Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to the treatment and/or prevention of respiratory inflammation and, more particularly, to the treatment and/or prevention of respiratory inflammation in a subject in need of such treatment or prevention, by administration of a combination of two different enzyme inhibitors.
• Asthma is a pulmonary disease that is characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness (manifested as bronchoconstriction), due to a variety of irritating stimuli.
• Airway obstruction in asthma can result from a combination of factors including spasm of airway smooth muscle, edema of airway mucosa, increased mucus secretion, and cellular infiltration of the airway walls. Symptoms of asthma usually begin quite suddenly with wheezing episodes, coughing, and shortness of breath.
• COPD chronic respiratory disorder characterized by airflow limitation, accompanied by shortness of breath, cough, wheezing, increased sputum production and occasionally fever. Id. Many factors contribute to the risk of developing COPD, including breathing heavy dust, air pollution, poor nutrition, childhood respiratory infections, chronic uncontrolled asthma, and even heredity. Nevertheless, almost 90% of COPD cases are caused by long-term cigarette smoking and/or passive exposure to cigarette smoke.
• Cigarette smoke contains an abundance of toxic and irritating substances. Over time, cigarette smoke produces inflammation in both the bronchial tubes of the lungs and the walls of the alveoli. In the alveoli, smoke-induced inflammatory cells destroy the capillaries and air sacs, giving rise to permanent lung damage or emphysema. In addition, cigarette smoke induces inflammation in the airways and causes swelling which reduces trie diameter of these passages. The inflammation in the bronchi also produces large amounts of mucus. The swelling of the bronchial tubes, the increased mucus production, and bronchial muscle spasm can obstruct airflow into and out of the lungs; all leading to COPD.
• the inflammatory responses characteristic of asthma and COPD result in infiltration of the respiratory tract with a variety of inflammatory cells, specifically eosinophils, mast cells, and CD4 + T-lymphocytes in asthma, and in COPD, primarily neutrophils, but also macrophages, and CD8+ T lymphocytes. See Bundschuh, D., etal., Pharm. Exper. Therap.,
• inflammatory cells release a variety of mediators, including histamine and the products of arachidonic acid metabolism, such as leukotrienes and prostaglandins, cytokines, interleukins IL-1 to IL-12, alpha-, beta- and gamma-interferon, tumor necrosis factor (TNF) and proteases, all ultimately leading to the harmful symptoms and the> histopathology of asthma and COPD.
• mediators including histamine and the products of arachidonic acid metabolism, such as leukotrienes and prostaglandins, cytokines, interleukins IL-1 to IL-12, alpha-, beta- and gamma-interferon, tumor necrosis factor (TNF) and proteases, all ultimately leading to the harmful symptoms and the> histopathology of asthma and COPD.
• TNF tumor necrosis factor
• proteases all ultimately leading to the harmful symptoms and the> histopathology of asthma and COPD.
• PDE 4 The enzyme phosphodieste
• Representative inflammatory cell-types include eosinophils, T lymphocytes, macrophages, neutrophils, dendritic cells, mast cells, and structural cells.
• PDE 4 One of the primary activities of PDE 4 is to metabolize excess intracellular levels of the signal transduction molecule adenosine cyclic 3',5'-monophosphate (cAMP).
• PDE 4 is responsible for the conversion of active intracellular cAMP to its inactive form.
• cAMP is a ubiquitous second messenger produced in cells in response to extracellular hormones and several neurotransmitters.
• cAMP is formed by the enzyme adenylyl cyclase.
• protein kinase A becomes activated and triggers the phosphorylation of a multitude of cellular constituents. Phosphorylation of several inflammatory cell constituents results in lower airway edema, reduced airway constriction, reduced cellular infiltration to the inflammatory site, reduced chemotaxis, cellular adhesion and proliferation, reduced superoxide generation, and prevention of inflammatory mediator release (e.g.
• Non-specific phosphodiesterase inhibitors are able to block the activity of more than one PDE isoform, often resulting in adverse side effects.
• Some of the adverse effects associated with, for example, the non-selective PDE inhibitor theophylline include hypotension, tachycardia, headache, and emesis.
• inhibitors with selectivity for specific PDE isoforms have been designed and synthesized.
• PDE 4 inhibitors such as cilomilast, lirimilast, and roflumilast, have been developed, and seem to maintain high anti-inflammatory activity while partially overcoming these side effects. See Bamette, M.S., et al., J. Pharmacol. Exp. Ther., 284:420-426 (1998); Giembycz, M.A., Expert Opin. Investig. Drugs, 70:1361 -1379 (2001); Sturton, G. and Fitzgerald, M., Chest, 121' ⁇ 92S-196S (2002); Bundschuh etal., supra.
• NSAIDs non-steroidal anti-inflammatory drugs
• Cox-1 cyclooxygenase-1
• Cox-2 cyclooxygenase-2
• Cox-1 is constituitively active and is responsible for the synthesis of housekeeping prostaglandins critical to maintaining normal renal function, gastric mucosal integrity, and vascular homeostasis.
• Cox-2 expression is induced by cytokines and growth factors in inflammatory cells, leading to the release of prostanoids, for example, prostaglandin E2, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity, inflammation, and edema. See e.g. Samad, T.A. etal., Nature 470:471 -5 (2001 ).
• 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.
• corticosteroids For inhaled corticosteroids, those side effects include fungal infections of the mouth and throat (thrush), hoarseness, cough, and, in some instances, delayed growth.
• thrush for more severe or chronic forms of asthma, orally ingested corticosteroids are prescribed either as short-term burst therapies to treat acute severe episodes or as routine maintenance therapies.
• Orally prescribed steroids are known to cause severe side effects, especially with higher doses and during the course of long-term therapies. Resistance to corticosteroids may develop over time to maintenance therapies, thus requiring increasingly higher dosing and a corresponding increase in side effects. It has also been noted that sudden cessation of corticosteroid therapy can give rise to an apparent worsening of the original inflammatory symptoms (steroid-rebound effect).
• the present invention is directed toward a novel method for the treatment or prevention of respiratory inflammation in a subject in need of such prevention or treatment, the method comprising administering to the subject a phosphodiesterase 4 inhibitor in combination with a Cox-2 inhibitor.
• the present invention is also directed to a novel therapeutic composition for the prevention or treatment of respiratory inflammation, the therapeutic composition comprising at least one Cox-2 inhibitor and at least one phosphodiesterase 4 inhibitor.
• the present invention is also directed to a novel pharmaceutical composition for the prevention or treatment of respiratory inflammation, the pharmaceutical composition comprising at least one Cox-2 inhibitor, at least one phosphodiesterase 4 inhibitor and a pharmaceutically- acceptable excipient.
• the present invention is also directed to a novel kit that is suitable for use in the prevention or treatment of respiratory inflammation, the kit comprising a first dosage form comprising a Cox-2 inhibitor and a second dosage comprising a phosphodiesterase 4 inhibitor, in amounts which comprise a therapeutically effective combination of the compounds for the prevention or treatment of the respiratory inflammation.
• a novel kit that is suitable for use in the prevention or treatment of respiratory inflammation, the kit comprising a first dosage form comprising a Cox-2 inhibitor and a second dosage comprising a phosphodiesterase 4 inhibitor, in amounts which comprise a therapeutically effective combination of the compounds for the prevention or treatment of the respiratory inflammation.
• the present invention provides methods and compositions that reduce dosages or reduce unwanted side effects in conventional treatments for respiratory inflammation.
• the present invention provides methods and compositions that improve the efficacy of treating a respiratory disorder that is considered resistant or intractable to known methods of therapy alone.
• DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [00023]
• respiratory inflammation may be treated and/or prevented in a subject that is in need of such treatment or prevention by administering to the subject a Cox-2 inhibitor in combination with one or more phosphodiesterase 4 inhibitors.
• an amount of a Cox-2 inhibitor and an amount of a phosphodiesterase 4 inhibitor are administered to the subject wherein the amount of the Cox-2 inhibitor and the amount of the phosphodiesterase 4 inhibitor together comprise a therapeutic amount.
• the administration of a Cox-2 inhibitor in combination with a phosphodiesterase 4 inhibitor for the prevention or treatment of respiratory inflammation provides an effect that is unexpectedly superior to the effect that would be expected based on the use of either agent alone.
• the administration of a Cox-2 inhibitor in combination with a phosphodiesterase 4 inhibitor is effective for improving respiratory inflammation, and in preferred embodiments can avoid or reduce certain disadvantages of current treatments.
• the combination therapy of the present invention would also be useful to prevent the occurrence of other symptoms associated with respiratory disorders such as, for example, coughing, congestion, dyspnea, wheezing, hyperventilation, difficulty breathing, bronchospasm, and bronchoconstriction in a subject suffering from such symptoms.
• the combination therapy of the invention would be useful, for example, to reduce the death rate or the number of non-fatal hospitalizations, or to prevent or retard the development of COPD, which can arise from chronic cigarette smoking.
• the combination therapy of a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor is also useful for decreasing the required number of separate dosages, thus, potentially improving patient compliance.
• the phrases "combination therapy”, “co- administration”, “co-administering”, “administration with”, “administering”, “combination”, or “co-therapy”, when referring to use of a Cox-2 inhibitor in combination with a phosphodiesterase 4 inhibitor, 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 to embrace co-administration of these agents in a substantially simultaneous manner as well.
• the Cox-2 inhibitor and phosphodiesterase 4 inhibitor may be administered in one therapeutic dosage form, such as in a single capsule, tablet, eye drop, aerosol, or injection, or in two separate therapeutic dosage forms, such as in separate capsules, tablets, eye drops, aerosols, 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 present invention takes advantage of the fact that the simultaneous presence of the combination of a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor in a subject has an unexpectedly greater efficacy than the administration of either agent alone.
• the second of the two drugs is administered to the subject within the therapeutic response time of the first drug to be administered.
• the present invention encompasses administration of a Cox-2 inhibitor to the subject and the later administration of a phosphodiesterase 4 inhibitor, as long as the phosphodiesterase 4 inhibitor is administered to the subject while the Cox-
• the present invention encompasses a method for preventing respiratory inflammation in a subject that is in need of such prevention, the method comprising administering to the subject a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor.
• prevention refers to any reduction, no matter how slight, of a subject's predisposition or risk for developing respiratory inflammation.
• the subject is any subject, and preferably is a subject that is at risk for, or is predisposed to, developing respiratory inflammation.
• a subject that is "predisposed to” or “at risk for,” both of which are used interchangeably herein, includes any subject with an increased chance for developing respiratory inflammation.
• the subject may be at risk due to genetic predisposition, diet, age, and the like.
• the subject may also be at risk due to physiological factors such as anatomical and biochemical abnormalities and certain autoimmune diseases.
• the present invention encompasses a method for treating respiratory inflammation in a subject that is in need of such treatment, the method comprising administering to the subject a Cox- 2 inhibitor and a phosphodiesterase 4 inhibitor.
• treating or “to treat” mean to alleviate symptoms, eliminate the causation of symptoms, either on a temporary or permanent basis, or to alter or slow the appearance of symptoms.
• treatment includes alleviation of, or elimination of causation of, symptoms associated with any of the diseases or disorders described herein.
• the term "subject” for purposes of treatment includes any vertebrate.
• the subject is typically a mammal.
• a subject "that is in need or prevention or treatment” is a subject who, by genetics, lifestyle, age, physical condition, accident, medical treatment, medical history, or otherwise, is at risk for contacting, or who has contacted, a disease or disorder. In the context of this application, the disease or disorder is respiratory inflammation.
• the term "respiratory inflammation” refers to any local response in the airway or lungs that is marked by capillary dilatation, leukocytic infiltration, and edema, and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissue.
• the respiratory inflammation can be associated with a disease or disorder including, but not limited to, asthma, chronic obstructive airway disorder, pneumonia, respiratory syncytial viral infection, bronchitis, bronchiolitis, idiopathic pulmonary fibrosis, cystic fibrosis, acute respiratory distress syndrome, bronchopulmonary dysplasia, occupational respiratory disease, particulate exposure, pleurisy, emphysema, and pulmonary edema.
• a component of the present invention is a Cox-2 inhibitor.
• cyclooxygenase-2 inhibitor or "Cox-2 inhibitor”, which can be used interchangeably herein, embrace compounds which inhibit the Cox-2 enzyme regardless of the degree of inhibition of the Cox-1 enzyme, and include pharmaceutically acceptable salts of those compounds.
• 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 compound is a non-steroidal anti-inflammatory drug (NSAID).
• preferred materials that can serve as the Cox-2 inhibitor of the present invention include non-steroidal anti-inflammatory drug compounds, a pharmaceutically acceptable salt thereof, or a pure (-) or (+) optical isomeric form thereof.
• NSAID compounds that are useful in the present invention include acemetacin, acetyl salicylic acid, alclofenac, alminoprofen, azapropazone, benorylate, benoxaprofen, bucloxic acid, carprofen, choline magnesium trisalicylate, clidanac, clopinac, dapsone, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, fenbufen, fenclofenec, fentiazac, floctafenine, flufenisal, flurbiprofen, (r)-flurbiprofen, (s)-flurbipro
• 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 IC 50 value for inhibition of Cox-2 (Cox-1 ICso Cox-2 IC5 0 ).
• Cox-2 selective inhibitor is any inhibitor for which the ratio of Cox-1 IC 50 to Cox-2 IC 50 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.
• IC 50 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.
• Preferred Cox-2 selective inhibitors have a Cox-1 IC 50 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.
• the term "prodrug” refers to a chemical compound that can be converted into an active Cox-2 selective inhibitor by metabolic or simple chemical processes within the body of the subject.
• a prodrug for a Cox-2 selective inhibitor is parecoxib, which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib.
• An example of a preferred 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, proynyl, 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 diaikoxyalkyl 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, pyrimidyl, 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.
• alkylsulfonyl denotes respectively divalent radicals -SO 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 carboxyradical 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 .
• 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 cylopropenyl, 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 ⁇ -alkyl; wherein each of R b and R c is independently selected from hydrido, Ci -C 3
• Ci -C 6 -alkyl Ci -C 6 -haloalkyl, Ci -C 6 -haloalkoxy, Ci -C 6 -haloalkylthio, Ci -C 6 -haloalkylsulfinyl, ⁇ -C 6 -haloalkylsulfonyl, Ci -C 3 -(haloalkyh - C 3 -hydroxyalkyl, Ci -C 6 -hydroxyalkyl, hydroxyimino-Ci -C 6 -alkyl, Ci -
• Cox-2 selective inhibitor of the present invention includes compounds having the structure of formula II:
• X 2 is selected from O, S, CR C R fa and NR a ; wherein R a is selected from hydrido, Ci -C 3 -alkyl, (optionally substituted phenyl)-C ⁇ -C 3 -alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-Ci -C ⁇ -alkyl; wherein each of B b and R c is independently selected from hydrido, Ci -C 3 -alkyl, phenyl-Ci -Ca -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 cycloprop
• 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 1 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, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyciosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbony
• 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 lower haloalkyl, lower cycloalkyl and phenyl; and 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 heterocyciosulfonyl, 6-membered nitrogen-containing heterocyciosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R 18 together with ring A forms a naph
• 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 heterocyciosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R 18 together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
• 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; and
• R 18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, fert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N- dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl, N- phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro, N,N- dimethylaminosulfonyl, aminosulfonyl, N-methy!aminosulfonyl, N- ethylsulfonyl, 2,2-dimethyl
• 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 trifluoromethyl and pentafluoroethyl;
• R 18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, f ⁇ rt-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N- phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N- dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2- dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, 2- methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; or wherein R 18 together with ring A forms a naphthyl radical; or an
• 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 heterocyciosulfonyl, and 6- membered nitrogen-containing heterocyciosulfonyl;
• 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 alkyl, lower alkoxy, and aryl; or an isomer or prodrug thereof.
• 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 from the group consisting of hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl
• R 23 is selected from the group consisting of
• 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-(trif!uoromethyl)-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,
• the Cox-2 inhibitor can be selected from the class of tricyclic Cox-2 selective inhibitors represented by the general structure of formula VII:
• Z 1 is selected rom the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;
• 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; and R is selected from the group consisting of a radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, amino
• the 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.
• the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.
• parecoxib See, U.S. Patent No. 5,932,598
• having the structure shown in B-27, and which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib, B-22, See, U.S. Patent No. 5,633,272
• the Cox-2 inhibitor of the present invention may be advantageously employed as the Cox-2 inhibitor of the present invention.
• 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
• COX-189 also termed lumiracoxib; CAS Reg. No. 220991-20-8
• formula VIII 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-
• 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 -
• 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: wherein: the rings T and M independently are a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms; at least one of the substituents 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
• L 2 are a methylenedioxy group
• R 36 , R 37 , R 38 and R 39 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, fury! and pyridyl; or,
• R 36 , R 37 or R 38 , R 39 are an oxygen atom
• Particular diarylmethylidenefuran derivatives that can serve as the Cox-2 selective inhibitor of the present invention include, for example, N-(2-cyclohexyloxynitrophenyl)methane sulfonamide, and (E)-4-[(4- methylphenyl)(tetrahydro-2-oxo-3-furanylidene) methyObenzenesulfonamide.
• 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.
• Conjugated linoleic, as described in U.S. Patent No. 6,077,868, is useful as a Cox-2 selective inhibitor in the present invention.
• 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 2 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; and 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 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 6 alkyl unsubstituted or substituted with C 3 -C ⁇ cycloalkyl, and C -C ⁇ 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 -Ce cycloalkyl; with the proviso that R 49 and R 50 are not the same.
• R 51 is selected from the group consisting of CH 3 , NH 2 , NHC(0)CF 3 , and
• Z 4 is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituents are chosen from the group consisting of hydrogen, halo, Ci -C 6 alkoxy, Ci -C 6 alkylthio, CN, Ci -C 6 alkyl, Ci ⁇ C 6 fluoroalkyl, N 3 , -C0 2 R 53 , hydroxyl, -C(R 54 )(R 55 )— OH, - C -C 6 alkyl-
• R 52 is chosen from the group consisting of: halo, Ci ⁇ C 6 alkoxy, Ci -C ⁇ alkylthio, CN, C -C 6 alkyl, d -C 6 fluoroalkyl, N 3 , — C0 2 R 57 , hydroxyl, —
• R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 6 , R 62 , and R 63 are each independently chosen from the group consisting of hydrogen andOt -C 6 alkyl; or R 54 and R 55 , R 58 and R 59 , or R 61 and R 62 together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6, or 7 atoms.
• 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 6 lower alkyl group;
• R 67 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a Ci -C 6 lower alkyl group, indanyl, pyrazinyl, or a substituted group represented by the following structures:
• 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 C -C 6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a trifluoromethoxy group, a carboxyl group, or an acetyl group.
• 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 6 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; Ci -C 6 alkyl, preferably C -C 3 alkyl; Ci -C 6 alkoxy, preferably Ci - C 3 alkoxy; carboxy; Ci -C 6 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.
• R 80 is selected from the group consisting of CH 3 , NH 2 , NHC(0)CF 3 , and NHCH 3 ;
• R 81 and R 82 are independently chosen from the group consisting of hydrogen and Ci -C ⁇ 0 alkyl; or R 81 and R 82 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
• Formula XVIII is: 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 O or 1 ; R 83 is selected from the group consisting of CH 3 , NH 2 , and NHC(0)CF 3 ;
• R 84 is chosen from the group consisting of halo, Ci -C 6 alkoxy, Ci -C 6 alkylthio, CN, Ci -C 6 alkyl, d -C 6 fluoroalkyl, N 3) — C0 2 R 92 , hydroxyl, —
• R 85 to R 89 are independently chosen from the group consisting of hydrogen and Ci -C 6 alkyl; or R 85 and R 89 , or R 89 and R 90 together with the atoms to which they are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R 85 and R 87 are joined to form a bond.
• 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" 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:
• heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1 , 2, or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of: (1) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) 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 103 )(R 104 )— OH, and (10) — C(R 103 )(R 104 )— O— Ci -C 4 alkyl
• 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 103 )(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 6 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 Ci -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 11 and R 112 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, acetamido, acetimido, ureido, formamido, or guanidino;
• R 110 is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl; wherein the loweralkyl, loweralkyl containing, loweralkoxy and loweralkanoyl groups contain from 1 to 3 carbon atoms.
• Pyrazole derivatives such as those described in U.S. Patent 6,136,831 can serve as a Cox-2 selective inhibitor of the present invention.
• Such pyrazole derivatives have the formula shown below in formula XXII:
• R 114 is hydrogen or halogen
• R 115 and R 116 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 18 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, N0 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 ,
• 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 1-6 C- atoms, which can optionally be mono- or polysubstituted by halogen, N0 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 R 12 , -NR 121 R 122 , -NHC(0)R 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 U.S. Patent Nos.5,474,995 and 6,239,173. Such phenyl heterocyclic compounds have the formula shown below in formula XXIV:
• 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 ,
• 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 additional 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— Ci -C 4
• R 127 is selected from the group consisting of:
• R 128 and R 128' are each independently selected from the group consisting of:
• Ci -C 6 alkyl (b) 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.
• 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 - C 4 alkylthio, nitro, amino, mono- or di-(C ⁇ -C 4 alkyl)amino and cyano; n is 0, 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 7 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 4 alkyl, hydroxyl, Ci -C 4 alkoxy and nitro;
• R 135 is Ci — C 6 alkyl or halo-substituted Ci -C 6 alkyl
• R 136 and R 137 are independently selected from hydrogen, C ⁇ -6 alkyl and halo-substituted Ci -C 6 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 -C 4 alkoxy, halo-substituted 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 ⁇
• Ci -C 4 alkylsulfonyl N-[(halo-substituted Ci -C 4 alkyl)sulfonyl]amino, Ci -C 4 alkanoyl, carboxy, (Ci -C alkoxy)carbonyl, carbamoyl, [N-(C ⁇ -C 4 alkyl)amino]carbonyl, [N, N-di(C ⁇ -C alkyl)aminojcarbonyl, cyano, nitro, mercapto, (Ci -C 4 alkyl)thio, (Ci -C 4 alkyl)sulfinyl, (Ci -C 4 alkyl)sulfonyl, aminosulfonyl, [N- (Ci -C 4 alkyl)arnino]sulfonyl and [N, N-di(C ⁇ -C 4 alkyl)amino]sulfonyl;
• X 21 is independently selected from halo, Ci -C 4 alkyl, hydroxyl, Ci -C 4 alkoxy, halo-substituted 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)amino,
• C 3 -C 8 cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are indepently selected from halo, Ci -C 4 alkyl, hydroxyl, Ci -C 4 alkoxy, amino, N-(C ⁇ -C 4 alkyl)amino and N, N-di(C ⁇ -C alkyl)amino;
• Ci -C 4 alkyl phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C 4 alkyl, hydroxyl,
• 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:
• L 4 is oxygen or sulfur
• Y 3 is a direct bond or Ci -C 4 alkylidene
• Q 6 is:
• Ci -C 6 alkyl or halosubstituted Ci -C 6 alkyl said alkyl being optionally substituted with up to three substituents independently selected from hydroxyl, Ci -C 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 -C 4 alkyl)amino, C0 2 H, C0 2 (Ci -C 4 alkyl), CONH 2 , CONH(C ⁇ -C 4 alkyl) and CON(C ⁇ -C 4 alkyl) 2 ;
• 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 alkyOamino, NHS0 2 R 143 , C0 2 H, C0 2 (Ci -C 4 alkyl), CONH 2 , CONH(d -C 4 alkyl), CON(C ⁇ -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) Ci -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(C ⁇ -C 4 alkyl) 2 , (c-4) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven (preferably up to seven) substituents
• X 22 is halo, Ci -C 4 alkyl, hydroxyl, Ci -C 4 alkoxy, halosubstitutued Ci -C 4 alkoxy, S(0) m R 143 , amino, mono- or di-(C ⁇ -C 4 alkyl)amino, NHS0 2 R 143 , nitro, halosubstitutued Ci -C 4 alkyl, CN, C0 2 H, C0 2 (d -C 4 alkyl), Ci -C 4 alkyl-OH, d -C 4 alkylOR 143 , CONH 2 , CONH(C ⁇ -C 4 alkyl) or CON(C ⁇ -C 4 alkyl) 2 ; R 143 is d -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;
• Z 11 is oxygen, sulfur or NR 144 ;
• 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, Ci -C 4 alkyl, hydroxyl, Ci -C 4 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-aryIoxy, 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:
• R 146 is selected from the group consisting of SCH 3 , — S(0) 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, CI or
• R 149 is H, Ci -C 4 alkyl optionally substituted with 1 to 3 groups of F, CI or
• Materials that can serve as a Cox-2 selective inhibitor of the present invention include bisaryl compounds that are described in U.S.
• 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, — N(C ⁇ -C 2 alkyl) 2 , — C(O) Ci -C 2 alkyl, — S— d -C 2 alkyl and — C(S) Ci -
• 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, CI or F; and 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. Patent No. 6,028,202. Such 1 ,5-diarylpyrazoles have the formula shown below in formula XXXI:
• R 55 , R 156 , R 157 , and R 158 are independently selected from the groups consisting of hydrogen, Ci -C 5 alkyl, C-j -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 -C 5 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 -
• R 160 is d -C 5 alkoxycarbonyl, phenoxycarbonyl, substituted phenoxycarbonyl where the phenyl substitutents are halogen, Ci -C 5 alkoxy, trihaloCi -C 5 alkyl or nitro;
• R 161 is Ci -C1 0 alkyl, substituted Ci -C ⁇ 0 alkyl where the substituents are halogen, trihaloCi -C 5 alkyl, Ci — C 5 alkoxy, carboxy, Ci -C 5 alkoxycarbonyl, amino, Ci -C 5 alkylamino, diCi -C 5 alkylamino, diCi -C 5 alkylaminoCi -C 5 alkylamino, Ci -Cs alkylaminoCi -
• R 161 is NR 163 R 164 where R 163 and R 164 are independently selected from hydrogen and C1. 5 alkyl or R 163 and R 164 may be taken together with the depicted nitrogen to form a heteroaryl ring of 5-7 ring members where one or more of the ring members is nitrogen, sulfur or oxygen where said heteroaryl ring may be optionally substituted with Ci -C 5 alkyl; R 162 is hydrogen, Ci -C 5 alkyl, nitro, amino, and halogen; and pharmaceutically acceptable salts thereof.
• Materials that can serve as a Cox-2 selective inhibitor of the present invention include 2-substituted imidazoles that are described in
• 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 d-s 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, 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 -C5 alkyloxycarbonyl, arylCi -C 5 alkyl, phthalimidoCi -C 5 alkyl, aminoCi -C 5 alkyl, diaminoCi -C 5 alkyl, succinimidoCi -C 5 alkyl, Ci -C 5 alkylcarbonyl, arylcarbonyl, Ci -C 5 alkylcarbonylCi -C 5 alkyl, aryloxycarbonylC-i -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 alky
• R 167 is (A 11 ) folk -(CH 165 ) q -X 24 wherein: A 11 is sulfur or carbonyl; n is 0 or 1 ; q is 0-9;
• 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 -C5 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(d -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 6 )alkyl, (Ci -
• R 173 is selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C 6 )alkyl, (Ci -C ⁇ jalkoxy and optionally substituted carboxyphenyl, wherein substituents on the
• R 174 is selected from the group consisting of hydrogen, OH, — OCOCH 3 , — COCH 3 and (Ci -C 6 )alkyl;
• R 175 is selected from the group consisting of hydrogen, OH, — OCOCH 3 ,
• 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 176 is Ci -C 6 alkyl, Ci -C 6 branched alkyl, C 4 -C 8 cycloalkyl, Ci -C 6 hydroxyalkyl, branched Ci -C 6 hydroxyalkyl, hydroxyl substituted C -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 - C 8 arylamino, Ci -C 6 alkylcarboxylic acid, branched Ci -C 6 alkylcarboxylic acid, Ci -C ⁇ alkylester, branched Ci -C ⁇ alkylester, C -C 8 aryl, C 4 -Cs arylcarboxylic acid, C -C 8 arylester, C 4 -C 8 aryl substituted Ci -C 6 alkyl, C 4 -Cs
• R 177 is Ci -C 6 alkyl, Ci -C 6 branched alkyl, C 4 -C a cycloalkyl, C 4 -C 8 aryl, C -Ca aryl-substituted -C 6 alkyl, Ci -C 6 alkoxy, -C 6 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, d -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 al
• X 25 is O, NH, or N— R 180 , where R 180 is Ci -C 6 or Ci -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
• 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,
• R 188 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;
• R 187 is selected from the group consisting of alkenylene, alkylene, halosubstituted alkenylene, and halo-substituted alkylene;
• R 188 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
• R d and R ⁇ are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
• 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 83 , 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 23 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;
• R 90 is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, — NHNH 2 , and — NCHN(R 191 )R 192 ;
• R 91 , R 192 , R 193 , and R 194 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 193 and R 94 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 , —
• 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 97 , 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.
• Benzosulphonamide derivatives that are described in U.S. Patent No. 6,004,948 are useful as Cox-2 selective inhibitors of the present invention.
• Such benzosulphonamide derivatives have the formula shown below in formula XXXVII:
• 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:
• 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 ) ⁇ -X 29 ; or
• R 202 and R 203 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 (CH 2 ) 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 , -NR 204 R 205 , — NHC(0)R 204 , — NHS(0) 2 R 204 ;
• R 204 and R 205 independently of each other denote hydrogen, alkyl, aralkyl or aryl; n is an integer from 0 to 6;
• R 206 is a straight-chained or branched Ci -C 4 alkyl group which may optionally be mono- or polysubstituted by halogen or alkoxy, or R 206 denotes CF 3 ; and m denotes an integer from 0 to 2; with the proviso that A 12 does not represent O if R 206 denotes CF 3 ; and the pharmaceutically acceptable salts thereof.
• 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
• 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.
• X 30 is -NHS0 2 R 209 wherein R 209 represents hydrogen or C -C 3 -alkyl;
• Y 9 is hydrogen, halogen, Ci -C 3 -alkyl substituted or not substituted by halogen, N0 2 , NH 2 , OH, OMe, C0 2 H, or CN; and
• Compounds that are useful as Cox-2 selective inhibitors of the present invention include prodrugs of Cox-2 inhibitors that are described in
• 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, alkylthioalkyl, arylcarbonyl,
• R 210 is selected from heterocyclyl, cycloalkyl, cycloalkenyl, and aryl, wherein R 210 is unsubstituted or substituted with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio;
• R 211 is selected from hydrido and alkoxycarbonylalkyl
• R 212 is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl
• a 13 is not tetrazolium, or pyridinium
• a 13 is not indanone when R 212 is alkyl or carboxyalkyl
• a 13 is not thienyl, when R 210 is 4-fluorophenyl, when R 211 is hydrido, and when R 212 is methyl or acyl
• R 2 3 is hydrido; or a pharmaceutically-acceptable salt thereof.
• 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)-1 H-pyrazol-1- yljphen 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, alkylaminocarbonylalkyl, alkylamino, aminoalkyl, alkyl
• R 21 and R 212 are independently selected from the group consisting of hydroxyalkyl and hydrido but at least one of R 211 and R 212 is other than hydrido;
• R 213 is selected from the group consisting of hydrido and fluoro.
• prodrug compounds disclosed in U.S. 6,613,790 that are useful as Cox-2 inhibitors of the present invention include, but are not limited to, N-(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1 H-pyrazol-1- yl]benzenesulfonamide, N,N-bis(2-hydroxyethyl)-4-[5-(4- methylphenyl)-3-(trif luoromethyl)-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:
• Z 16 is O or S
• R 216 is optionally substituted aryl
• R 217 is aryl optionally substituted with aminosulfonyl
• 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.
• 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, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
• R 221 is selected from lower alkyl and amino
• R 222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof.
• 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 selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
• R 224 is selected from lower alkyl and amino; and
• R 225 is selected from hydrido, lower alkyl; or a pharmaceutically-acceptable
• 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 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 220 is otionallv substituted at a substitutable position with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R 221 is selected from lower alkyl and amino; and R 222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof.
• 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 lower al
• 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
• R 222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof.
• 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 selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;
• R 224 is selected from lower alkyl and amino; and
• R 225 is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt
• 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: XXXXVII
• R 226 and R 227 are independently selected from the group consisting of H, halogen, Ci -C ⁇ alkyl, Ci -C ⁇ alkoxy, and Ci -C ⁇ alkoxy substituted by one or more fluorine atoms;
• R ⁇ B is halogen, CN, CON R ⁇ ⁇ R ⁇ C0 2 H, C0 2 Ci -C 6 alkyl, or
• R 229 is Ci -C 6 alkyl or NH 2 ;
• R 225 and R 225 are independently selected from the group consisting of H, C -C 6 alkyl, phenyl, phenyl substituted by one or more atoms or groups selected from the group consisting of halogen, Ci -C ⁇ alkyl, Ci -C ⁇ 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 ester thereof.
• 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: 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; and R 232 represents a substituted or non-substituted aromatic group of 5 to
• 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.
• R 235 is a hydrogen atom or an alkyl group having 1 -3 carbon atoms
• R 236 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 236 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.
• X 34 is selected from the group consisting of:
• R 240 is selected from the group consisting of:
• 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
• heteroaryl which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1 , 2, or 3 additional N atoms; or a monocyclic ring of 6 atoms having one hetero atom which is N, and optionally 1 , 2, or 3 additional N atoms, wherein groups (b) and (c) above are each optionally substituted with 1 -3 substituents independently selected from the group consisting of: halo, Ci -Cio alkoxy, Ci -Cio alkylthio, CN, Ci -Cio alkyl, optionally substituted to its maximum with halo, and N 3 ; R 241 is selected from the group consisting of
• R 242 and R 243 are each independently selected from the group consisting of: hydrogen, halo, and Ci -C 6 alkyl, optionally substituted to its maximum with halo; and R 244 is selected from the group consisting of: hydrogen and Ci -C 6 alkyl, optionally substituted to its maximum with halo.
• Examples of pyrone compounds that are useful as Cox-2 selective inhibitors of the present invention include, but are not limited to: 4-(4-Methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 3-(4-Fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 3-(3-Fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 6-Difluoromethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one,
• free-B-ring flavanoids such as those described in U.S. Published Application No. 2003/0165588, are useful as Cox-2 selective inhibitors of the present invention.
• Such free-B-ring flavanoids have the general structure shown in formula XXXXXI:
• 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:
• the ring of the formula (R 255 )-A-(SO m R 254 ) is selected from the group consisting of:
• R 254 is an (d-C 6 )alkyl radical optionally substituted by one to four fluoro substituents
• C 6 )alkyl-0-(C 0)-, (C C 6 )alkyl-NH-.
• 2-phenylpyran-4-one derivatives such as those described in U.S. Patent No. 6,518,303 are also useful as Cox-2 selective inhibitors of the present invention.
• Such 2-phenylpyran-4-one derivatives have the general formula shown below in formula XXXXXIII:
• 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; and X 36 represents a single bond, an oxygen atom, a sulfur atom or a methylene group; or a pharmaceutically acceptable salt thereof.
• Examples of 2-phenylpyran-4-one derivatives useful in the present invention include, but are not limited to:
• 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.
• Examples of specific compounds that are useful as Cox-2 selective inhibitors include, without limitation: a1 ) 8-acety!-3-(4-f luorophenyl)-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-
• 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
• 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 57067, T-614, BMS-347070 (Bristol Meyers Squibb, described in U.S. Patent No. 6,180,651), JTE-522 (Japan Tabacco), S-2474 (Shionogi),
• 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.
• the Cox-2 selective inhibitor is celecoxib.
• the second component of the present invention is a phosphodiesterase 4 inhibitor.
• Examples of phosphodiesterase 4 inhibitors that are useful in the present invention are presented in Table 3.
• the phosphodiesterase 4 inhibitor of the present invention is preferably selected from the group consisting of roflumilast, cilomilast, etazolate hydrochloride, Ro 20-1724, rolipram, (fl)-(-)-rolipram, (S)-(+)- rolipram, zardaverine, V11294A, CDP840, denbufylline, mesopram, cipamfylline, SCH 351591 , SCH 365351 , L-791 ,943, 7-benzylamino-6- chloro-2-piperazino-pteridine, piclamilast, NVP-ABE171 , 4-(8- benzo[1 ,2,5]oxadiazol-5-yl-[1 ,7]napthyridine-6-yl)-benzoic acid, YM976, KF19514, arofylline, XT-44, T-440, at
• the phrases "therapeutic amount”, “therapeutically-effective”, and “effective for the prevention or treatment" are intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in the severity of the respiratory inflammation and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
• a respiratory disorder symptom or a respiratory disorder-related complication symptom is considered ameliorated or improved if any benefit is achieved, no matter how slight.
• any reduction in inflammation, bronchospasm, bronchoconstriction, shortness of breath, wheezing, lower extremity edema, ascites, productive cough, hemoptysis, or cyanosis in a subject suffering from a respiratory disorder such as COPD, no matter how slight, would be considered an ameliorated symptom.
• a respiratory disorder such as COPD
• the amount of the Cox-2 inhibitor and the phosphodiesterase 4 inhibitor required for use in the treatment or prevention of respiratory disorders and respiratory disorder-related complications 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 mg/kg to about 25 mg/kg per day; more preferably about 0.5 mg/kg to about 10 mg kg per day.
• a typical indicated dose is about 0.5 mg to 7 grams orally per day.
• a 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 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 oral administration to 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.
• the dosage level of a phosphodiesterase 4 inhibitor will necessarily depend on the particular phosphodiesterase 4 inhibitor that is used. However, in general, the appropriate dosage level of a phosphodiesterase 4 inhibitor will generally be from about 0.0001 mg per kg to about 200 mg per kg subject body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.001 mg per kg to about 100 mg per kg per day; more preferably about 0.01 mg per kg to about 50 mg per kg per day; even more preferably about 0.1 mg per kg to about 10 mg per kg subject body weight.
• a combination therapy comprising a phosphodiesterase 4 inhibitor that is intended for oral administration to humans may contain from about 10 micrograms to about 10 grams of active agent optionally compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. More preferably, the phosphodiesterase 4 inhibitor is dosed at between about 0.1 mg and about 1 gram. Even more preferably, the phosphodiesterase 4 inhibitor is dosed at between about 1 mg and about 750 mg. More preferably still, the phosphodiesterase 4 inhibitor is dosed at between about 100 mg and about 500 mg.
• the effectiveness of a particular dosage of a Cox-2 inhibitor in combination with a phosphodiesterase 4 inhibitor is determined by monitoring the effect of a given dosage on the progress or prevention of a particular symptom of the respiratory disorder.
• laboratory tests can be used to diagnose and/or follow the presence or degree of airflow obstruction.
• the degree and severity of asthma and COPD can be determined by measuring lung expiratory flow volume and expiratory flow rates. Such a measurement can be accomplished with, for example, a spirometer, flow volume loop, or pneumotach, before and after each of the treatments.
• the use of spirometry can be a standard test for determining the efficacy of a combination of Cox-2 inhibitors and phosphodiesterase 4 inhibitors after administration to a subject suffering from a pulmonary inflammatory disorder.
• Spirometry is a medical test that measures the physical volume of air an individual forcibly inhales or exhales into a device.
• the objective of spirometry is to assess ventilatory function.
• a device called a spirometer is used to measure how much air the lungs can hold and how well the respiratory system is able to move air into and out of the lungs.
• An estimate of flow rate, or the rate at which the volume is changing as a function of time can also be calculated with spirometery. See College of Physicians and Surgeons of Alberta, "Guidelines For Spirometry & Flow Volume Measurements" ⁇ 998) .
• FVC Vital Capacity
• FEV Forced Expiratory Volume
• FVC is the maximum volume of air, measured in liters, that can be forcibly and rapidly exhaled.
• FEV 1 is the volume of air expelled in the first second of a forced expiration.
• Normal parameters for a subject not suffering from an inflammatory disorder such as asthma or COPD are: Tidal volume - 5 to 7 milliliters per kilogram of body weight; Expiratory reserve volume - 25% of vital capacity; Inspiratory capacity - 75% of vital capacity forced expiratory volume - 75% of vital capacity after 1 second, 94% after 2 seconds, and 97% after 3 seconds.
• Spirometry results are expressed as a percentage, and are considered abnormal if less than 80% of the normal predicted value.
• An abnormal result usually indicates the presence of some degree of obstructive lung disease such as COPD and chronic bronchitis, or restrictive lung disease such as pulmonary fibrosis or asthma.
• an abnormally low FEV 1/FVC means that a subject's airflow is obstructed. If someone has COPD, a low FEV 1 not only reveals that the person has obstructive lung disease, but measures how severe the obstruction is.
• the combination of a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor can be supplied in the form of a novel therapeutic composition that is believed to be within the scope of the present invention.
• the combination of a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor can be supplied in the form of a novel therapeutic composition that is believed to be within the scope of the present invention.
• compositions can be provided in a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition.
• pharmaceutically acceptable carriers or 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 negated or inhibited to such an extent that treatment is ineffective.
• the Cox-2 inhibitor and the phosphodiesterase 4 inhibitor are administered to a subject together in one pharmaceutical carrier. In another embodiment, they are administered separately.
• the pharmaceutical compositions may be administered enterally, parenterally, or topically, such as by inhalation.
• Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art.
• Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, and syrups.
• the pharmaceutical composition may be at or near body temperature.
• the combination of a Cox-2 inhibitor and a phosphodiesterase 4 inhibitor, 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 oleaginous suspensions.
• 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, such as, 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 sorbito
• 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.
• 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.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
• a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1 ,3-butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed, including synthetic mono- or diglycerides.
• n-3 polyunsaturated fatty acids may find use in the preparation of injectables.
• the therapeutic composition containing the Cox-2 inhibitor and the phosphodiesterase 4 inhibitor can be administered by direct inhalation into the respiratory system 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 patient's intestinal tract (a risk associated with oral administration), and eliminating the need for repeated subcutaneous injections.
• delivery of drugs to the pulmonary system by means of aerosol inhalation may be used for targeted local administration for the treatment of respiratory ailments. 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.
• One type of solid particulate aerosol generator is an insufflator.
• Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff.
• 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.
• the powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active materials, a suitable powder diluent, such as lactose, arid an optional surfactant.
• 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 the phosphodiesterase 4 inhibitor in a liquified propellant.
• 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.
• EHD electrohydrodynamic
• 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.
• Oral is another preferred route of administration for the combination therapy.
• 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.
• 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.
• 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.
• a dispersing or wetting agent 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 alone or in combination with the phosphodiesterase 4 inhibitor 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.
• buccal or "sub- lingual" administration which includes lozenges or a chewable gum ⁇ omprising 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.
• Other methods for administration of the Cox-2 inhibitor compound and the phosphodiesterase 4 inhibitor 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.
• 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 80, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art.
• such 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 and phosphodiesterase 4 inhibitor topical composition.
• 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 dimethylsu If oxide (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;
• kits that are suitable for use in performing the methods of treatment described above.
• the kit contains a first dosage form comprising a Cox-2 inhibitor in one or more of the forms identified above and a second dosage form comprising a phosphodiesterase 4 inhibitor, in amounts which comprise a therapeutically effective combination for the prevention or treatment of respiratory inflammation.
• the first dosage form and the second dosage form together comprise a therapeutically effective amount of the compounds for the prevention or treatment of respiratory disorders.
• This solution is added dropwise at 15°-20° C. to a suspension prepared from 4.9 g of 4-amino-3,5-dichloropyridine and 2.0 g of sodium hydride (80% strength in mineral oil) in 60 ml of dry tetrahydrofuran, with stirring and cooling. After stirring for one hour, the reaction mixture is acidified to a pH of 2.0 with 1 N hydrochloric acid. The toluene/tetrahydrofuran phase is separated off and the aqueous phase is extracted two additional times with ethyl acetate. The combined organic phases are washed with saturated sodium hydrogen carbonate solution and water, dried over sodium sulphate, and evaporated under vacuum. The residue is crystallized from isopropanol.
• a therapeutic composition of the present invention can be produced by intermixing finely powdered roflumilast (5 mg, as prepared in Example 2) and celecoxib (25 mg, as produced in Example 1 , or as available from Pharmacia Corporation, Peapack, NJ, under the tradename CELEBREX®), in a laboratory mill or mixing device suitable for mixing of powders without generating shear force or temperature sufficient to degrade either of the two compounds.
• the combination of roflumilast and celecoxib can be dispersed in a suitable carrier such as water or ethanol, and combined with a pharmaceutically acceptable chlorofluorocarbon propellant.
• a suitable carrier such as water or ethanol
• a pharmaceutically acceptable chlorofluorocarbon propellant is sufficient for the production of 250 inhaled aerolsolized human single dose units, each dose containing 20 ⁇ g of roflumilast and 100 ⁇ g of celecoxib.
• the doses can be administered, for example, using a metered dose inhaler.

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