undergoing consistent long term regimens of NSAID therapy.
• 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.
• Cox-1 cyclooxygenase-1
• Cox-2 cyclooxygenase-2
• 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.
• 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.
• 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.
• psychiatric disorders Despite the recent advances that have been made in understanding psychiatric disorders, they remain notoriously difficult to treat or prevent.
• 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.
• the present invention is also directed to a novel method o-f 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.
• the present invention is also directed to a novel therapeutic composition comprising a Cox-2 inhibitor and an antidepressant agent.
• the present invention is also directed to a novel pharmaceutical comprising a Cox-2 inhibitor, an antidepressant agent, and a pharmaceutically acceptable carrier.
• 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.
• trie present invention Among the several advantages found to be achieved by trie present invention, therefore, may be noted the provision of improved methods, therapeutic compositions, pharmaceutical compositions, and kits for the prevention or treatment of psychiatric disorders such as depression.
• Other advantages achieved by the present invention include 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.
• the present invention provides methods, compositions, and kits that reduce dosages or reduce unwanted side effects in conventional treatments for psychiatric disorders.
• 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.
• 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.
• the therapy of the present invention is useful, for example, to reduce such psychiatric disorder symptoms as a mood that is depressed, irritable, anxious, comfortable, 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.
• 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.
• 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 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.
• 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.
• 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 one antidepressant agent.
• 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.
• 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.
• 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.
• 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®).
• fluoxetine causes sexual dysfunction, which can lead to reduced patient compliance with the treatment regimen.
• the administration of a Cox-2 inhibitor in combination with an antidepressant agent is an effective treatment for psychiatric 1 disorders and psychiatric disorder-related symptoms, and in preferred embodiments, is superior to the use of either agent alone.
• 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.
• 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.
• 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 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.
• 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.
• 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.
• 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.
• the second drug is administered while the first drug is still having an efficacious effect on the subject.
• 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.
• 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.
• therapeutic response time means the duration of time that a compound is present or detectable within a subject's body at therapeutic concentrations.
• 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.
• the Cox-2 inhibitor may still be administered in multiple dosage forms.
• 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.
• the present invention provides a method for treating or preventing psychiatric disorders in a subject in need of such treatment or prevention.
• 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.
• a Cox-2 inhibitor alone or in combination with an antidepressant agent.
• 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.
• 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.
• Treating 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 appearance of symptoms or symptom worsening.
• 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.
• 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.
• 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.
• a psychiatric disorder-related symptom such as a depressed mood
• the treatment of the underlying psychiatric disorder, such as depression will likewise improve the symptoms of the associated complication.
• 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.
• 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.
• a component of the present invention is a Cox-2 inhibitor.
• 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.
• the inhibitors used in the methods described herein may block the enzyme activity directly by acting as a substrate for the enzyme.
• 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-
• 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.
• the Cox-2 inhibitor is a Cox-2 selective inhibitor.
• 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.
• the selectivity of a Cox-2 inhibitor varies depending upon the condition under which the test is performed and on the inhibitors being tested.
• 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.
• 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 ⁇ M, more preferred of less than about 0.5 ⁇ M, and even more preferred of less than about 0.2 ⁇ M.
• Cox-2 selective inhibitors have a Cox-1 IC50 of greater than about 1 ⁇ M, and more preferably of greater than 20 ⁇ M. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
• compounds that act as prodrugs of Cox-2-selective inhibitors are also included within the scope of the present invention.
• 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.
• 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 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.
• 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.
• 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.
• 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 1 -C 5 ", 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.
• alkenyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains at least one double bond.
• the alkenyl radicals may be optionally substituted with groups such as those defined below.
• suitable alkenyl radicals include propenyl, 2-chloropropylenyl, buten-1yl, isobutenyl, penten-1yl, 2-methylbuten-1-yl, 3-methylbuten-1 ⁇ yl, hexen-1-yl, 3- hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like.
• 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.
• alkynyl radicals examples 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.
• oxo means a single double-bonded oxygen.
• hydro denotes 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 (-CH 2 -) radical.
• halo means halogens such as fluorine, chlorine, and bromine or iodine atoms.
• haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
• 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.
• 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.
• 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.
• 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.
• alkoxy radicals include methoxy, butoxy, and trifluoromethoxy.
• 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.
• aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane, and biphenyl.
• 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, Z 1 , Z 2 , or Z 3 is C, S, P, O, or N, with the proviso that one of Z, Z 1 , Z 2 , or Z 3 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.
• the optional substituents are understood to be attached to Z, Z 1 , Z 2 , or Z 3 only when each is C.
• heterocycle also includes fully saturated ring structures, such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others.
• heteroaryl embraces unsaturated heterocyclic radicals.
• unsaturated heterocyclic radicals include thienyl, pyrryl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, and tetrazolyl.
• the term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
• sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -S0 2 -
• Alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above.
• arylsulfonyl embraces sulfonyl radicals substituted with an aryl radical.
• aminonosulfonyl denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide
• carboxyalkyl embraces radicals having a carboxy radical as defined above, attached to an alkyl radical.
• alkylcarbonyl embraces radicals having a carbonyl radical substituted with an alkyl radical.
• An example of an “alkylcarbonyl” radical is CH 3 - (CO) -.
• amino whether used alone or with other terms, such as “aminocarbonyl”, denotes -NH 2 . [0O77]
• heterocycloalkyl embraces heterocyclic- substituted alkyl radicals such as pyridylmethyl and thienylmethyl.
• aralkyl or "arylalkyl” embrace aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
• benzyl and phenylmethyl are interchangeable.
• cycloalkyl embraces radicals having three to ten carbon atoms, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• cycloalkenyl embraces unsaturated radicals having three to ten carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
• 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, (CH 3 -S-).
• alkylsulfinyl embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(-O) - atom.
• 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.
• 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.
• 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:
• X 1 is selected from O, S, CR C R b and NR a ; wherein R a is selected from hydrido, Ci -C 3 -alkyl, (optionally substituted phenyl)-C ⁇ -C 3 -alkyl, acyl and carboxy-Ci -C 6 -alkyl; wherein each of R b and R° is independently selected from hydrido, Ci -C 3 -alkyl, phenyl-Ci -C 3 -alkyl, Ci -C 3 -perfluoroalkyl, chloro, Ci -C 6 -alkylthio, Ci -C ⁇ -alkoxy, nitro, cyano and cyano-C-i -C 3 -alkyl; or wherein CR ⁇ R c forms a 3-6 membered cycloalkyl ring; wherein R 1 is selected from carboxyl, aminocarbonyl, Ci -C ⁇ -
• Ci -CQ -alkylthio Ci -C ⁇ -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Ci -C 6 -alkoxy-Ci -C 6 -alkyl, aryl-Ci -C 6 -alkyloxy, heteroaryl-Ci -C 6 -alkyloxy, aryl-Ci -C 6 -alkoxy-Ci -C 6 -alkyl, Ci -C 6 -haloalkyl, Ci -C 6 -haloaikoxy, Ci -C 6 -haloalkylthio, Ci -C 6 -haloalkylsulfinyl, Ci -C 6 -haloalkylsulfonyl, d -C 3 -(haloalkyl-i -
• X 2 is selected from O, S, CR C R b and NR a ; wherein R a is selected from hydrido, Ci -C 3 -alkyl, (optionally substituted phenyl)-C ⁇ -C -alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-Ci -C ⁇ -alkyl; wherein each of R b and R c is independently selected from hydrido, Ci -C 3 -alkyl, phenyl-Ci -C 3 -alkyl, Ci -C 3 -perfluoroalkyl, chloro, Ci -C 6 -alkylthio, Ci -C 6 -alkoxy, nitro, cyano and cyano-Ci -C 3 -alkyl; or wherein CR C R b form a cyclopropyl
• X 3 is selected from the group consisting of O or S or NR a ; wherein R a is alkyl; wherein R 9 is selected from the group consisting of H and aryl; wherein R 10 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R 11 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 R 12 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,
• X 4 is selected from O or S or NR a ; wherein R a is alkyl; wherein R 13 is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R 14 is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R 15 is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alky
• X 5 is selected from the group consisting of O or S or NR b ;
• R b is alkyl;
• R 16 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
• R 17 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, nitro and alkylsulfonyl; and
• R 18 is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalky
• X 5 is selected from the group consisting of oxygen and sulfur
• R 1 ⁇ is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl
• R 17 is selected from the group consisting of lower haloalkyl, lower cycloalkyl and phenyl
• R 18 is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, lower 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
• the Cox-2 selective inhibitor may also be a compound of Formula V, wherein: X 5 is selected from the group consisting of oxygen and sulfur; R 16 is carboxyl; R 17 is lower haloalkyl; and R 18 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 18 together with ring A forms a naphth
• the Cox-2 selective inhibitor may also be a compound of
• X 5 is selected from the group consisting of oxygen and sulfur
• R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl
• R 17 is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl
• R 18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, terf-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tert
• X 5 is selected from the group consisting of oxygen and sulfur
• R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl
• R 17 is selected from the group consisting trifluoromethyl and pentafluoroethyl
• R 18 is one or more radicals selected from the grou consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, fe/if-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N- dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2- dimethylethyl)aminosulfonyl
• Cox-2 selective inhibitor of the present invention can also be a compound having the structure of Formula VI:
• X 6 is selected from the group consisting of O and S;
• R 19 is lower haloalkyl;
• R 20 is selected from the group consisting of hydrido, and halo;
• R 21 is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, and 6- membered nitrogen-containing heterocyclosulfonyl;
• R 22 is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy, and aryl;
• R 23 is selected from the group consisting of the group consisting of hydrido, halo, lower al
• the Cox-2 selective inhibitor can also be a compound of having the structure of Formula VI, wherein: X 6 is selected from the group consisting of O and S; R 19 is selected from the group consisting of trifluoromethyl and pentafluoroethyl; R 20 is selected from the group consisting of hydrido, chloro, and fluoro; R 21 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; R 22 is selected
• 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
• Z 1 is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings
• 24 R is selected from the group consisting of heterocyclyl, cycloalkyl, 24 cycloalkenyl and aryl, wherein R 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;
• 25 R is selected from the group consisting of methyl or amino
• 26 R is selected from the group consisting of a radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl,
• 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.
• 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.
• 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.
• the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.
• parecoxib See, U.S. Patent No.
• a preferred form of parecoxib is sodium parecoxib.
• 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.
• 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:
• R 27 is methyl, ethyl, or propyl
• R 28 is chloro or fluoro
• R 29 is hydrogen, fluoro, or methyl
• R 30 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxyl;
• R 31 is hydrogen, fluoro, or methyl
• R 32 is chloro, fluoro, trifluoromethyl, methyl, or ethyl, provided that R 28 , R 29 , R 30 and R 31 are not all fluoro when R 27 is ethyl and
• R 30 is H.
• 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:
• R 27 is ethyl
• R 28 and R 30 are chloro
• R 29 and R 31 are hydrogen
• R 32 is methyl
• Another phenylacetic acid derivative Cox-2 selective inhibitor is a compound that has the structure shown in formula VIII, wherein:
• R 27 is propyl
• R 28 and R 30 are chloro; R 29 and R 31 are methyl; and
• R 32 is ethyl
• 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:
• R 27 is methyl
• R 28 is fluoro
• R 32 is chloro
• R 29 , R 30 , and R 31 are hydrogen.
• 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:
• X 7 is O; J is 1 -phenyl; R 33 is 2-NHS0 2 CH 3 ; R 34 is 4-N0 2 ; and there is no
• R 35 group (nimesulide), or
• X 7 is O; J is 1-oxo-inden-5-yl; R 33 is 2-F; R 34 is 4-F; and R 35 is 6- NHS0 2 CH 3 , (flosulide); or
• X 7 is O; J is cyclohexyl; R 33 is 2-NHS0 2 CH 3 ; R 34 is 5-N0 2 ; and there is no R 35 group, (NS-398); or X 7 is S; J is 1-oxo-inden-5-yl; R 33 is 2-F; R 34 is 4-F; and R 35 is 6-N " S0 2 CH 3
• X 7 is S; J is thiophen-2-yl; R 33 is 4-F; there is no R 34 group; and R 35 is 5-
• R 34 is 4-F; and R 35 is 4-(p-S0 2 CH 3 )C 6 H 4 , (L-784512).
• 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 -
• 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:
• 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 Q 1 , Q 2 , L 1 or L 2 is an — S(0) n — R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having
• R >36 , R )37 , R )38 and R j39 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, R 36 , R 37 or R 38 , R
• Particular diarylmethylidenefuran derivatives that can serve as the Cox-2 selective inhibitor of the present invention include, for example, N-(2-cyclohexyloxynitrophenyI)methane sulfonamide, and (E)-4- [(4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene) methyfjbenzenesulfonamide.
• 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.
• 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.
• 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:
• Z is an oxygen atom; one of R 40 and R 41 is a group of the formula
• R 43 is lower alkyl, amino or lower alkylamino
• R 44 , R 45 , R 46 and R 47 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 R 44 , R 45 , R 46 and R 47 is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and R 30 is a lower alkyl or a halogenated lower alkyl, and a pharmaceutically acceptable salt thereof.
• 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:
• Z 3 is selected from the group consisting of linear or branched Ci - C ⁇ alkyl, linear or branched Ci -C ⁇ alkoxy, unsubstituted, mono-, di- or tri- substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, Ci -C 3 alkoxy, CN, Ci -C 3 fluoroalkyl Ci -C 3 alkyl, and -C0 2 H; R 48 is selected from the group consisting of NH 2 and CH 3 , R 49 is selected from the group consisting of Ci -C ⁇ alkyl unsubstituted or substituted with C 3 -C 6 cycloalkyl, and C 3 -C 6 cycloalkyl; R 50 is selected from the group consisting of Ci -C 6 alkyl unsubstituted or substituted with one, two or three fluoro atoms, and C 3 - C cycloalkyl; with
• R 51 is selected from the group consisting of CH 3 , NH 2 , NHC(0)CF 3 , and NHCH 3 ;
• Z 4 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, Ci -C 6 alkoxy, Ci -C 6 alkylthio, CN, Ci -C 6 alkyl, d -C 6 fluoroalkyl, N 3) -C0 2 R 53 , hydroxyl, -C(R 54 )(R 55 )— OH, - C-, - C 6 alkyl-C0 2 — R 56 , Ci -C 6 fluoroalkoxy;
• R 52 is selected from the group consisting of halo, Ci -C ⁇ alkoxy, Ci -C 6 alkylthio, CN, Ci -C 6 alkyl, Ci
• X 8 is an oxygen atom or a sulfur atom
• R 64 and R 65 are independently a hydrogen atom, a halogen atom, a Ci -C ⁇ lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a nitro group, a nitrile group, or a carboxyl group;
• R 66 is a group of a formula: S(0) n R 68 wherein n is an integer of 0-2, R 68 is a hydrogen atom, a Ci -C 6 lower alkyl group, or a group of a formula: NR 69 R 70 wherein R 69 and R 70 , identical to or different from each other, are independently a hydrogen atom, or a Ci -C ⁇ lower alkyl group; and
• R 67 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofur
• R 71 through R 75 are independently a hydrogen atom, a halogen atom, a Ci -C 6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a group of a formula: S(0) n R 68 , a group of a formula: NR 69 R 70 , a trifluoromethoxy group, a nitrile group a carboxyl group, an acetyl group, or a formyl group, wherein n, R 68 , R 69 and R 70 have the same meaning as defined by R 66 above; and R 76 is a hydrogen atom, a halogen atom, a Ci -C ⁇ lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a trifluoromethoxy group, a carboxyl
• 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- sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines have the formula shown below in formula XV:
• X 9 is selected from the group consisting of Ci -C 6 trihalomethyl, preferably trifluoromethyl; Ci -C ⁇ alkyl; and an optionally substituted or di-substituted phenyl group of formula XVI:
• R 77 and R 78 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; C -C ⁇ alkyl, preferably Ci -C 3 alkyl; Ci -C ⁇ alkoxy, preferably Ci - C 3 alkoxy; carboxy; Ci -C ⁇ trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano; Z 5 is selected from the group consisting of substituted and unsubstituted aryl.
• 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:
• X 10 is fluoro or chloro.
• 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:
• X 11 is selected from the group consisting of O, S, and a bond; n is 0 or 1 ; R 83 is selected from the group consisting of CH 3 , NH 2 , and NHC(0)CF 3 ; R 84 is selected from the group consisting of halo, Ci -CQ alkoxy, Ci -C 6 alkylthio, CN, Ci -C 6 alkyl, Ci -C 6 fluoroalkyl, N 3) — C0 2 R 92 , hydroxyl, — d -C 6 alkyl-C0 2 — R 9b , Ci -C 6 fluoroalkoxy, N0 2 , NR 9 a 6 D D R9 a 7', and NHCOR J9 a 8 o .; R 85 to R 89 are independently selected from the group consisting of hydrogen and Ci -C 6 alkyl; or R 85 and R 89 , or R 89 and R 90
• 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:
• R 99 is selected from the group consisting of S(0) 2 CH 3 , S(0) 2 NH 2 ,
• R 100 is selected from the group consisting of
• Q 3 is Q 4 , C0 2 H, C(R 103 )(R 104 )OH
• Q 4 is C0 2 — Ci -C 4 alkyl, tetrazolyl-5-yl, or C(R 1 03 )(R 104 )O— Ci -C 4 alkyl;
• R 103 , R 104 and R 105 are each independently selected from the group consisting of hydrogen and Ci -C ⁇ alkyl; or
• R 103 and R 104 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 R 105 groups on the same carbon form a saturated monocyclic carbon ring of 3,
• R 106 is hydrogen or d -C 6 alkyl
• R 107 is hydrogen, Ci — C 6 alkyl or aryl
• 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:
• R 108 is:
• R 113 is hydrogen, loweral yl, hydroxyl, loweralkoxy, amino, loweralkylamino, diloweralkylamino or cyano
• R 111 and R 1 2 are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy, trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl; R 109 is amino, mono or diloweralkyl amino, acet
• R >114 is hydrogen or halogen
• R 115 and R 16 are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or lower alkanoyloxy
• R 117 is lower haloalkyl or lower alkyl
• X 14 is sulfur, oxygen or NH
• Z 6 is lower alkylthio, lower alkylsulfonyl or sulfamoyl; or a pharmaceutically acceptable salt thereof.
• 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:
• X 15 denotes oxygen, sulphur or NH
• R 118 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 heteroaryl group optionally mono- or polysubstituted or mixed substituted by halogen, alkyl, CF 3 , cyano or alkoxy;
• R 119 and R 120 independently from one another, denote hydrogen, an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH 2 ) n -X 16 ; or R 119 and R 120 , 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 (CH 2 ) n — X 16 ;
• X 16 denotes halogen, NO 2 , —OR 121 , —COR 121 , — C0 2 R 121 , — OC0 2 R 121 , — CN, — CONR 121 OR 122 , —CONR 121 R 122 , — SR 121 , — S(0)R 121 , — S(0) 2
• n denotes a whole number from 0 to 6;
• R 123 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;
• R 124 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, N0 2 , — OR 121 , — COR 121
• R 121 and R 122 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.
• Compounds that are useful as Cox-2 selective inhibitors of the present invention include phenyl heterocycles that are described in
• X 17 — Y 1 — Z 7 - is selected from the group consisting of (a) — CH 2 CH 2 CH 2 — , (b) — C(0)CH 2 CH 2 — , (c) — CH 2 CH 2 C(O)— , (d) — CR 129 (R 129' )— O— C(O)— ,
• X 17 — Y 1 — Z 7 - is selected from the group consisting of
• R 125 is selected from the group consisting of (a) S(0) 2 CH 3 , (b) S(0) 2 NH 2 ,
• R 126 is selected from the group consisting of
• 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 additionally 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 ad itional N atoms; said substituents are selected from the group consisting of (1 ) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) Ci -C 6 alkyl, (4) Ci -C 6 alkoxy, (5) Ci -C 6 alkylthio, (6) CN, (7) CF 3 , (8) N 3 , (9) — C(R 129 )(R 130 )— OH, and (10) — C(R 129 )(R 130 )— O—
• R 128 and R 128' are each independently selected from the group consisting of
• R 129 , R 129' , R 130 , R 131 and R 132 are each independently selected from the group consisting of
• Ci -C 6 alkyl or R 129 and R 130 or R 131 and R 132 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3 , 4, 5, 6 or 7 atoms;
• Q 5 is C0 2 H, C0 2 — Ci -C 4 alkyl, tetrazolyl-5-yl, C(R 131 )(R 132 )(OH), or
• Patent No. 6,239,173 is 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(2H)- furanone.
• 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: or the pharmaceutically acceptable salts thereof wherein:
• a 9 is Ci -C 6 alkylene or — NR 133 — ;
• Z 9 is CH or N;
• Z 10 and Y 2 are independently selected from — CH 2 — , O, S and — N— R 133 ; m is 1 , 2 or 3; q and r are independently 0, 1 or 2;
• X 18 is independently selected from halogen, Ci -C 4 alkyl, halo-substituted Ci -C 4 alkyl, hydroxyl, Ci -C 4 alkoxy, halo-substituted Ci -C 4 alkoxy, Ci -
• n O, 1 , 2, 3 or 4;
• L 3 is oxygen or sulfur
• R 133 is hydrogen or Ci -C 4 alkyl
• R 134 is hydroxyl, Ci -C 6 alkyl, halo-substituted Ci -C 6 alkyl, Ci -C 6 alkoxy, halo-substituted Ci -C 6 alkoxy, C 3 -C cycloalkoxy, Ci -C 4 alkyl(C 3 -C 7 cycloalkoxy), — NR 136 R 137 , Ci -C 4 alkylphenyl-O— or phenyl-O— , said phenyl being optionally substituted with one to five substituents independently selected from halogen, Ci -C alkyl, hydroxyl, Ci -C 4 alkoxy and nitro;
• R 135 is Ci -C 6 alkyl or halo-substituted Ci -C 6 alkyl; and
• R 136 and R 137 are independently selected from hydrogen, C 1 - 6 alkyl and halo-substituted Ci -C ⁇ alkyl.
• 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:
• a 10 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 atom(s) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
• X 20 is independently selected from halo, Ci -C 4 alkyl, hydroxyl, Ci -
• Ci -C 4 alkyl hydroxyl-substituted Ci -C 4 alkyl, (Ci -C 4 alkoxy)C ⁇ -C 4 alkyl, halo-substituted Ci -C 4 alkoxy, amino, N-(C ⁇ -C 4 alkyl)amino, N, N-di(C ⁇ -C 4 alkyl)amino, [N-(C ⁇ -C 4 alkyl)amino]C ⁇ - C 4 alkyl, [N, N-di(C ⁇ -C 4 alkyl)amino]C ⁇ -C 4 alkyl, N-(C ⁇ -C 4 alkanoyl)amonio, N-(C ⁇ -C 4 alkyl)(C ⁇ -C 4 alkanoyl)amino, N-[(C ⁇ — C 4 alkyl)sulfonyl]amino,
• R 138 is selected from hydrogen; straight or branched Ci -C 4 alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from
• 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:
• XXVII and the pharmaceutically acceptable salts thereof, wherein: L 4 is oxygen or sulfur; Y 3 is a direct bond or Ci -C 4 alkylidene; Q 6 is: (a) Ci -C 6 alkyl or halosubstituted Ci -C 6 alkyl, said alkyl being optionally substituted with up to three substituents independently selected from hydroxyl, C-i -C 4 alkoxy, amino and mono- or di-( Ci -C 4 alkyl)amino,
• R 141 is hydrogen or Ci -C ⁇ alkyl optionally substituted with a substituent selected independently from hydroxyl, OR 143 , nitro, amino, mono- or di-( Ci
• R 142 is: (a) hydrogen, (b) Ci -C 4 alkyl,
• R 145 is selected from: (c-1) Ci -C 22 alkyl or C 2 -C 22 alkenyl, said alkyl or alkenyl being optionally substituted with up to four substituents independently selected from: (c-1-1 ) halo, hydroxyl, OR 143 , S(0) m R 143 , nitro, amino, mono- or di-( Ci ⁇ C 4 alkyl)amino, NHS0 2 R 143 , C0 2 H, C0 2 Ci -C 4 alkyl), CONH 2 , CONH(d -C 4 alkyl), CON(d -C 4 alkyl) 2 , OC(0)R 143 , thienyl, naphthyl and groups of the following formulas:
• (c-2) Ci -C 22 alkyl or C 2 -C 22 alkenyl, said alkyl or alkenyl being optionally substituted with five to forty-five halogen atoms, (c-3) -Y 5 — C 3 -C- 7 cycloalkyl or -Y 5 — C 3 -C 7 cycloalkenyl, said cycloalkyl or cycloalkenyl being optionally substituted with up to three substituent independently selected from: (c-3-1 ) d -C 4 alkyl, hydroxyl, OR 143 , S(0) m R 143 , amino, mono- or di- ( Ci -C 4 alkyl)amino, CONH 2 , CONH(C -C 4 alkyl) and CON(d -C 4 alkyl) 2l (c-4) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven (preferably up to seven) substituent
• X 22 is halo, Ci -C 4 alkyl, hydroxyl, Ci -C 4 alkoxy, halosubstitutued Ci -C4 alkoxy, S(0) m R 143 , amino, mono- or di-(d -C 4 alkyl)amino, NHS0 2 R 143 , nitro, halosubstitutued Ci -C 4 alkyl, CN, C0 2 H, C0 2 (Ci -C ⁇ alkyl), Ci -C 4 alkyl-OH, Ci -C 4 alkylOR 143 , CONH 2 , CONH(C ⁇ -C 4 alkyl) or CON(C ⁇ -C 4 alkyl) 2 ;
• R 143 is Ci -C 4 alkyl or halosubstituted Ci -C 4 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; Z 11 is oxygen, sulfur or NR 144 ; and
• R 144 is hydrogen, Ci -C 6 alkyl, halosubstitutued Ci -C 4 alkyl or -Y 5 - phenyl, said phenyl being optionally substituted with up to two substituents independently selected from halo, C -C alkyl, hydroxyl, Ci -C alkoxy,
• X 22 is hydrogen
• L 4 is oxygen
• R 141 is hydrogen
• R 142 is acetyl
• 6,077,869 can serve as Cox-2 selective inhibitors of the present invention.
• X 23 and Y 6 are selected from hydrogen, halogen, alkyl, nitro, amino, hydroxy, methoxy and methylsulfonyl; or a pharmaceutically acceptable salt thereof,.
• 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: or a pharmaceutical salt thereof, wherein:
• R 46 is selected from the group consisting of SCH 3 , — S(0) 2 CH 3 and —
• R 147 is selected from the group consisting of OR 150 , mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
• R 150 is unsubstituted or mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
• R 148 is H, Ci -C 4 alkyl optionally substituted with 1 to 3 groups of F, Cl or
• R 149 is H, Ci -C 4 alkyl optionally substituted with 1 to 3 groups of F, Cl or
• Z 13 is C or N; when Z 13 is N, R 151 represents H or is absent, or is taken in conjunction with R 152 as described below: when Z 13 is C, R 151 represents H and R 152 is a moiety which has the ; following characteristics:
• R 151 and R 152 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 energetically stable configuration planar with ring A to within about 15 degrees; said ring D further being substituted with 1 R a group selected from the group consisting of Ci -C 2 alkyl, — OC ⁇ -C 2 alkyl, — NHCi -C 2 alkyl, —
• Y 7 represents N, CH or C— OC ⁇ -C 3 alkyl, and when Z 13 is N, Y 7 can also represent a carbonyl group;
• R 153 represents H, Br, Cl or F
• R 154 represents H or CH 3 .
• Compounds useful as Cox-2 selective inhibitors of the present invention include 1 ,5-diarylpyrazoles that are described in U.S.
• R 155 , R 156 , R 157 , and R 158 are independently selected from the groups consisting of hydrogen, Ci -C 5 alkyl, Ci -C 5 alkoxy, phenyl, halo, hydroxyl,
• Ci -C 5 alkylsulfonyl Ci -C 5 alkylthio, trihaloCi -C 5 alkyl, amino, nitro and
• R 159 is hydrogen, Ci -C 5 alkyl, trihaloCi -C 5 alkyl, phenyl, substituted phenyl where the phenyl substitutents are halogen, Ci -C 5 alkoxy, trihaloCi -C5 alkyl or nitro or R 159 is heteroaryl of 5-7 ring members where at least one of the ring members is nitrogen, sulfur or oxygen;
• R 160 is hydrogen, Ci -C 5 alkyl, phenyl Ci -C 5 alkyl, substituted phenyl Ci - C 5 alkyl where the phenyl substitutents are halogen, Ci -C 5 alkoxy, trihaloCi -C 5 alkyl or nitro, or R 160 is Ci -C 5 alkoxycarbonyl, phenoxycarbonyl, substituted phenoxycarbonyl where the phenyl substitutents are halogen, Ci -C 5 alkoxy, trihaloCi -C
• 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: wherein:
• R 164 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 C ⁇ _ 5 alkyl, halogen, nitro, trifluoromethyl and nitrile;
• R 165 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 Ci -C 5 alkyl and halogen, or substituted phenyl, ' l wherein the substituents are independently selected from one or members of the group consisting of Ci -C 5 alkyl, halogen, nitro, trifluoromethyl and nitrile;
• R 166 is hydrogen, 2-(trimethylsilyl)ethoxymethyl), Ci -C 5 alkoxycarbonyl, aryloxycarbonyl, arylCi -C 5 alkyloxycarbonyl, arylCi -C 5 alkyl, phthalimidoCi -C 5 alkyl, aminoCi -C 5 alkyl, diaminoCi -C5 alkyl, succinimidoCi -C5 alkyl, Ci -C 5 alkylcarbonyl, arylcarbonyl, Ci -C5 alkylcarbonylCi -C 5 alkyl, aryloxycarbonylCi -C 5 alkyl, heteroarylCi -C 5 alkyl where the heteroaryl contains 5 to 6 ring atoms, or substituted arylCi -C 5 alkyl, wherein the aryl substituents are independently selected from one or more members of the group consisting of Ci -C 5 alkyl
• X 24 is selected from the group consisting of hydrogen, hydroxyl, halogen, vinyl, ethynyl, Ci -C 5 alkyl, C 3 -C 7 cycloalkyl, Ci -C 5 alkoxy, phenoxy, phenyl, arylCi -C 5 alkyl, amino, Ci -C 5 alkylamino, nitrile, phthalimido, amido, phenylcarbonyl, Ci -C 5 alkylaminocarbonyl, phenylaminocarbonyl, arylCi -C 5 alkylaminocarbonyl, Ci -C 5 alkylthio, Ci -C 5 alkylsulfonyl, phenylsulfonyl, substituted sulfonamido, wherein the sulfonyl substituent is selected from the group consisting of Ci
• 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:
• R 168 and R 169 are independently selected from the group consisting of hydrogen, halogen, (Ci -C 6 )alkyl, (Ci -C 6 )alkoxy, nitro, amino, Dydroxyl, trifluoro, — S(C ⁇ -C 6 )alkyl, — SO(C ⁇ -C 6 )alkyl and — S0 2 (Ci -C 6 )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:
• R 171 and R 172 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C ⁇ jalkyl, (Ci -
• C 6 )alkoxy NOH, — NR 174 R 175 , — OCH 3 , — OCH 2 CH 3 , — OS0 2 NHC0 2
• CH 3 CHC0 2 CH 2 CH 3 , — CH C0 2 H, — CH 2 C0 2 CH3, — CH2 CO2 CH2
• R 173 is selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C 6 )alkyl, (Ci -Ce)alkoxy and optionally substituted carboxyphenyl, wherein substituents on the carboxyphenyl group are selected from the group consisting of halogen, hydroxyl, amino, (Ci -
• R 174 is selected from the group consisting of hydrogen, OH, — OCOCH 3 ,
• R 175 is selected from the group consisting of hydrogen, OH, — OCOCH 3 ,
• R 170 through R 173 may not all be hydrogen; and pharmaceutically acceptable salts, esters and pro-drug forms thereof.
• 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:
• R >1 1 7'6 0 is Ci -C 6 alkyl, Ci -C 6 branched alkyl, C 4 -C 8 cycloalkyl, Ci -C 6 hydroxyalkyl, branched Ci -C ⁇ hydroxyalkyl, hydroxyl substituted C 4 -C 8 aryl, primary, secondary or tertiary Ci -C 6 alkylamino, primary, secondary or tertiary branched Ci -C 6 alkylamino, primary, secondary or tertiary C 4 - C 8 arylamino, Ci -C 6 alkylcarboxylic acid, branched Ci -C 6 alkylcarboxylic acid, Ci -C 6 alkylester, branched Ci -C 6 alkylester, C 4 -C 8 aryl, C 4 -C 8 arylcarboxylic acid, C 4 -C 8 arylester, C 4 -C 8 aryl substituted Ci -
• R 177 is Ci -C 6 alkyl, Ci -C 6 branched alkyl, C -C 8 cycloalkyl, C 4 -C 8 aryl, C 4 -C 8 aryl-substituted Ci -C ⁇ alkyl, Ci -C ⁇ alkoxy, Ci -C ⁇ branched alkoxy, C 4 -C 8 aryloxy, or halo-substituted versions thereof or R 177 is halo where halo is chloro, fluoro, bromo, or iodo; R 178 is hydrogen, Ci -C ⁇ alkyl or Ci -C 6 branched alkyl; R 179 is Ci -C 6 alkyl, C 4 -C 8 aroyl, C 4 -C 8 aryl, C 4 -C 8 heterocyclic alkyl or aryl with O, N or S in the ring, C 4 -C 8 aryl-substituted Ci -C 6
• X 25 is O, NH, or N— R 180 , where R 180 is Ci -C 6 or d -C 6 branched alkyl.
• 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:
• X 26 is selected from the group consisting of O, S, — NR 185 , — NOR a , and - NNR b R c ;
• R 185 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;
• R a , R b , and R c are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;
• R 181 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,
• X 26' is halogen; m is an integer from 0-5; n is an integer from 0-10; p is an integer from 0-10;
• R 182 , R 183 , and R 184 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, mercaptoal
• X 27 is selected from the group consisting of S(0) 2 , S(0)(NR 191 ), S(O),
• X 28 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;
• R 190 is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, — NHNH 2 , and — NCHN(R 91 )R 192 ;
• R 191 , R 192 , R 93 , and R 94 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 193 and R 194 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 NR 188 ;
• Y 8 is selected from the group consisting of -OR 195 , — SR 195 , — C(R 197 )(R 198 )R 195 , — C(0)R 195 , — C(0)OR 195 , — N(R 197 )C(0)R 195 , - NC(R 197 )R 195 , and — N(R 197 )R 195 ;
• R 195 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 199 R 200 ; and
• R 197 , R 198 , R 199 , and R 200 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl.
• 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: R 201 A 12 °w Xff /? ⁇ R xxxvu R 206 / ⁇ ⁇
• a 12 denotes oxygen, sulphur or NH
• R 201 denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted by halogen, alkyl, CF 3 or alkoxy;
• D 5 denotes a group of formula XXXVIII or XXXIX:
• XXXIX R 202 and R 203 independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH 2 ) n -X 29.
• R 5 202 and R203 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) n -X 29
• R 202 ' denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or , heteroaryl group or a group (CH 2 ) n -X 29 , wherein: X 29 denotes halogen, N0 2) —OR 204 , —COR 204 , — C0 2 R 204 , — OC0 2 R 204 , -CN, -CONR 204 OR 205 , -CONR 204 R 205 , -SR 204 , - S(0)R 204 , — S(0) 2 R 204 ,
• 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:
• R 207 and R 208 are respectively a hydrogen; Ci -C 4 -alkyl substituted or not substituted by halogens; C 3 -C 7 -cycloalkyl; Ci -C ⁇ -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).
• 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.
• 1 H-indole derivatives have the formula shown below in formula XXXXI:
• 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 inhibitors have the formula shown below in formula XXXXII:
• a 13 is a ring substituent selected from partially unsaturated heterocyclic, heteroaryl, cycloalkenyl and aryl, wherein A 13 is unsubstituted or substituted with one or more radicals selected from alkylcarbonyl, 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, alkylthioalky
• substituted sulfonamide prodrugs of Cox-2 inhibitors disclosed in U.S. Patent No. 6,436,967 that are useful in the present invention include: N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1- yl]phen yl]sulfonyl]propanamide;
• a 13 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, alkylaminocarbony
• 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)-l 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.
• 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:
• R 214 is furyl, thiazolyl or oxazolyl
• R 215 is hydrogen, fluoro or ethyl
• X 31 and X 32 are independently hydrogen or chloro.
• 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:
• XXXXIV wherein: Z 16 is O or S, R 216 is optionally substituted aryl, R 217 is aryl optionally substituted with aminosulfonyl, and R 218 and R 219 cooperate to form an optionally substituted 5- membered ring.
• 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.
• substituted hydroxamic acid derivatives have the general formulas shown below in formulas XXXXV and XXXXVI:
• a 14 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;
• Y 10 is selected from lower alkenylene and lower alkynylene;
• R 220 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 220 is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl,
• 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 15 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; Y 11 is selected from lower alkylene, lower alkenylene and lower alkynylene; R 223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 223 is optionally substituted at a substitutable position with one or more substituents
• Heterocyclo substituted hydroxamic acid derivatives described in U.S. Patent No. 6,512,121 have the formula shown above in formula XXXXV, wherein: A 14 is a ring substiuent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isochiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A 14 is optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y 10 is lower alkylene, lower alkenylene, and lower alkynylene; R 220 is a substituent selected from 5- and
• 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 15 is a ring substituent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, 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, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarboryl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y 11 is selected from lower alkyl, lower alkenyl and lower alkynyl; R 223 is a substituent selected from 5-
• a 14 is thienyl optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
• Y 10 is ethylene, isopropylene, propylene, butylene, lower alkenylene, and lower alkynylene;
• R 220 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 220 is optionally substituted at a substituent
• 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 15 is thienyl optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y 11 is selected from lower alkyl, lower alkenyl and lower alkynyl; R 223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 223 is optionally substituted at a substitutable position with one or more substituents
• 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:
• R 226 and R 227 are independently selected from the group consisting of H, halogen, Ci -C 6 alkyl, Ci -C 6 alkoxy, and Ci — C 6 alkoxy substituted by one or more fluorine atoms;
• R 228 is halogen, CN, CON R 230 R 231 , C0 2 H, C0 2 Ci -C 6 alkyl, or NHS0 2 R 230 ;
• R 229 is Ci -C 6 alkyl or NH 2 ;
• R 225 and R 225 are independently selected from the group consisting of H, Ci -C 6 alkyl, phenyl, phenyl substituted by one or more atoms or groups selected from the group consisting of halogen, Ci — C 6 alkyl, Ci -C 6 alkoxy, and Ci -C 6 alkoxy substituted by one or more fluorine atoms, or a pharmaceutically acceptable salt, solvate, ester, or salt or solvate of such este
• 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:
• X 33 represents halo, hydrido, or alkyl
• Y 12 represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N- acylamino)-sulfonyl, (N-alkylamino)sulfonyl, or alkylthio
• Z 17 represents oxygen or sulfur atom
• R 233 and R 234 are selected independently from lower alkyl radicals
• R 232 represents a substituted or non-substituted aromatic group of 5 to 10 atoms; or a pharmaceutically-acceptable salt thereof.
• 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 XXXIX':
• R is a hydrogen atom or an alkyl group having 1-3 carbon atoms
• R >2 ⁇ 36 is a hydrogen atom, a hydroxyl group, an organothiol group that is bound to the selenium atom by its sulfur atom, or R 235 and R >23 ⁇ 6 are joined to each other by a single bond
• R 237 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
• R 238 and R 239 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 R ⁇ ,238 and R 239 are joined to each other to form a methylenedioxy group, a salt thereof, or a hydrate thereof.
• Pyrones such as
• 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:
• X 34 is selected from the group consisting of (a) ; a bond, (b) - TM(CH 2 ) m — , wherein m 1 or 2, (c) - -C(O)-, (d) -0-, (e) -S-, and ( ) - -N(R 244 ) ⁇ ;
• R 240 is selected from the group consisting of (a) Ci -Cio alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, Ci -Cio alkoxy, Ci -Cio 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
• 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-methyls lfonyl)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,
• 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:
• R 246 , R 247 , R 248 , R 249 , and R 250 are independently selected from the group consisting of -H, -OH, -SH, -OR, -SR, -NH 2 , -NHR 245 , - N(R 245 ) 2 , -N(R 245 ) 3 + X 35- , 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 R 245 is an alkyl group having between 1-10 carbon atoms; and X 35 is selected from the group of pharmaceutically acceptable counter anions including, hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride and carbonate.
• 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 XXXXII: XXXXII
• m 0, 1 or 2;
• X 35 is >CR 255 or >N;
• R 253 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
• R 254 is an (C ⁇ -C 6 )alkyl radical optionally substituted by one to fourfluoro substituent
• R 256 represents an alkyl or -NR 259 R 260 group, wherein R 259 and R 260 each independently represents a hydrogen atom or an alkyl group;
• R 257 represents an alkyl, C 3 -C 7 cycloalkyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups;
• R 258 represents a methyl, hydroxymethyl, alkoxymethyl, C 3 -C 7 cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile ⁇ , trifluoromethyl or difluoromethyl group or a CH 2 - R 261 group* wherein R 261 represents an alkyl group;
• X 36 represents a single bond, an oxygen atom, a sulfur atom or a methylene group; or a pharmaceutically acceptable salt thereof.
• 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,
• 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);
• 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-
• 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.
• 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.
• Preferred Cox-2 selective inhibitor compounds are those compounds selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS
• 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.
• 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.
• 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. 5,466,323 to Talley, et. al.
• 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 96/03335.
• 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 94/27930.
• Isoxazoles useful in the present invention can be prepared by the methods described in WO 96/25405.
• Imidazoles useful in the present invention can be prepared by the methods described in WO 96/03338. Preparation of imidazoles is also described in WO 96/03387.
• Cyclopentene Cox-2 inhibitors useful in the present invention can be prepared by the methods described in U.S. Patent No. 5,344,991.
• Terphenyl compounds useful in the present invention can be prepared by the methods described in WO 96/16934.
• Thiazole compounds useful in the present invention can be prepared by the methods described in WO 96/03392.
• 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.
• Benzopyranopyrazolyl compounds useful in the present invention can be prepared by the methods described in WO 96/09304.
• Chromene compounds useful in the present invention can be prepared by the methods described in WO 93/47690. 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. 6,077,350. 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.
• 5-Alkyl-2-arylaminophenylacetic acids and derivatives useful in the present invention can be prepared by the methods described in WO 99/11605.
• 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.
• 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.
• the valdecoxib used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent
• etoricoxib used in the compositions and methods of the present invention can be prepared in the manner set forth in WO 98/03434.
• meloxicam used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent
• 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 WO 00/24719.
• (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 363134.
• the compound 2-[(2-chloro-6-fluorophenyl)aminoj-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.
• the compound N-[2-(cyclohexyloxy)-4- nitrophenyljmethanesulfonamide used in the compositions and methods of the present invention can be prepared in the manner set forth in U.S. Patent No. 4, ⁇ 5,367.
• 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.
• An optional component of the combination therapy embodiments of the present invention is an antidepressant agent.
• anti-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.
• 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 antagonist and reuptake inhibitors, norepinephrine dopamine reuptake inhibitor, and serotonin reuptake accelerators.
• 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.
• SSRI serotonin reuptake inhibitor
• the present invention encompasses one or more of the antidepressant agents described in Table 3 below.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 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.
• 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.
• 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.
• 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.
• 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.
• 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, amoxapine, moclobemide, trimipramine, selegiline, protriptyline, viloxazine, alprazolam, pargyline, dextroamphet
• 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 present invention.
• 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.
• 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.
• 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.
• the present invention also encompasses a novel therapuetic composition comprising at least one Cox-2 inhibitor and one or more antidepressant agents.
• 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.
• 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 composition comprising at least one Cox-2 inhibitor, at least one antidepressant agent, and a pharmaceutically acceptable carrier.
• 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.
• 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.
• 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.
• pharmaceutically acceptable is used herein to mean that the modified noun is appropriate for use in a pharmaceutical product.
• 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.
• the Cox-2 inhibitor alone or in combination with the antidepressant agent are administered to a subject together in one pharmaceutical carrier.
• the Cox-2 inhibitor and the antidepressant agent are administered separately.
• the pharmaceutically acceptable carrier can also be selected on the basis of the desired route of administration of the compound.
• the carrier is suitable for oral administration.
• 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.
• 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, maleic, 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, ⁇ -hydroxybut
• 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, 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.
• basic ion exchange resins such as
• 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.
• 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-methylglucamine) and procaine.
• Exemplary pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic 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.
• 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 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.
• compositions may be administered enterally and parenterally.
• Oral intra-gastric
• 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.
• 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.
• 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.
• 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.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
• 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.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• an oil medium for example, peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions can be produced that contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions.
• 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 mono
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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, 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.
• 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.
• 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.
• 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.
• 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 inhalation or by means of a manually-operated pump.
• 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.
• 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.
• the electric force exerted on the surface of the droplet overcomes the surface tension of the liquid, thereby generating a stream 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.
• 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.
• 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.
• 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.
• buccal 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.
• the prevent invention further encompasses intranasal administration comprising the compounds set forth herein.
• Intranasal dosage forms include, but are not limited to, aerosols, drops, gels, powders, and mixtures thereof.
• Cox-2 inhibitor compound and/or the antidepressant agent include dermal patches that release the medicaments directly into a subject's skin.
• Topical delivery systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, collyriums, solutions or suspensions.
• compositions of the present invention can optionally be supplemented with additional agents such as, for example, viscosity enhancers, preservatives, surfactants and penetration enhancers.
• Viscosity is an important attribute of many medications.
• Such viscosity-building agents 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 polyquatemium-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.
• such preservatives are employed at a level of from 0.001% to 1 .0% by weight.
• the solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition.
• co-solvents include polysorbate 20, 60, and 60, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-6 ⁇ , F- ⁇ 4 and P-103), cyclodextrin, or other agents known to those skilled in the art.
• co-solvents are employed at a level of from 0.01 % to 2% by weight.
• 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.
• a penetration enhancer may be added to a Cox-2 inhibitor topical composition or a Cox-2 inhibitor and antidepressant agent or topical composition.
• 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 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
• 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.
• the amount of the combination therapy with the Cox-2 inhibitor and antidepressant agent together comprises a therapeutically effective amount of the combined therapy.
• 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, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances.
• 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.
• 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.
• prophylactic refers to the prevention of psychiatric disorders or a psychiatric disorder-related symptom
• therapeutic refers to the effective treatment of an existing disorder such as psychiatric disorders or a psychiatric disorder-related symptom.
• 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.
• the appropriate dosage level of a Cox-2 inhibitor 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 rng/kg to about 25 mg/kg per day; more preferably about 0.5 mg/kg to about 10 mg/kg per day. [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.
• 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.
• 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 rng.
• 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 indicated 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.
• 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 outpatient therapy or in a hospitalized setting.
• 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.
• 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.
• TRH thyrotropin- releasing hormone
• DST dexamethasone suppression test
• REM rapid eye movement
• 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.
• 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.
• the mammal is a human.
• an adult human weighs approximately seventy kilograms.
• 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 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.
• 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 any subject who requires improved tolerability to any conventional psychiatric disorder treatment agent for psychiatric disorders therapy.
• 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, 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 d ⁇ ysmorphic 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.
• the present invention encompasses the treatment or prevention of depression.
• 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 dosa ge form comprising a Cox-2 inhibitor and a second dosage form comprising at least one antidepressant agent.
• EXAMPLE 1 [0282] This example shows the preparation of the Cox-2 inhibitor, celecoxib.
• Step 1 Preparation of 1-(4- methylphenyl)-4,4,4- trifluorobutane-1 ,3-dione.
• 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 17 H 14 N 3 0 2 SF 3 ; 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 This example illustrates the production of a composition containing celecoxib and an antidepressant agent, and of a pharmaceutical composition containing the combination.
• 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) available from the Roerig Division of Pfizer Inc, NY, NY.
• Zoloft® contains 100mg of sertraline.
• a therapeutic composition of the present invention can be formed by intermixing sertraline, 100 g; and 4-[5-(4-methylphenyl)-3-
• each single dose unit contains about 100 mg of sertraline and about 200 mg of celecoxib.
• 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.
• 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.

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