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WO2005049014A1 - Cox-2 inhibitors for the treatment or prevention of diabetes-related ocular disorders - Google Patents

Cox-2 inhibitors for the treatment or prevention of diabetes-related ocular disorders Download PDF

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Publication number
WO2005049014A1
WO2005049014A1 PCT/US2004/039330 US2004039330W WO2005049014A1 WO 2005049014 A1 WO2005049014 A1 WO 2005049014A1 US 2004039330 W US2004039330 W US 2004039330W WO 2005049014 A1 WO2005049014 A1 WO 2005049014A1
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Prior art keywords
trifluoromethyl
carboxylic acid
benzopyran
alkyl
cox
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French (fr)
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Martin B. Wax
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Pharmacia LLC
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Pharmacia LLC
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the prevention and treatment of diabetes-associated ocular disorders, and more particularly to the prevention and treatment of diabetic retinopathy by pharmacologic interventions.
  • Diabetes mellitus affects 6.2% of the American population with over 1 million new cases diagnosed each year, and it is the sixth leading cause of death in the United States. Complications associated with diabetes include heart disease, stroke, high blood pressure, kidney disease, and ocular disease. Diabetes is the leading cause of new cases of blindness among adults between the ages of 20 and 74 years old, and diabetic retinopathy is the underlying cause of as many as 24,000 new cases of blindness diagnosed each year.
  • Diabetic retinopathy results from damage to the blood vessels in the retina caused by high levels of glucose in the blood, and occurs in two types.
  • Nonproliferative diabetic retinopathy is the most common form and represents the earliest stages of the disease. When the walls of the capillaries in the retina weaken, protrusions called microaneurysms occur and, as they swell, blood and fluid leaks into the retina.
  • Proliferative diabetic retinopathy occurs as a progression of the disease when new, abnormal blood vessels grow on the retina and optic nerve, and may invade the jelly-like substance of the vitreous, inside the eye.
  • diabetic retinopathy the best preventative measure for diabetic retinopathy is proper control of blood glucose levels, using insulin to treat type I diabetes mellitus (insulin-dependent diabetes) and, for the treatment of type II diabetes mellitus (non-insulin-dependent diabetes), a variety of anti-diabetic agents including sulfonylureas, alpha-glucosidase inhibitors, and other pharmaceutical agents.
  • Conventional surgical treatment of diabetic retinopathy is by one of two procedures, either photocoagulation or vitrectomy.
  • Photocoagulation involves the use of a laser to seal leaks in the abnormal blood vessels that develop in the eye.
  • a vitrectomy the blood-filled vitreous is removed, improving vision.
  • These surgical procedures often have deleterious effects for patients, including diminished night vision, reduced peripheral vision, and decreases in visual acuity.
  • the retinopathy can worsen even after surgical treatment.
  • somatostatin analogues such as octreotide has shown promise (see Grant, M. and Caballero, S. Drugs Today 38:783-91 (2002)), as well as the administration of aminoguanidine. See Kern, T.S. and Engerman, R.L., Diabetes 50:1636-1642 (2001). Treatment with antioxidants such as vitamins E and C, selenium, and ⁇ -carotene in diabetic rats has also shown some advantageous effect. See Kowluru, R.A. et al., Diabetes 50:1938-42 (2001). The effectiveness of aspirin in inhibiting the progression of diabetic retinopathy has been controversial, but has been described in several studies as having a slight beneficial effect.
  • 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 (prostaglandin E2) which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity, inflammation, and edema.
  • prostanoids prostaglandin E2
  • peripheral nociceptor terminals and produce localized pain hypersensitivity, inflammation, and edema.
  • NSAIDs inhibit prostaglandin synthesis by blocking the activity of both Cox-1 and Cox-2
  • side effects associated with long-term administration of these drugs such as gastrointestinal bleeding and ulcers are thought to be a result of inhibiting the homeostatic functions of Cox-1 , while the inhibiton of Cox-2 accounts for their analgesic properties.
  • the present invention is directed to a novel method for the prevention and treatment of diabetes-associated ocular disorders in a subject, the method comprising administering to the subject a Cox-2 inhibitor.
  • the present invention is also directed to a novel method for the prevention and treatment of diabetes-associated ocular disorders in a subject, the method comprising administering to the subject a Cox-2 inhibitor in combination with one or more conventional anti-diabetic agents.
  • the present invention is also directed to a novel therapeutic composition for the prevention and treatment of diabetes-associated ocular disorders, the therapeutic composition comprising at least one Cox- 2 inhibitor and at least one anti-diabetic agent.
  • the present invention is also directed to a novel pharmaceutical composition for the prevention and treatment of diabetes-associated ocular disorders, the pharmaceutical composition comprising at least one
  • Cox-2 inhibitor and at least one anti-diabetic agent and a pharmaceutically-acceptable excipient.
  • the present invention is also directed to a novel kit that is suitable for use in the prevention and treatment of diabetes-associated ocular disorders, the kit comprising a first dosage form comprising a Cox-2 inhibitor and a second dosage comprising an anti-diabetic agent, in amounts which comprise a therapeutically effective combination of the compounds for the prevention or treatment of the diabetic retinopathy.
  • a novel kit that is suitable for use in the prevention and treatment of diabetes-associated ocular disorders
  • the kit comprising a first dosage form comprising a Cox-2 inhibitor and a second dosage comprising an anti-diabetic agent, in amounts which comprise a therapeutically effective combination of the compounds for the prevention or treatment of the diabetic retinopathy.
  • diabetes-related ocular disorders 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 alone or in combination with one or more conventional anti-diabetic agents.
  • the method comprises administering to the subject one or more Cox-2 inhibitors in an amount that constitutes a therapeutic amount.
  • the Cox-2 inhibitor is administered to the subject in combination with one or more conventional anti-diabetic agents.
  • the subject is administered an amount of the Cox-2 inhibitor and an amount of the anti- diabetic agent that together comprise a therapeutic amount.
  • the administration of a Cox-2 inhibitor for the prevention or treatment of diabetes-related ocular disorders is an unexpectedly effective treatment and preventative therapy.
  • the administration of a Cox-2 inhibitor in combination with a conventional anti-diabetic agent for the prevention or treatment of diabetes-related ocular disorders provides a therapeutic effect that is unexpectedly superior to the therapeutic effect that would be expected based on the use of either agent alone.
  • the administration of either a Cox-2 inhibitor alone or a Cox-2 inhibitor in combination with an anti- diabetic agent is effective for improving the symptoms of diabetes-related ocular disorders, and in preferred embodiments can avoid or reduce certain disadvantages of current treatments.
  • 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 conventional anti-diabetic agent are intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended to embrace co-administration of these agents in a substantially simultaneous manner as well.
  • the Cox-2 inhibitor and conventional anti-diabetic agent may be administered in one therapeutic dosage form, such as in a single capsule, tablet, eye drop, or injection, or in two separate therapeutic dosage forms, such as in separate capsules, tablets, eye drops, 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 in one embodiment, takes advantage of the fact that the simultaneous presence of the combination of a Cox-2 inhibitor and a conventional anti-diabetic agent in a subject has a 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 conventional anti-diabetic agent, as long as the anti- diabetic agent is administered to the subject while the Cox-2 inhibitor is still present in the subject at a level, which in combination with the level of the conventional anti-diabetic agent is therapeutically effective, and vice versa.
  • the present invention encompasses a method for preventing a diabetes-related ocular disorder and, in particular, diabetic retinopathy, in a subject that is in need of such prevention, the method comprising administering to the subject a Cox-2 inhibitor alone or in combination with a conventional anti-diabetic agent.
  • prevention refers to any reduction, no matter how slight, of a subject's predisposition or risk for developing a diabetes-related ocular disorder.
  • the subject is any subject, and preferably is a subject that is at risk for, or is predisposed to, developing a diabetes-related ocular disorder.
  • 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 a diabetes-related ocular disorder.
  • 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 a diabetes-related ocular disorder and, in particular, diabetic retinopathy, in a subject that is in need of such treatment, the method comprising administering to the subject a Cox-2 inhibitor alone or in combination with a conventional anti-diabetic agent.
  • treating means 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 symptoms are those associated with diabetes-related ocular disorders such as, but not limited to, diabetic retinopathy.
  • a subject suffering from diabetic retinopathy may develop glaucoma, macular degeneration, or detached retina as a result of the retinopathy.
  • the term "subject" for purposes of treatment includes any vertebrate.
  • the vertebrate is a human or animal subject who is in need of prevention or treatment for an optic neuropathy.
  • the subject is typically a mammal.
  • "Mammal”, as that term is used herein, refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cattle, etc., Preferably, the mammal is a human.
  • 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.
  • the disease or disorder is a diabetes-related ocular disorder.
  • the term "diabetes-related ocular disorder” means any disorder of the eye arising from complications associated with diabetes. These include, but are not limited to, diabetic retinopathy, glaucoma, macular degeneration, and detached retina. In particular, the term “diabetes-related ocular disorder” includes diabetic retinopathy.
  • a component of the present invention is a Cox-2 inhibitor.
  • the Cox-2 inhibitor compound is a non-steroidal anti-inflammatory drug (NSAID). Therefore, preferred materials that can serve as the Cox-2 inhibitor of the present invention include non-steroidal anti-inflammatory drug compounds, a pharmaceutically acceptable salt thereof, or a pure (-) or (+) optical isomeric form thereof.
  • NSAID non-steroidal anti-inflammatory drug
  • 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. However, for the purposes of this specification, the selectivity of a Cox-2 inhibitor can be measured as a ratio of the in vitro or in vivo IC 5 o value for inhibition of Cox-1 , divided by the IC 5 0 value for inhibition of Cox-2 (Cox-1 IC 50 /Cox-2 IC 50 ).
  • a Cox-2 selective inhibitor is any inhibitor for which the ratio of Cox-1 IC50 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 IC 50 of less than about 1 ⁇ M, more preferred of less than about 0.5 ⁇ M, and even more preferred of less than about 0.2 ⁇ M.
  • Cox-2 selective inhibitors have a Cox-1 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.
  • compounds that act as prodrugs of Cox-2-selective inhibitors are also included within the scope of the present invention.
  • prodrug refers to a chemical compound that can be converted into an active Cox-2 selective inhibitor by metabolic or simple chemical processes within the body of the subject.
  • Cox-2 selective inhibitor is parecoxib, which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib.
  • An example of a preferred Cox-2 selective inhibitor prodrug is sodium parecoxib.
  • a class of prodrugs of Cox-2 inhibitors is described in U.S. Patent No. 5,932,598.
  • the Cox-2 selective inhibitor of the present invention can be, for example, the Cox-2 selective inhibitor meloxicam, Formula B-1 (CAS registry number 71125-38-7), or a pharmaceutically acceptable salt or prodrug thereof.
  • the Cox-2 selective inhibitor can be the Cox-2 selective inhibitor RS 57067, 6-[[5-(4- chlorobenzoyl)-1 ,4-dimethyl-1 H-pyrrol-2-yl]methyl]-3(2H)-pyridazinone, Formula B-2 (CAS registry number 179382-91-3), or a pharmaceutically acceptable salt or prodrug thereof.
  • alkyl either alone or within other terms such as “haloalkyl” and “alkylsulfonyl”; embraces linear or branched radicals having one to about twenty carbon atoms.
  • Lower alkyl radicals have one to about ten carbon atoms. The number of carbon atoms can also be expressed as "C 1 -C 5 ", for example.
  • Examples of lower alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the, like.
  • alkenyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains at least one double bond.
  • the alkenyl radicals may be optionally substituted with groups such as those defined below.
  • suitable alkenyl radicals include propenyl, 2-chloropropylenyl, buten-1yl, isobutenyl, penten-1yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3- hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like.
  • alkynyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds, such radicals preferably containing 2 to about 6 carbon atoms, more preferably from 2 to about 3 carbon atoms.
  • the alkynyl radicals may be optionally substituted with groups such as described below.
  • alkynyl radicals examples include ethynyl, proynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3- methylbutyn-1-yl, hexyi-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
  • 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.
  • cyano used either alone or with other terms, such as “cyanoalkyl”, refers to C ⁇ N.
  • nitro denotes -NO 2 .
  • 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
  • Benzopyrans that can serve as a Cox-2 selective inhibitor of the present invention include substituted benzopyran derivatives that are described in U.S. Patent Nos. 6,271 ,253 and 6,492,390.
  • One such class of compounds is defined by the general formula shown below in formula I:
  • X 1 is selected from O, S, CR C R b and NR a ; wherein R a is selected from hydrido, Ci -C 3 -alkyl, (optionally substituted phenyl)-C ⁇ -C 3 -alkyl, acyl and carboxy-Ci -C 6 -alkyl; wherein each of R b and R c is independently selected from hydrido, C-i -C 3 -alkyl, phenyl-Ci -C 3 -alkyl, Ci -C 3 -perfluoroalkyl, chloro, Ci -CQ - alkylthio, Ci -C ⁇ -alkoxy, nitro, cyano and cyano-Ci -C 3 -alkyl; or wherein CR b R c forms a 3-6 membered cycloalkyl ring; wherein R 1 is selected from carboxyl, aminocarbonyl, Ci -C
  • 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 b 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 R b and R c is independently selected from hydrido, Ci -C 3
  • X 3 is selected from the group consisting of O or S or NR a ; wherein R a is alkyl; wherein R 9 is selected from the group consisting of H and aryl; wherein R 10 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R 11 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R 12 is selected from the group consisting of one or more radicals selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino,
  • X 4 is selected from O or S or NR a ; wherein R a is alkyl; wherein R 13 is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R 14 is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R 15 is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alky
  • X 5 is selected from the group consisting of O or S or NR b ; R b is alkyl;
  • R 16 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
  • R 17 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is independently optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and
  • R 18 is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, and alkylcarbonyl
  • 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 selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
  • R 17 is selected from the group consisting of lower haloalkyl, lower cycloalkyl and phenyl;
  • R 18 is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5- membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, lower alkylsulfonyl, 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
  • X 5 is selected from the group consisting of oxygen and sulfur
  • R 16 is carboxyl
  • R 17 is lower haloalkyl; and R 18 is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen- containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R 18 together with ring
  • A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
  • 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 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, terf-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N- dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl, N- phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro, N,N- dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N- ethylsulfonyl, 2,2-dimethylethy
  • 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, ferf-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 iso
  • Cox-2 selective inhibitor of the present invention can also be a compound having the structure of Formula VI:
  • X 6 is selected from the group consisting of O and S;
  • R 19 is lower haloalkyl
  • R 20 is selected from the group consisting of hydrido, and halo
  • R 21 is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, and 6- membered nitrogen-containing heterocyclosulfonyl;
  • R 22 is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy, and aryl;
  • R 23 is selected from the group consisting of the group consisting of hydrido, halo, lower 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, methylpropylaminosuifonyl, methylsulfonyl, and morpholinosulfonyl;
  • R 22 is selected from the group consisting of hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl; and R 23 is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl; or an isomer or prodrug thereof.
  • Table 1 Examples of Chromene Cox-2 Selective Inhibitors
  • the chromene Cox-2 inhibitor is selected from (S)-6-chloro-7-(1 ,1-dimethylethyl)-2-(trifluoromethyl)-2H-1- benzopyran-3-carboxylic acid, (2S)-6,8-dimethyl-2-(trifluoromethyl)-2H- chromene-3-carboxylic acid, (2S)-6-chloro-8-methyl-2-(trifluoromethyl)-2H- chromene-3-carboxylic acid, (2S)-8-ethyl-6-(trifluoromethoxy)-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6,8-dichloro-2- (trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid, (2S)-6-chloro-5,7- dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and mixtures thereof
  • Z 1 is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;
  • 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
  • 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, aminocarbonyl, aminocarbonylalkyl, alkyla
  • 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 selective 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 ⁇ 2'8 0 and R )3 ⁇ 0 U are chloro; R 29 and R 31 are methyl; and
  • R 32 is ethyl
  • phenylacetic acid derivative Cox-2 selective inhibitor that is disclosed in WO 02/20090 is a compound that is referred to as
  • COX-189 also termed lumiracoxib; CAS Reg. No. 220991-20-8, having the structure shown in formula VIII, wherein:
  • R 27 is methyl
  • R 28 is fluoro
  • R 32 is chloro
  • R 29 , R 30 , and R 31 are hydrogen.
  • Cox-2 selective inhibitors that can be used in the present invention have the general structure shown in formula IX, where the J group is a carbocycle or a heterocycle.
  • Preferred embodiments have the structure:
  • X 7 is O; J is 1 -phenyl; R 33 is 2-NHS0 2 CH 3 ; R 34 is 4-N0 2 ; and there is no
  • R 35 group (nimesulide), or
  • X 7 is O; J is 1-oxo-inden-5-yl; R 33 is 2-F; R 34 is 4-F; and R 35 is 6-
  • R 35 group (NS-398); or
  • X 7 is S; J is 1-oxo-inden-5-yl; R 33 is 2-F; R 34 is 4-F; and R 35 is 6-N " S0 2 CH 3
  • X 7 is S; J is thiophen-2-yl; R 33 is 4-F; there is no R 34 group; and R 35 is 5-
  • R 34 is 4-F; and R 35 is 4-(p-S0 2 CH 3 )C 6 H 4 , (L-784512).
  • Cox-2 selective inhibitor NS-398 also known as N-(2- cyclohexyloxynitrophenyl) methane sulfonamide (CAS RN 123653-11-2), having a structure as shown below in formula B-29, has been described in, for example, Yoshimi, N. et al., in Japanese J. Cancer Res., 90(4):406 -
  • Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylmethylidenefuran derivatives that are described in U.S. Patent No. 6,180,651. Such diarylmethylidenefuran derivatives have the general formula shown below in formula X:
  • the rings T and M independently are a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms; at least one of the substituents Q 1 , Q 2 , L 1 or L 2 is an — S(0) n — R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an -S0 2 NH 2 group; and is located in the para position, the others independently being a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower O-alkyl radical having 1 to 6 carbon atoms, or Q 1 and Q 2 or L 1 and
  • 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, furyl and pyridyl; or, R 36 , R 37 or R 38 , R 39 are an oxygen atom; or R 36 , R 37 or R 38 , R 39 , together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms; or an isomer or prodrug thereof.
  • 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) methyljbenzenesulfonamide.
  • 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
  • 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 6 alkoxy, unsubstituted, mono-, di- or tri- substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, Ci -C 3 alkoxy, CN, Ci -C 3 fluoroalkyl Ci -C 3 alkyl, and -C0 2 H;
  • R 48 is selected from the group consisting of NH 2 and CH 3 ,
  • R 49 is selected from the group consisting of Ci -C ⁇ alkyl unsubstituted or substituted with C 3 -C ⁇ cycloalkyl, and C 3 -C ⁇ cycloalkyl;
  • R 50 is selected from the group consisting of:
  • Ci -C ⁇ alkyl unsubstituted or substituted with one, two or three fluoro atoms, and C 3 -C 6 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, - d -C 6 alkyl-
  • R 52 is chosen from the group consisting of: halo, Ci -C ⁇ alkoxy, Ci -C 6 alkylthio, CN, Ci -C 6 alkyl, Ci -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 61 , R 62 , and R 63 are each independently chosen from the group consisting of hydrogen andCi -C ⁇ 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(O) n R 68 wherein n is an integer of 0 ⁇ 2, R 68 is a hydrogen atom, a Ci -C ⁇ lower alkyl group, or a group of a formula: NR 69
  • R 70 wherein R 69 and R 70 , identical to or different from each other, are independently a hydrogen atom, or a Ci -C ⁇ lower alkyl group;
  • 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 Ci -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 ⁇ trihalomethyl, preferably trifluoromethyl; Ci -C ⁇ alkyl; and an optionally substituted or di-substituted phenyl group of formula XVI:
  • R 77 and R 78 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; Ci -C ⁇ alkyl, preferably Ci -C 3 alkyl; Ci -C ⁇ alkoxy, preferably Ci - C 3 alkoxy; carboxy; Ci -C ⁇ trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano; Z 5 is selected from the group consisting of substituted and unsubstituted aryl.
  • Compounds useful as Cox-2 selective inhibitors of the present invention include heterocycles that are described in U.S. Patent No.
  • 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 10 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 0 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, Ci -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 99 is selected from the group consisting of S(0) 2 CH 3 , S(0) 2 NH 2 ,
  • R 100 is selected from the group consisting of:
  • 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 al
  • 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— d -C 4 alkyl;
  • R 103 , R 104 and R 105 are each independently selected from the group consisting of hydrogen and Ci -C ⁇ alkyl; or
  • R 103 and R 104 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms, or two R 105 groups on the same carbon form a saturated monocyclic carbon ring of 3,
  • R 106 is hydrogen or 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 08 is:
  • R 111 and R 112 are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy, trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfmyl, 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 r15 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 20 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 121 , — NR 121 R 122 , — NHC(0)R 121 , — NHS(0) 2 R 121 , or a polyfluoroalkyl group;
  • 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:
  • 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 1S is independently selected from halogen, Ci -C 4 alkyl, halo-substituted Ci -C 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 O, 1 , 2, 3 or 4; L 3 is oxygen or sulfur;
  • R 133 is hydrogen or C -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 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 alkyl, hydroxyl, Ci -C 4 alkoxy, halo-substituted Ci -C alkyl, hydroxyl-substituted Ci -C alkyl, (Ci -C 4 alkoxy)C ⁇ -C 4 alkyl, halo-substituted Ci -C 4 alkoxy, amino, N-(C ⁇ -C 4 alkyl)amino,
  • Ci -C alkyl)sulfonyl N-[(halo-substituted Ci -C alkyl)sulfonyl]amino, Ci -C alkanoyl, carboxy, (Ci -C alkoxy)carbonyl, carbamoyl, [N-(C ⁇ -C alkyl)amino]carbonyl, [N, N-di(C ⁇ -C 4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (Ci -C 4 alkyl)thio, (Ci -C 4 alkyl)sulfinyl, (Ci -C alkyl)sulfonyl, aminosulfonyl, [N- (Ci -C 4 alkyl)amino]sulfonyl and [N, N-di(C ⁇ -C alkyl)amino]sulfonyl;
  • X 21 is independently selected from halo, Ci -C 4 alkyl, hydroxyl, Ci -C alkoxy, halo-substituted Ci -C 4 alkyl, hydroxyl-substituted Ci -C 4 alkyl, (Ci -C 4 alkoxy)C ⁇ -C alkyl, halo-substituted Ci -C 4 alkoxy, amino, N-(C ⁇ -C alkyl)amino, N, N-di(C ⁇ -C 4 alkyl)amino, [N-(C ⁇ -C alkyl)amino]C ⁇ -C 4 alkyl, [N, N-di(C ⁇ -C 4 alkyl)amino]C ⁇ -C 4 alkyl, N- ⁇ -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 alkyl)amino and N, N-di(C ⁇ -C 4 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 4 alkoxy, amino and mono- or di-( Ci -C 4 alkyl)amino,
  • R 141 is hydrogen or Ci -C ⁇ alkyl optionally substituted with a substituent selected independently from hydroxyl, OR 143 , nitro, amino, mono- or di-( d -C 4 alkyl)amino, C0 2 H, C0 2 (Ci -C 4 alkyl), CONH 2 , CONH(C ⁇ -C 4 alkyl) and CON(C ⁇ -C 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-( d -C 4 alkyl)amino, NHS0 2 R 143 , C0 2 H, C0 2 (Ci -C 4 alkyl), CONH 2 , CONH(C ⁇ -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(d -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 (Ci -C 4 alkyl), Ci -C 4 alkyl-OH, Ci -C 4 alkylOR 143 , CONH 2 , CONH(C ⁇ -C 4 alkyl) or CON(C ⁇ -C 4 alkyl) 2 ; R 143 is Ci -C 4 alkyl or halosubstituted Ci -C 4 alkyl; m is 0, 1 or 2; n is 0, 1 , 2 or 3; p is 1 , 2, 3, 4 or 5;
  • 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-aryloxy, 4-aryl furan-2-ones that are described in U.S. Patent No. 6,140,515. Such 2-aryloxy, 4-aryl furan-2-ones have the formula shown below in formula XXIX:
  • R 146 is selected from the group consisting of SCH 3 , — S(0) 2 CH 3 and —
  • R 147 is selected from the group consisting of OR 150 , mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
  • R 150 is unsubstituted or mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
  • R 148 is H, Ci -C alkyl optionally substituted with 1 to 3 groups of F, Cl or
  • R 149 is H, Ci -C 4 alkyl optionally substituted with 1 to 3 groups of F, Cl or
  • 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, —
  • Y 7 represents N, CH or C— OC ⁇ -C 3 alkyl, and when Z 13 is N, Y 7 can also represent a carbonyl group;
  • R 153 represents H, Br, Cl or F
  • R 154 represents H or CH 3 .
  • Compounds useful as Cox-2 selective inhibitors of the present invention include 1 ,5-diarylpyrazoles that are described in U.S. Patent No.
  • R 155 , R 156 , R 157 , and R 158 are independently selected from the groups consisting of hydrogen, Ci -C 5 alkyl, Ci -C 5 alkoxy, phenyl, halo, hydroxyl,
  • Ci -C 5 alkylsulfonyl Ci -C 5 alkylthio, trihaloCi -C 5 alkyl, amino, nitro and
  • R 159 is hydrogen, Ci -C 5 alkyl, trihaloCi -C 5 alkyl, phenyl, substituted phenyl where the phenyl substitutents are halogen, d -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 161 is NR 163 R 164 where R 163 and R 164 are independently selected from hydrogen and C 1 . 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 C 1 . 5 alkyl, halogen, nitro, trifluoromethyl and nitrile;
  • R 165 is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, substituted heteroaryl; wherein the substituents are independently selected from one or more members of the group consisting of Ci -C 5 alkyl and halogen, or substituted phenyl, wherein the substituents are independently selected from one or members of the group consisting of Ci -C 5 alkyl, halogen, nitro, trifluoromethyl and nitrile;
  • R 166 is hydrogen, 2-(trimethylsilyl)ethoxymethyl), Ci -C 5 alkoxycarbonyl, aryloxycarbonyl, arylCi -C 5 alkyloxycarbonyl, arylCi -C 5 alkyl, phthalimidoCi -C 5 alkyl, aminoCi -C 5 alkyl, diaminoCi -C 5 alkyl, succinimidoCi -C 5 alkyl, Ci -C 5 alkylcarbonyl, arylcarbonyl, Ci -C 5 alkylcarbonylCi -C 5 alkyl, aryloxycarbonylCi -C 5 alkyl, heteroarylCi -C 5 alkyl where the heteroaryl contains 5 to 6 ring atoms, or substituted arylCi -C 5 alkyl, wherein the aryl substituents are independently selected from one or more members of the group consisting of Ci -C 5 alkyl
  • R 167 is (A 11 ) folk -(CH 1 -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 -C 5 alkylamino, nitrile, phthalimido, amido, phenylcarbonyl, Ci -C 5 alkylaminocarbonyl, phenylaminocarbonyl, arylCi -C 5 alkylaminocarbonyl, Ci -C 5 alkylthio, Ci -C 5 alkylsulfonyl, phenylsulfonyl, substituted sulfonamido, wherein the sulfonyl substituent is selected from the group consisting of Ci
  • Materials that can serve as a Cox-2 selective inhibitor of the present invention include 1 ,3- and 2,3-diarylcycloalkano and cycloalkeno pyrazoles that are described in U.S. Patent No. 6,083,969. Such 1 ,3- and
  • 2,3-diarylpyrazole compounds have the general formulas shown below in formulas XXXIII and XXXIV:
  • R 168 and R 169 are independently selected from the group consisting of hydrogen, halogen, (Ci -C 6 )alkyl, (Ci -C 6 )alkoxy, nitro, amino, Dydroxyl, trifluoro, — S(C ⁇ -C 6 )alkyl, — SO(C ⁇ -C 6 )alkyl and — S0 2 (Ci -C 6 )alkyl; and the fused moiety M is a group selected from the group consisting of an optionally substituted cyclohexyl and cycloheptyl group having the formulae:
  • R 171 and R 172 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C 6 )alkyl, (Ci -
  • R 173 is selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C 6 )alkyl, (Ci -C 6 )alkoxy and optionally substituted carboxyphenyl, wherein substituents on
  • 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 d -C 8 aryl, primary, secondary or tertiary Ci -C 6 alkylamino, primary, secondary or tertiary branched Ci -C 6 alkylamino, primary, secondary or tertiary C 4 - C 8 arylamino, Ci -C 6 alkylcarboxylic acid, branched Ci -C 6 alkylcarboxylic acid, Ci -C 6 alkylester, branched Ci -C 6 alkylester, C 4 -C 8 aryl, C -C 8 arylcarboxylic acid, C 4 -C 8 arylester, C -C 8 aryl substituted Ci -C 6 alkyl, C 4 -
  • R 177 is Ci -C 6 alkyl, Ci ⁇ C 6 branched alkyl, C -C 8 cycloalkyl, C 4 -C 8 aryl, C 4 -C 8 aryl-substituted Ci -C ⁇ alkyl, Ci -C ⁇ alkoxy, Ci -C 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 6 alkyl or Ci -C ⁇ branched alkyl; R 179 is Ci -C 6 alkyl, C 4 -C 8 aroyl, C 4 -C 8 aryl, C 4 -C 8 heterocyclic alkyl or aryl with O, N or S in the ring, C 4 -C 8 aryl-substituted Ci -C 6
  • X 25 is O, NH, or N— R 180 , where R 180 is Ci -C 6 or Ci -C 6 branched alkyl.
  • Materials that can serve as a Cox-2 selective inhibitor of the present invention include pyhdazinone compounds that are described in U.S. Patent No. 6,307,047. Such pyridazinone compounds have the formula shown below in formula XXXVI:
  • X 26 is selected from the group consisting of O, S, — NR 185 , — NOR a , and - NNR b R c ;
  • R 185 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;
  • R a , R b , and R c are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;
  • R 181 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,
  • 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 e 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, aminoaikylcarbonyloxyalkoxy aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercapto
  • X 27 is selected from the group consisting of S(0) 2 , S(0)(NR 191 ), S(O),
  • X 28 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;
  • R 190 is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, — NHNH 2 , and — NCHN(R 191 )R 192 ;
  • R 191 , R 192 , R 193 , and R 194 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 193 and R 194 can be taken together, with the nitrogen to which they are attached, to form a 3-6 membered ring containing 1 or 2 heteroatoms selected from the group consisting of 0, 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 197 , R 198 , R 199 , and R 200 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl.
  • 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 ) n -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, 0, 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 ,
  • 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 0 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: wherein:
  • 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 Ci -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 213 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 211 and R 212 are independently selected from the group consisting of hydroxyalkyl and hydrido but at least one of R 211 and R 2 2 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- yljbenzenesulfonamide, N,N-bis(2-hydroxyethyl)-4-[5-(4- methylphenyl)-3-(trifluoromethyl)-1 H-pyraz ol-1 -yljbenzenesulfonamide, 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 ⁇ 2 2 1 1 4 4 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 j218 and R 5 219 cooperate to form an optionally substituted 5-membered ring.
  • Materials that can serve as Cox-2 selective inhibitors of the present invention include substituted hydroxamic acid derivatives that are described in U.S. Patent Nos. 6,432,999, 6,512,121 , and 6,515,014. These compounds also act as inhibitors of the lipoxygenase-5 enzyme.
  • substituted hydroxamic acid derivatives have the general formulas shown below in formulas XXXXV and XXXXVI:
  • a 14 is pyrazolyl optionally substituted with a substituent selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
  • Y 10 is selected from lower alkenylene and lower alkynylene;
  • R 220 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R 220 is optionally substituted at a substitutable position with one or more substituents selected from lower alkyl, 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; and
  • R 222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocycl
  • 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
  • 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-
  • a 15 is a ring substituent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A is optionally substituted with a substituent selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarboryl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y 11 is selected from lower alkyl, lower alkenyl and lower alkynyl;
  • R 223 is a substituent selected from 5- 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, nitto, 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 thereof.
  • Thiophene substituted hydroxamic acid derivatives described in U.S. Patent No. 6,515,014 have the formula shown above in formula XXXXV, wherein: 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 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;
  • 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 ,22 z 8 o is halogen, CN, CON 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, Ci -C ⁇ 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 ⁇ 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 23 ⁇ 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 -C ⁇ 0 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 ⁇ alkyl, optionally substituted to its maximum with halo; and R 244 is selected from the group consisting of: hydrogen and Ci -C ⁇ 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 24 6 ) R 24 7 _ R 248 j R 249 _ and R 25 o 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 55 )-A-(SO m R 254 ) is selected from the group consisting of:
  • R 254 is an (C ⁇ -C 6 )alkyl radical optionally substituted by one to four fluoro substituents;
  • C 6 )alkyl-0-(C 0)-, (d-Ce)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-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo(1 ,2- a)pyridine; a2) 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone; a3) 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-
  • 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. 5,466,323 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 Cox-2 selective inhibitor is administered from about 0.1 mg per kg to about 25 mg per kg subject body weight. [000148] In one embodiment of the present invention, the Cox-2 selective inhibitor is administered from about 0.5 mg per kg to about 10 mg per kg subject body weight.
  • an optional component of the present invention is a conventional anti-diabetic agent.
  • a conventional anti-diabetic agent refers to any compound or combination of compounds that is capable of controlling glucose metabolism and, ultimately, blood glucose levels in a subject suffering from diabetes.
  • Examples of preferred classes of conventional anti-diabetic agents that are suitable for use in the present invention are listed in Table 3 and include, but are not limited to, insulin, insulin analogs, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglinitides, and biguanides.
  • the anti-diabetic agent is an insulin or insulin analog selected from the group consisting of insulin, insulin human, buffered insulin human, insulin zinc, insulin human zinc, prompt insulin zinc, extended insulin zinc, extended insulin human zinc, isophane insulin, isophane insulin human, isophane insulin human and insulin human, insulin glargine, insulin aspart, insulin lispro, and mixtures thereof.
  • the anti-diabetic agent is a sulfonylurea selected from the group consisting of acetohexamide, chlorpropamide, gliclazide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide, and mixtures thereof.
  • the anti-diabetic agent is an alpha- glucosidase inhibitor selected from the group consisting of acarbose, migitol, and mixtures thereof.
  • the anti-diabetic agent is a thiazolidinedione selected from the group consisting of ciglitazone, englitazone, troglitazone, pioglitazone, rosiglitazone, and mixtures thereof.
  • the anti-diabetic agent is a meglinitide selected from the group consisting of repaglinide, nateglimide, and mixtures thereof.
  • the anti-diabetic agent is a biguanide selected from the group consisting of buformin, metformin, phenformin, and mixtures thereof.
  • the amount of the anti-diabetic agent utilized in the present invention is dependent on the specific anti-diabetic agent selected.
  • Therapeutically effective amounts of various anti-diabetic agents that are useful in the present method and composition are listed in Table 3.
  • the combination of a Cox-2 inhibitor and an anti-diabetic agent 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 an anti-diabetic agent 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.
  • compositions 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 conventional anti-diabetic agent are administered to a subject together in one pharmaceutical carrier. In another embodiment, they are administered separately.
  • the pharmaceutical compositions may be administered enterally and parenterally.
  • 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 combinations of the present invention can be administered topically into the eye in the form of liquid drops. Eye drops can be formulated to contain a suitable amout of the active agents along with various formulatory ingredients, such as antimicrobial preservatives and tonicity agents.
  • Suitable antimicrobial preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, and other agents equally well-known to those skilled in the art. Such preservatives, if utilized, will typically be employed in an amount between about 0.001% and about 1.0% by weight.
  • suitable agents which may be used to adjust the tonicity or osmolality of the formulations include: sodium chloride, potassium chloride, mannitol, dextrose, glycerin, and propylene glycol.
  • compositions can be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, gels and erodible solid ocular inserts.
  • the subject method of administering a Cox-2 inhibitor alone or in combination with a conventional anti-diabetic agent and compositions comprising the same can also be administered parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrastemally, 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, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally- occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin.
  • 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.
  • Insulins and insulin analogues cannot be taken orally, but must be administered subcutaneously to avoid breakdown in the gastrointestinal tract. Therefore, when the anti-diabetic agent of the present invention is an insulin or insulin analog, the preferred administration of the composition would be by subcutaneously administered sterile injectable solution as described above.
  • 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.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • 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 conventional anti-diabetic agent may be formulated with sweetening agents, for example glycerol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • Administration can also be by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature, but liquid at the rectal temperature and will therefore, melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperature, but liquid at the rectal temperature and will therefore, melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • buccal or "sub- lingual" administration which includes lozenges or a chewable gum comprising the compounds, set forth herein.
  • the compounds can be deposited in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compounds in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Other methods for administration of the Cox-2 inhibitor compound and the conventional anti-diabetic agent include dermal patches that release the medicaments directly into a subject's skin.
  • Topical delivery systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, collyriums, solutions or suspensions.
  • 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.
  • a penetration enhancer is an agent used to increase the permeability of the skin to an active agent to increase the rate at which the drug diffuses through the skin and enters the tissues and bloodstream.
  • a penetration enhancer may be added to a Cox-2 inhibitor topical composition or a Cox-2 inhibitor and conventional anti-diabetic agent topical composition.
  • Examples of penetration enhancers suitable for use with the compositions of the present invention include: alcohols, such as ethanol and isopropanol; polyols, such as n-alkanols, limonene, terpenes, dioxolane, propylene glycol, ethylene glycol, other glycols, and glycerol; sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformamide, methyl dodecyl sulfoxide, dimethylacetamide; esters, such as isopropyl myristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate, and capric/caprylic triglycerides; ketones; amides, such as acetamides; oleates, such as triolein; various surfactants, such as sodium lauryl sulfate; various alkanoic acids, such as caprylic acid; lactam compounds, such
  • 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 an anti-diabetic agent, in amounts which comprise a therapeutically effective combination for the prevention or treatment of diabetic retinopathy.
  • the first dosage form and the second dosage form together comprise a therapeutically effective amount of the compounds for the prevention or treatment of diabetes-related ocular disorders.
  • Step 1 Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-
  • Step 2 Preparation of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1 H-pyrazol-1 -yljbenzenesulfonamide.
  • Insulin may be supplied by any one of several commercially available preparations, such as Humulin® N, available from Eli Lilly and
  • Humulin® N is supplied at a concentration of 100 units per milliliter.
  • Celecoxib can be prepared as described in Example 1 or, alternatively, can be obtained under the trade name CELEBREX® from Pharmacia Corporation, Peapack, NJ.
  • a therapeutic composition of the present invention can be produced by intermixing the insulin suspension (50 ml supplied by Eli Lilly and Company as Humulin® N, at a concentration of 100 units/ml); and 4- [5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide (20 g, as produced in Example 1 , or as available from Pharmacia Corporation, Peapack, NJ, under the trade name CELEBREX®), in a suspension or solution with a sterile pharmaceutically acceptable liquid.
  • Glipizide can be supplied by any commercial preparations, such as GLUCOTROL®. GLUCOTROL® is supplied in the form of tablets by Pfizer, Inc, New York, NY. [000196] Celecoxib can be prepared as described in Example 1 or, alternatively, can be obtained under the trade name CELEBREX® from
  • a therapeutic composition of the present invention can be produced by intermixing solid or powdered glipizide (500 mg, available as GLUCOTROL® from Pfizer, Inc.); and 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-l H-pyrazol-1 -yljbenzenesulfonamide (200 g, as produced in Example 1 , or as available from Pharmacia Corporation, Peapack, NJ, under the trade name 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. [000198] After mixing, the combination of glipizide and celecoxib forms a therapeutic composition that is sufficient for the production of 1000 human single dose unit, each dose containing 5 mg of glipizide and 200 mg of celecoxib.

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Abstract

A method is described for the prevention or treatment of diabetes-­related ocular disorders in a subject, the method comprising administering to the subject a Cox-2 inhibitor alone or in combination with a conventional anti-diabetic agent. Also described are therapeutic and pharmaceutical compositions and kits that are useful in the present invention.

Description

COX-2 INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES-RELATED OCULAR DISORDERS
BACKGROUND OF THE INVENTION (1) Field of the Invention [0001] The present invention relates to the prevention and treatment of diabetes-associated ocular disorders, and more particularly to the prevention and treatment of diabetic retinopathy by pharmacologic interventions. (2) Description of the Related Art [0002] Diabetes mellitus affects 6.2% of the American population with over 1 million new cases diagnosed each year, and it is the sixth leading cause of death in the United States. Complications associated with diabetes include heart disease, stroke, high blood pressure, kidney disease, and ocular disease. Diabetes is the leading cause of new cases of blindness among adults between the ages of 20 and 74 years old, and diabetic retinopathy is the underlying cause of as many as 24,000 new cases of blindness diagnosed each year. [0003] Diabetic retinopathy results from damage to the blood vessels in the retina caused by high levels of glucose in the blood, and occurs in two types. Nonproliferative diabetic retinopathy is the most common form and represents the earliest stages of the disease. When the walls of the capillaries in the retina weaken, protrusions called microaneurysms occur and, as they swell, blood and fluid leaks into the retina. Proliferative diabetic retinopathy occurs as a progression of the disease when new, abnormal blood vessels grow on the retina and optic nerve, and may invade the jelly-like substance of the vitreous, inside the eye. The appearance of the new blood vessels in combination with leaking of fluid from existing, weakened capillaries causes loss of vision and can lead to retinal detachment, glaucoma, and eventual blindness. [0004] Currently, the best preventative measure for diabetic retinopathy is proper control of blood glucose levels, using insulin to treat type I diabetes mellitus (insulin-dependent diabetes) and, for the treatment of type II diabetes mellitus (non-insulin-dependent diabetes), a variety of anti-diabetic agents including sulfonylureas, alpha-glucosidase inhibitors, and other pharmaceutical agents. Conventional surgical treatment of diabetic retinopathy is by one of two procedures, either photocoagulation or vitrectomy. Photocoagulation involves the use of a laser to seal leaks in the abnormal blood vessels that develop in the eye. In a vitrectomy, the blood-filled vitreous is removed, improving vision. These surgical procedures often have deleterious effects for patients, including diminished night vision, reduced peripheral vision, and decreases in visual acuity. Moreover, because the underlying cause of diabetic retinopathy is not well understood, the retinopathy can worsen even after surgical treatment.
[0005] Recently, alternative pharmaceutical approaches to the treatment of diabetic retinopathy have been explored. The efficacy of a diverse array of pharmacologic agents has been tested in clinical trials, as well as in studies utilizing animal models of diabetes. Several drugs that showed promise in theory failed to have an effect in practice. An example is angiotensin-converting enzyme (ACE) inhibitors, vasodilators traditionally used to treat chronic heart failure and high blood pressure. A pilot study determined that ACE inhibitors are not beneficial to patients with moderate to severe diabetic retinopathy. See Pradham, R. et al., J Diabetes Complications 76:377-81 (2002). Several other agents have demonstrated varying degrees of efficacy in the treatment of diabetic retinopathy. The use of somatostatin analogues such as octreotide has shown promise (see Grant, M. and Caballero, S. Drugs Today 38:783-91 (2002)), as well as the administration of aminoguanidine. See Kern, T.S. and Engerman, R.L., Diabetes 50:1636-1642 (2001). Treatment with antioxidants such as vitamins E and C, selenium, and β-carotene in diabetic rats has also shown some advantageous effect. See Kowluru, R.A. et al., Diabetes 50:1938-42 (2001). The effectiveness of aspirin in inhibiting the progression of diabetic retinopathy has been controversial, but has been described in several studies as having a slight beneficial effect. See Kern and Engerman, 2001 supra. However, while these treatments inhibit the development and progression of diabetic retinopathy to some extent, they fail to more completely resolve the disease. Therefore, there remains a need to develop improved pharmacologic treatments for diabetic retinopathy. [0006] Given the evidence presented above that aspirin, a member of the class of nonsteroidal anti-inflammatory drugs (NSAIDs), is able to prevent and relieve some physiological manifestations of diabetic retinopathy, the question is raised of whether other types of anti- inflammatory drugs might have a similar effect on the development and progression of the disease. It is now recognized that many of the traditional NSAIDs are inhibitors of two cyclooxygenases, cyclooxygenase-
1 (Cox-1) and cyclooxygenase-2 (Cox-2). These two enzymes are involved in the critical initiation step of prostaglandin synthesis; the addition of molecular oxygen to arachidonic acid in the cell membrane. See Needleman, P. et al., Annu Rev Biochem, 55:69-102 (1986). [0007] 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 (prostaglandin E2) which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity, inflammation, and edema. See e.g. Samad, T.A. et al., Nature 410:471-5 (2001). Because many common NSAIDs inhibit prostaglandin synthesis by blocking the activity of both Cox-1 and Cox-2 , side effects associated with long-term administration of these drugs such as gastrointestinal bleeding and ulcers are thought to be a result of inhibiting the homeostatic functions of Cox-1 , while the inhibiton of Cox-2 accounts for their analgesic properties. [0008] Research into the area of arachidonic acid metabolism has resulted in the discovery of compounds that inhibit the Cox-2 enzyme to a greater extent than the activity of Cox-1. The Cox-2-selective inhibitors are believed to offer advantages that include the capacity to prevent or reduce inflammation while avoiding harmful side effects associated with the inhibition of Cox-1. Thus, Cox-2 selective inhibitors have shown great promise for use in therapies, especially in therapies that require maintenance administration. [0009] While the effects of Cox-2 inhibitors on inflammation and inflammation-related disorders have been relatively widely recognized, the effects of Cox-2 inhibitors on ocular diseases and disorders have not been as widely reported. Although aspirin has been described as having beneficial effects on the development of diabetic retinopathy (see Kern and Engerman, 2001 supra.), treatment with aspirin is contraindicated in diabatic patients due to the associated renal complications of the disease.
[00010] Despite the recent advances that have been made in developing pharmacologic treatments for diabetic retinopathy, it remains largely unpreventable and difficult to effectively treat. It would be useful, therefore, to provide efficacious methods and compositions for the prevention and treatment of ocular disorders and in particular, methods and compositions for the prevention and treatment of diabetic retinopathy. SUMMARY OF THE INVENTION [00011] Briefly, therefore, the present invention is directed to a novel method for the prevention and treatment of diabetes-associated ocular disorders in a subject, the method comprising administering to the subject a Cox-2 inhibitor.
[00012] The present invention is also directed to a novel method for the prevention and treatment of diabetes-associated ocular disorders in a subject, the method comprising administering to the subject a Cox-2 inhibitor in combination with one or more conventional anti-diabetic agents.
[00013] The present invention is also directed to a novel therapeutic composition for the prevention and treatment of diabetes-associated ocular disorders, the therapeutic composition comprising at least one Cox- 2 inhibitor and at least one anti-diabetic agent.
[00014] The present invention is also directed to a novel pharmaceutical composition for the prevention and treatment of diabetes-associated ocular disorders, the pharmaceutical composition comprising at least one
Cox-2 inhibitor and at least one anti-diabetic agent and a pharmaceutically-acceptable excipient.
[00015] The present invention is also directed to a novel kit that is suitable for use in the prevention and treatment of diabetes-associated ocular disorders, the kit comprising a first dosage form comprising a Cox-2 inhibitor and a second dosage comprising an anti-diabetic agent, in amounts which comprise a therapeutically effective combination of the compounds for the prevention or treatment of the diabetic retinopathy. [00016] Among the several advantages found to be achieved by the present invention, therefore, may be noted the provision of a method and compositions for the treatment of diabetes associated ocular disorders, and in particular, for diabetic retinopathy, and the provision of such method and compositions that are efficacious, safe, and easy to administer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[00017] In accordance with the present invention, it has been discovered that diabetes-related ocular disorders 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 alone or in combination with one or more conventional anti-diabetic agents.
[00018] In one embodiment of the present invention, the method comprises administering to the subject one or more Cox-2 inhibitors in an amount that constitutes a therapeutic amount. [00019] In another embodiment of the method, the Cox-2 inhibitor is administered to the subject in combination with one or more conventional anti-diabetic agents. [00020] In a preferred embodiment of the present method, the subject is administered an amount of the Cox-2 inhibitor and an amount of the anti- diabetic agent that together comprise a therapeutic amount. [00021] 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 diabetes-related ocular disorder and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
[00022] In preferred embodiments, the administration of a Cox-2 inhibitor for the prevention or treatment of diabetes-related ocular disorders is an unexpectedly effective treatment and preventative therapy.
Additionally, the administration of a Cox-2 inhibitor in combination with a conventional anti-diabetic agent for the prevention or treatment of diabetes-related ocular disorders provides a therapeutic effect that is unexpectedly superior to the therapeutic effect that would be expected based on the use of either agent alone. The administration of either a Cox-2 inhibitor alone or a Cox-2 inhibitor in combination with an anti- diabetic agent is effective for improving the symptoms of diabetes-related ocular disorders, and in preferred embodiments can avoid or reduce certain disadvantages of current treatments. [00023] As used herein, 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 conventional anti-diabetic agent, are intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended to embrace co-administration of these agents in a substantially simultaneous manner as well. Thus, the Cox-2 inhibitor and conventional anti-diabetic agent may be administered in one therapeutic dosage form, such as in a single capsule, tablet, eye drop, or injection, or in two separate therapeutic dosage forms, such as in separate capsules, tablets, eye drops, or injections.
[00024] Sequential administration of such treatments encompasses both relatively short and relatively long periods between the administration of each of the drugs of the present method. However, for purposes of the present invention, the second drug is administered while the first drug is still having an efficacious effect on the subject. Thus, the present invention, in one embodiment, takes advantage of the fact that the simultaneous presence of the combination of a Cox-2 inhibitor and a conventional anti-diabetic agent in a subject has a greater efficacy than the administration of either agent alone.
[00025] Preferably, the second of the two drugs is administered to the subject within the therapeutic response time of the first drug to be administered. For example, the present invention encompasses administration of a Cox-2 inhibitor to the subject and the later administration of a conventional anti-diabetic agent, as long as the anti- diabetic agent is administered to the subject while the Cox-2 inhibitor is still present in the subject at a level, which in combination with the level of the conventional anti-diabetic agent is therapeutically effective, and vice versa.
[00026] In one embodiment, the present invention encompasses a method for preventing a diabetes-related ocular disorder and, in particular, diabetic retinopathy, in a subject that is in need of such prevention, the method comprising administering to the subject a Cox-2 inhibitor alone or in combination with a conventional anti-diabetic agent.
[00027] As used herein, the term "prevention" refers to any reduction, no matter how slight, of a subject's predisposition or risk for developing a diabetes-related ocular disorder. For purposes of prevention, the subject is any subject, and preferably is a subject that is at risk for, or is predisposed to, developing a diabetes-related ocular disorder.
[00028] As used herein, 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 a diabetes-related ocular disorder. 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.
[00029] In another embodiment, the present invention encompasses a method for treating a diabetes-related ocular disorder and, in particular, diabetic retinopathy, in a subject that is in need of such treatment, the method comprising administering to the subject a Cox-2 inhibitor alone or in combination with a conventional anti-diabetic agent.
[00030] The terms "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. The term "treatment" includes alleviation of, or elimination of causation of, symptoms associated with any of the diseases or disorders described herein. In the context of this invention, the symptoms are those associated with diabetes-related ocular disorders such as, but not limited to, diabetic retinopathy. For example, a subject suffering from diabetic retinopathy may develop glaucoma, macular degeneration, or detached retina as a result of the retinopathy. Therefore, the method of the present invention is efficacious in preventing or treating associated ocular disorders which may develop from the progression of the underlying diabetic retinopathy. [00031] The term "subject" for purposes of treatment includes any vertebrate. Preferably, the vertebrate is a human or animal subject who is in need of prevention or treatment for an optic neuropathy. The subject is typically a mammal. "Mammal", as that term is used herein, refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cattle, etc., Preferably, the mammal is a human. 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 a diabetes-related ocular disorder.
[00032] As used herein, the term "diabetes-related ocular disorder" means any disorder of the eye arising from complications associated with diabetes. These include, but are not limited to, diabetic retinopathy, glaucoma, macular degeneration, and detached retina. In particular, the term "diabetes-related ocular disorder" includes diabetic retinopathy. [00033] A component of the present invention is a Cox-2 inhibitor. The terms "cyclooxygenase-2 inhibitor", or "Cox-2 inhibitor", which can be used interchangeably herein, embrace compounds which inhibit the Cox-2 enzyme regardless of the degree of inhibition of the Cox-1 enzyme, and include pharmaceutically acceptable salts of those compounds. Thus, for purposes of the present invention, a compound is considered a Cox-2 inhibitor irrespective of whether the compound inhibits the Cox-2 enzyme to an equal, greater, or lesser, degree than the Cox-1 enzyme.
[00034] In one embodiment of the present invention, it is preferred that the Cox-2 inhibitor compound is a non-steroidal anti-inflammatory drug (NSAID). Therefore, preferred materials that can serve as the Cox-2 inhibitor of the present invention include non-steroidal anti-inflammatory drug compounds, a pharmaceutically acceptable salt thereof, or a pure (-) or (+) optical isomeric form thereof.
[00035] Examples of NSAID compounds that are useful in the present invention include acemetacin, acetyl salicylic acid, alclofenac, alminoprofen, azapropazone, benorylate, benoxaprofen, bucloxic acid, carprofen, choline magnesium trisalicylate, clidanac, clopinac, dapsone, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, fenbufen, fenclofenec, fentiazac, floctafenine, flufenisal, flurbiprofen, (r)-flurbiprofen, (s)-flurbiprofen, furofenac, feprazone, flufenamic acid, fluprofen, ibufenac, ibuprofen, indometacin, indomethacin, indoprofen, isoxepac, isoxicam, ketoprofen, ketorolac, miroprofen, piroxicam, meloxicam, mefenamic, mefenamic acid, meclofenamic acid, meclofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxipinac, oxyphenbutazone, phenylbutazone, podophyllotoxin derivatives, proglumetacin, piprofen, pirprofen, prapoprofen, salicylic acid, salicylate, sudoxicam, suprofen, sulindac, tenoxicam, tiaprofenic acid, tiopinac, tioxaprofen, tolfenamic acid, tolmetin, zidometacin, zomepirac, and 2-fluoro-a-methyl[1 ,1'-biphenyl]-4-acetic acid, 4-(nitrooxy)butyl ester.
[00036] In a preferred embodiment, the Cox-2 inhibitor is a Cox-2 selective inhibitor. The term "Cox-2 selective inhibitor" embraces compounds which selectively inhibit the Cox-2 enzyme over the Cox-1 enzyme, and also include pharmaceutically acceptable salts and prodrugs of those compounds.
[00037] In practice, the selectivity of a Cox-2 inhibitor varies depending upon the condition under which the test is performed and on the inhibitors being tested. However, for the purposes of this specification, the selectivity of a Cox-2 inhibitor can be measured as a ratio of the in vitro or in vivo IC5o value for inhibition of Cox-1 , divided by the IC50 value for inhibition of Cox-2 (Cox-1 IC50/Cox-2 IC50). A Cox-2 selective inhibitor is any inhibitor for which the ratio of Cox-1 IC50 to Cox-2 IC50 is greater than 1. In preferred embodiments, this ratio is greater than 2, more preferably greater than 5, yet more preferably greater than 10, still more preferably greater than 50, and more preferably still greater than 100.
[00038] As used herein, the term "IC50" refers to the concentration of a compound that is required to produce 50% inhibition of cyclooxygenase activity. Preferred Cox-2 selective inhibitors of the present invention have a Cox-2 IC50 of less than about 1 μM, more preferred of less than about 0.5 μM, and even more preferred of less than about 0.2 μM.
[00039] Preferred Cox-2 selective inhibitors have a Cox-1 IC50 of greater than about 1 μM, and more preferably of greater than 20 μM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects. [00040] Also included within the scope of the present invention are compounds that act as prodrugs of Cox-2-selective inhibitors. As used herein in reference to Cox-2 selective inhibitors, the term "prodrug" refers to a chemical compound that can be converted into an active Cox-2 selective inhibitor by metabolic or simple chemical processes within the body of the subject. One example of a prodrug for a Cox-2 selective inhibitor is parecoxib, which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib. An example of a preferred 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. [00041] 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.
Figure imgf000012_0001
[00042] In another embodiment of the invention the Cox-2 selective inhibitor can be the Cox-2 selective inhibitor RS 57067, 6-[[5-(4- chlorobenzoyl)-1 ,4-dimethyl-1 H-pyrrol-2-yl]methyl]-3(2H)-pyridazinone, Formula B-2 (CAS registry number 179382-91-3), or a pharmaceutically acceptable salt or prodrug thereof.
Figure imgf000012_0002
[00043] As used herein, the term "alkyl", either alone or within other terms such as "haloalkyl" and "alkylsulfonyl"; embraces linear or branched radicals having one to about twenty carbon atoms. Lower alkyl radicals have one to about ten carbon atoms. The number of carbon atoms can also be expressed as "C1-C5", for example. Examples of lower alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the, like. [00044] The term "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. Examples of 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.
[00045] The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds, such radicals preferably containing 2 to about 6 carbon atoms, more preferably from 2 to about 3 carbon atoms. The alkynyl radicals may be optionally substituted with groups such as described below. Examples of suitable alkynyl radicals include ethynyl, proynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3- methylbutyn-1-yl, hexyi-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals, and the like. [00046] The term "oxo" means a single double-bonded oxygen.
[00047] The terms "hydrido", "-H", or "hydrogen", denote a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical, or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH2 -) radical. [00048] The term "halo" means halogens such as fluorine, chlorine, and bromine or iodine atoms. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have a bromo, chloro, or a fluoro atom within the radical. Dihalo alkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. [00049] The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
[00050] The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and 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. Examples of "alkoxy" radicals include methoxy, butoxy, and trifluoromethoxy. [00051] The term "aryl", whether used alone or with other terms, means a carbocyclic aromatic system containing one, two, or three rings wherein such rings may be attached together in a pendent manner, or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane, and biphenyl. The term "heterocyclyl" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms are replaced by N, S, P, or O. This includes, for example, structures such as:
Figure imgf000014_0001
where Z, Z1, Z2, or Z3 is C, S, P, O, or N, with the proviso that one of Z, Z1, Z2, or Z3 is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z1, Z2, or Z3 only when each is C. The term "heterocycle" also includes fully saturated ring structures, such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others. [00052] The term "heteroaryl" embraces unsaturated heterocyclic radicals. Examples of 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.
[00053] The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2- "Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. The term "arylsulfonyl" embraces sulfonyl radicals substituted with an aryl radical. The term "aminosulfonyl"denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide
Figure imgf000015_0001
[00054] The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -C02-H. The term
"carboxyalkyl" embraces radicals having a carboxyradical as defined above, attached to an alkyl radical. The term "carbonyl", whether used alone or with other terms, such as "alkylcarbonyl", denotes - (C=0) -. The term "alkylcarbonyl", embraces radicals having a carbonyl radical substituted with an alkyl radical. An example of an "alkylcarbonyl" radical is CH3 - (CO) -. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl (C=0) radical. Examples of such "alkoxycarbonyl" radicals include (CH3)3-C-O-C=0) - and - (0=)C- OCH3. The term "amino", whether used alone or with other terms, such as "aminocarbonyl", denotes
-NH2. [00055] The term "heterocycloalkyl" embraces heterocyclic-substituted alkyl radicals such as pyridylmethyl and thienylmethyl. The terms "aralkyl", or "arylalkyl" embrace aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable. The term "cycloalkyl" embraces radicals having three to ten carbon atoms, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" embraces unsaturated radicals having three to ten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
[00056] The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of "alkylthio" is methylthio, (CH3 -S-). The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(-O) - atom.
The term "acyl", whether used alone, or within a term such as "acylamino", denotes a radical provided by the residue after removal of hydroxyl from an organic acid. [00057] The term "cyano", used either alone or with other terms, such as "cyanoalkyl", refers to C≡N. The term "nitro" denotes -NO2.
[00058] In one embodiment of the invention the Cox-2 selective inhibitor is of the chromene/chroman structural class, which encompasses substituted benzopyrans or substituted benzopyran analogs, as well as substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes having the structure of any one of the general Formulas I, II, III, IV, V, and
VI, shown below, and including, by way of non-limiting example, the structures disclosed in Table 1 , and the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof. [00059] 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:
Figure imgf000017_0001
wherein X1 is selected from O, S, CRC Rb and NRa ; wherein Ra is selected from hydrido, Ci -C3 -alkyl, (optionally substituted phenyl)-Cι -C3 -alkyl, acyl and carboxy-Ci -C6 -alkyl; wherein each of Rb and Rc is independently selected from hydrido, C-i -C3 -alkyl, phenyl-Ci -C3 -alkyl, Ci -C3 -perfluoroalkyl, chloro, Ci -CQ - alkylthio, Ci -Cε -alkoxy, nitro, cyano and cyano-Ci -C3 -alkyl; or wherein CRb Rc forms a 3-6 membered cycloalkyl ring; wherein R1 is selected from carboxyl, aminocarbonyl, Ci -Cβ - alkylsulfonylaminocarbonyl and Ci -Cβ -alkoxycarbonyl; wherein R2 is selected from hydrido, phenyl, thienyl, Ci -C6 -alkyl and C2 -CQ -alkenyl; wherein R3 is selected from Ci -C3 -perfluoroalkyl, chloro, Ci -C6 - alkylthio, Ci -Cβ -alkoxy, nitro, cyano and cyano-Ci -C3 -alkyl; wherein R4 is one or more radicals independently selected from hydrido, halo, Ci -C6 -alkyl, C2 -C6 -alkenyl, C2 -C6 -alkynyl, halo-C2 -C6 - alkynyl, aryl-Ci -C3 -alkyl, aryl-C2 -CΘ -alkynyl, aryl-C2 -C6 -alkenyl, Ci - Os -alkoxy, methylenedioxy, Ci -Cε -alkylthio, Ci -CQ -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Ci -C6 -alkoxy-C1 -C6 -alkyl, aryl-Ci -C& -alkyloxy, heteroaryl-Ci -Cβ -alkyloxy, aryl-Ci -C6 -alkoxy-Ci -C6 -alkyl, Ci -C6 -haloalkyl, Ci -C6 -haloalkoxy, Ci -C6 -haloalkylthio, Ci -Ce -haloalkylsulfinyl, Ci -Cβ -haloalkylsulfonyl, Ci -C3 -(haloalkyl-i - C3 -hydroxyalkyl, Ci -C6 -hydroxyalkyl, hydroxyimino-Ci -C6 -alkyl, Ci - Ce -alkylamino, arylamino, aryl-Ci -C6 -alkylamino, heteroarylamino, heteroaryl-Ci -Cβ -alkylamino, nitro, cyano, amino, aminosulfonyl, Ci -CQ -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-Ci - C6 -alkylaminosulfonyl, heteroaryl-Ci -C6 -alkylaminosulfonyl, heterocyclylsulfonyl, Ci -C6 -alkylsulfonyl, aryl-Ci -C6 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-Ci -CQ - alkylcarbonyl, heteroaryl-Ci -C6 -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, Ci -Ci -alkoxycarbonyl, formyl, Ci -C6 - haloalkylcarbonyl and C-i -C6 -alkylcarbonyl; and wherein the A ring atoms A1 , A2, A3 and A4 are independently selected from carbon and nitrogen with the proviso that at least two of A1, A2, A3 and A4 are carbon; or wherein R4 together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.
[00060] Another class of benzopyran derivatives that can serve as the
Cox-2 selective inhibitor of the present invention includes compounds having the structure of formula II:
Figure imgf000018_0001
wherein X2 is selected from O, S, CRC Rb and NRa ; wherein Ra is selected from hydrido, Ci -C3 -alkyl, (optionally substituted phenyl)-Cι -C3 -alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-Ci -Cβ -alkyl; wherein each of Rb and Rc is independently selected from hydrido, Ci -C3
-alkyl, phenyl-Ci -C3 -alkyl, Ci -C3 -perfluoroalkyl, chloro, Ci -C6 - alkylthio, Ci -C6 -alkoxy, nitro, cyano and cyano-Ci -C3 -alkyl; or wherein CRC Rb form a cyclopropyl ring; wherein R5 is selected from carboxyl, aminocarbonyl, Ci -Cβ - alkylsulfonylaminocarbonyl and Ci -CQ -alkoxycarbonyl; wherein R6 is selected from hydrido, phenyl, thienyl, C2 -Cβ -alkynyl and C2 -C6 -alkenyl; wherein R7 is selected from Ci -C3 -perfluoroalkyl, chloro, Ci -C6 - alkylthio, Ci -C6 -alkoxy, nitro, cyano and cyano-Ci -C3 -alkyl; wherein R8 is one or more radicals independently selected from hydrido, halo, Ci -C6 -alkyl, C2 -C6 -alkenyl, C2 -C6 -alkynyl, halo-C2 -C6 - alkynyl, aryl-Ci -C3 -alkyl, aryl-C2 -Cβ -alkynyl, aryl-C2 -CQ -alkenyl, Ci - Cβ -alkoxy, methylenedioxy, Ci -CQ -alkylthio, Ci -CQ -alkylsulfinyl, — 0(CF2)2 O — , aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Ci -Cβ -alkoxy- Ci -C6 -alkyl, aryl-Ci -CQ -alkyloxy, heteroaryl-Ci -CQ -alkyloxy, aryl-Ci -
C6 -alkoxy-Ci -C6 -alkyl, Ci -C6 -haloalkyl, Ci -C6 -haloalkoxy, Ci -C6 - haloalkylthio, Ci -C6 -haloalkylsulfinyl, Ci -C6 -haloalkylsulfonyl, Ci -C3 - (haloalkyl-Ci -C3 -hydroxyalkyl), Ci -C6 -hydroxyalkyl, hydroxyimino-Ci - C6 -alkyl, Ci -C6 -alkylamino, arylamino, aryl-Ci -Cβ -alkylamino, heteroarylamino, heteroaryl-Ci -C6 -alkylamino, nitro, cyano, amino, aminosulfonyl, Ci -Cβ -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-Ci -C6 -alkylaminosulfonyl, heteroaryl-Ci - C6 -alkylaminosulfonyl, heterocyclylsulfonyl, Ci -C6 -alkylsulfonyl, aryl-Ci -C6 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-Ci -C6 -alkylcarbonyl, heteroaryl-Ci -C6 -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, Ci -Cβ -alkoxycarbonyl, formyl, Ci -C6 -haloalkylcarbonyl and Ci -C6 -alkylcarbonyl; and wherein the D ring atoms D1, D2, D3 and D4 are independently selected from carbon and nitrogen with the proviso that at least two of D1, D2, D3 and D4 are carbon; or wherein R8 together with ring D forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.
[00061] Other benzopyran Cox-2 selective inhibitors useful in the practice of the present invention are described in U.S. Patent Nos.
6,034,256 and 6,077,850. The general formula for these compounds is shown in formula III:
Figure imgf000020_0001
wherein X3 is selected from the group consisting of O or S or NRa; wherein Ra is alkyl; wherein R9 is selected from the group consisting of H and aryl; wherein R10 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R11 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R12 is selected from the group consisting of one or more radicals selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R12 together with ring E forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof; and including the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof. [00062] A related class of compounds useful as Cox-2 selective inhibitors in the present invention is described by Formulas IV and V below:
Figure imgf000021_0001
wherein X4 is selected from O or S or NRa ; wherein Ra is alkyl; wherein R13 is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R14 is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R15 is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R15 together with ring G forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [00063] Formula V is:
Figure imgf000021_0002
wherein:
X5 is selected from the group consisting of O or S or NRb; Rb is alkyl;
R16 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
R17 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
R18 is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R18 together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
[00064] The Cox-2 selective inhibitor may also be a compound of Formula V, wherein:
X5 is selected from the group consisting of oxygen and sulfur;
R16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
R17 is selected from the group consisting of lower haloalkyl, lower cycloalkyl and phenyl; and
R18 is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5- membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R18 together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [00065] The Cox-2 selective inhibitor may also be a compound of
Formula V, wherein:
X5 is selected from the group consisting of oxygen and sulfur;
R16 is carboxyl;
R17 is lower haloalkyl; and R18 is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen- containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R18 together with ring
A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
[00066] The Cox-2 selective inhibitor may also be a compound of Formula V, wherein:
X5 is selected from the group consisting of oxygen and sulfur;
R16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
R17 is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; and
R18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, terf-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N- dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl, N- phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro, N,N- dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N- ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N,N-dimethylaminosulfonyl,
N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or wherein R2 together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
[00067] The Cox-2 selective inhibitor may also be a compound of
Formula V, wherein:
X5 is selected from the group consisting of oxygen and sulfur;
R16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
R17 is selected from the group consisting trifluoromethyl and pentafluoroethyl; and
R18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, ferf-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 R18 together with ring A forms a naphthyl radical; or an isomer or prodrug thereof.
[00068] The Cox-2 selective inhibitor of the present invention can also be a compound having the structure of Formula VI:
Figure imgf000024_0001
wherein:
X6 is selected from the group consisting of O and S;
R19 is lower haloalkyl; R20 is selected from the group consisting of hydrido, and halo;
R21 is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, and 6- membered nitrogen-containing heterocyclosulfonyl;
R22 is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy, and aryl; and
R23 is selected from the group consisting of the group consisting of hydrido, halo, lower alkyl, lower alkoxy, and aryl; or an isomer or prodrug thereof.
[00069] The Cox-2 selective inhibitor can also be a compound of having the structure of Formula VI, wherein:
X6 is selected from the group consisting of O and S; R19 is selected from the group consisting of trifluoromethyl and pentafluoroethyl;
R20 is selected from the group consisting of hydrido, chloro, and fluoro;
R21 is selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, , benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosuifonyl, methylsulfonyl, and morpholinosulfonyl;
R22 is selected from the group consisting of hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl; and R23 is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl; or an isomer or prodrug thereof. Table 1. Examples of Chromene Cox-2 Selective Inhibitors
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0002
[00070] In preferred embodiments the chromene Cox-2 inhibitor is selected from (S)-6-chloro-7-(1 ,1-dimethylethyl)-2-(trifluoromethyl)-2H-1- benzopyran-3-carboxylic acid, (2S)-6,8-dimethyl-2-(trifluoromethyl)-2H- chromene-3-carboxylic acid, (2S)-6-chloro-8-methyl-2-(trifluoromethyl)-2H- chromene-3-carboxylic acid, (2S)-8-ethyl-6-(trifluoromethoxy)-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6,8-dichloro-2- (trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid, (2S)-6-chloro-5,7- dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and mixtures thereof. [00071] In a preferred embodiment of the invention the Cox-2 inhibitor can be selected from the class of tricyclic Cox-2 selective inhibitors represented by the general structure of formula VII:
Figure imgf000031_0001
wherein: Z1 is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; 24
R is selected from the group consisting of heterocyclyl, cycloalkyl, 24 cycloalkenyl and aryl, wherein R is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; 25
R is selected from the group consisting of methyl or amino; and 26
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, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N- arylaminocarbonyl, N-alkyl-N- arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N- arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl- N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N- arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; or a prodrug thereof.
[00072] In a preferred embodiment of the invention 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.
[00073] Additional information about selected examples of the Cox-2 selective inhibitors discussed above can be found as follows: celecoxib (CAS RN 169590-42-5, C-2779, SC-58653, and in U.S. Patent No.
5,466,823); deracoxib (CAS RN 169590-41-4); rofecoxib (CAS RN 162011-90-7); compound B-24 (U.S. Patent No. 5,840,924); compound B- 26 (WO 00/25779); and etoricoxib (CAS RN 202409-33-4, MK-663, SC- 86218, and in WO 98/03484).
Table 2. Examples of Tricyclic COX-2 Selective Inhibitors
Figure imgf000034_0001
Figure imgf000035_0001
[00074] In a more preferred embodiment of the invention, the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib. [00075] In a preferred embodiment, parecoxib (See, U.S. Patent No. 5,932,598), having the structure shown in B-27, and which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib, B-22, (See, U.S. Patent No. 5,633,272), may be advantageously employed as the Cox-2 inhibitor of the present invention.
Figure imgf000036_0001
[00076] A preferred form of parecoxib is sodium parecoxib. [00077] 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.
Figure imgf000036_0002
B-28
[00078] In a further embodiment of the invention, the Cox-2 inhibitor can be selected from the class of phenylacetic acid derivative Cox-2 selective inhibitors represented by the general structure of formula VIII:
Figure imgf000037_0001
wherein:
R27 is methyl, ethyl, or propyl;
R28 is chloro or fluoro;
R29 is hydrogen, fluoro, or methyl;
R30 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxyl;
R31 is hydrogen, fluoro, or methyl; and
R32 is chloro, fluoro, trifluoromethyl, methyl, or ethyl, provided that R28, R29, R30 and R31 are not all fluoro when R27 is ethyl and
R30 is H.
[00079] 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:
R27 is ethyl;
R28 and R30 are chloro;
R29 and R31 are hydrogen; and
R32 is methyl.
[00080] Another phenylacetic acid derivative Cox-2 selective inhibitor is a compound that has the structure shown in formula VIII, wherein:
R27 is propyl;
R ι2'80 and R )3ύ0U are chloro; R29 and R31 are methyl; and
R32 is ethyl.
[00081] Another phenylacetic acid derivative Cox-2 selective inhibitor that is disclosed in WO 02/20090 is a compound that is referred to as
COX-189 (also termed lumiracoxib; CAS Reg. No. 220991-20-8), having the structure shown in formula VIII, wherein:
R27 is methyl;
R28 is fluoro;
R32 is chloro; and
R29, R30, and R31 are hydrogen.
[00082] Compounds having a structure similar to that shown in formula
VIII, that can serve as the Cox-2 selective inhibitor of the present invention, are described in U.S. Patent Nos. 6,451 ,858, 6,310,099,
6,291 ,523, and 5,958,978.
[00083] Other Cox-2 selective inhibitors that can be used in the present invention have the general structure shown in formula IX, where the J group is a carbocycle or a heterocycle. Preferred embodiments have the structure:
Figure imgf000038_0001
wherein:
X7 is O; J is 1 -phenyl; R33 is 2-NHS02CH3; R34 is 4-N02; and there is no
R35 group, (nimesulide), or
X7 is O; J is 1-oxo-inden-5-yl; R33 is 2-F; R34 is 4-F; and R35 is 6-
NHS02CH3, (flosulide); or X7 is O; J is cyclohexyl; R33 is 2-NHS02CH3; R34 is 5-N02; and there is no
R35 group, (NS-398); or
X7 is S; J is 1-oxo-inden-5-yl; R33 is 2-F; R34 is 4-F; and R35 is 6-N"S02CH3
• Na+, (L-745337); or
X7 is S; J is thiophen-2-yl; R33 is 4-F; there is no R34 group; and R35 is 5-
NHS02CH3, (RWJ-63556); or
X7 is O; J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)furan-(5H)-3-yl; R33 is
3-F; R34 is 4-F; and R35 is 4-(p-S02CH3)C6H4, (L-784512).
[00084] The Cox-2 selective inhibitor NS-398, also known as N-(2- cyclohexyloxynitrophenyl) methane sulfonamide (CAS RN 123653-11-2), having a structure as shown below in formula B-29, has been described in, for example, Yoshimi, N. et al., in Japanese J. Cancer Res., 90(4):406 -
412 (1999).
Figure imgf000039_0001
[00085] An evaluation of the anti-inflammatory activity of the Cox-2 selective inhibitor, RWJ 63556, in a canine model of inflammation, was described by Kirchner et al., in J Pharmacol Exp Ther282, 1094-1101 (1997).
[00086] Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylmethylidenefuran derivatives that are described in U.S. Patent No. 6,180,651. Such diarylmethylidenefuran derivatives have the general formula shown below in formula X:
Figure imgf000040_0001
wherein: the rings T and M independently are a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms; at least one of the substituents Q1, Q2, L1 or L2 is an — S(0)n — R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an -S02NH2 group; and is located in the para position, the others independently being a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower O-alkyl radical having 1 to 6 carbon atoms, or Q1 and Q2 or L1 and L2 are a methylenedioxy group; and
R36, R37, R38 and R39 independently are a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or, R36, R37 or R38, R39 are an oxygen atom; or R36, R37 or R38, R39, together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms; or an isomer or prodrug thereof. [00087] 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) methyljbenzenesulfonamide.
[00088] Other Cox-2 selective inhibitors that are useful in the present invention include darbufelone (Pfizer), CS-502 (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516 (Servier), SD 8381 (Pharmacia, described in U.S. Patent No. 6,034,256), BMS-347070 (Bristol Myers Squibb, described in U.S. Patent No.
6,180,651), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1367 (Chiroscience), L-748731 (Merck), CT3 (Atlantic Pharmaceutical), CGP- 28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), 6-dioxo-9H-purin-8-yl-cinnamic acid (Glaxo Wellcome), and S-2474 (Shionogi).
[00089] 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. [00090] Conjugated linoleic, as described in U.S. Patent No. 6,077,868, is useful as a Cox-2 selective inhibitor in the present invention. [00091] 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:
Figure imgf000042_0001
wherein:
Z2 is an oxygen atom; one of R40 and R41 is a group of the formula
Figure imgf000042_0002
wherein:
R43 is lower alkyl, amino or lower alkylamino; and
R44, R45, R46 and R47 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxyl or amino, provided that at least one of R44, R45, R46 and R47 is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and
R30 is a lower alkyl or a halogenated lower alkyl, and a pharmaceutically acceptable salt thereof.
[00092] 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:
Figure imgf000043_0001
wherein:
Z3 is selected from the group consisting of linear or branched Ci -Cβ alkyl, linear or branched Ci -C6 alkoxy, unsubstituted, mono-, di- or tri- substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, Ci -C3 alkoxy, CN, Ci -C3 fluoroalkyl Ci -C3 alkyl, and -C02 H;
R48 is selected from the group consisting of NH2 and CH3,
R49 is selected from the group consisting of Ci -Cβ alkyl unsubstituted or substituted with C3 -Cβ cycloalkyl, and C3 -Cβ cycloalkyl;
R50 is selected from the group consisting of:
Ci -Cβ alkyl unsubstituted or substituted with one, two or three fluoro atoms, and C3 -C6 cycloalkyl; with the proviso that R49 and R50 are not the same.
[00093] Pyridines that are described in U.S. Patent Nos. 6,596,736,
6,369,275, 6,127,545, 6,130,334, 6,204,387, 6,071 ,936, 6,001 ,843 and
6,040,450, and can seve as Cox-2 selective inhibitors of the present invention, have the general formula described by formula XIII:
Figure imgf000044_0001
wherein:
R51 is selected from the group consisting of CH3, NH2, NHC(0)CF3, and
NHCH3;
Z4 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 -C6 alkoxy, Ci -C6 alkylthio, CN, Ci -C6 alkyl, Ci -C6 fluoroalkyl, N3, -C02R53, hydroxyl, -C(R54)(R55)— OH, - d -C6 alkyl-
C02— R56, Ci -C6 fluoroalkoxy;
R52 is chosen from the group consisting of: halo, Ci -Cβ alkoxy, Ci -C6 alkylthio, CN, Ci -C6 alkyl, Ci -C6 fluoroalkyl, N3, — C02R57, hydroxyl, —
C(R58)(R59)— OH, — Ci -C6 alkyl-C02— R60, Ci -C6 fluoroalkoxy, N02,
NR61R62, and NHCOR63;
R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, and R63, are each independently chosen from the group consisting of hydrogen andCi -Cβ alkyl; or R54 and R55, R58 and R59, or R61 and R62 together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6, or 7 atoms.
[00094] Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylbenzopyran derivatives that are described in U.S. Patent No. 6,340,694. Such diarylbenzopyran derivatives have the general formula shown below in formula XIV:
Figure imgf000045_0001
wherein:
X8 is an oxygen atom or a sulfur atom;
R64 and R65, identical to or different from each other, are independently a hydrogen atom, a halogen atom, a Ci -Cβ lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a nitro group, a nitrile group, or a carboxyl group;
R66 is a group of a formula: S(O)nR68 wherein n is an integer of 0~2, R68 is a hydrogen atom, a Ci -Cβ lower alkyl group, or a group of a formula: NR69
R70 wherein R69 and R70, identical to or different from each other, are independently a hydrogen atom, or a Ci -Cβ lower alkyl group; and
R67 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a Ci -C6 lower alkyl group, indanyl, pyrazinyl, or a substituted group represented by the following structures:
Figure imgf000046_0002
wherein:
R71 through R75, identical to or different from one another, are independently a hydrogen atom, a halogen atom, a Ci -C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a group of a formula: S(0)nR68, a group of a formula: NR69 R70, a trifluoromethoxy group, a nitrile group a carboxyl group, an acetyl group, or a formyl group, wherein n, R68, R69 and R70 have the same meaning as defined by R66 above; and
R76 is a hydrogen atom, a halogen atom, a Ci -C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a trifluoromethoxy group, a carboxyl group, or an acetyl group.
[00095] 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:
Figure imgf000047_0001
wherein:
X9 is selected from the group consisting of Ci -Cβ trihalomethyl, preferably trifluoromethyl; Ci -Cβ alkyl; and an optionally substituted or di-substituted phenyl group of formula XVI:
Figure imgf000047_0002
wherein:
R77 and R78 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; Ci -Cβ alkyl, preferably Ci -C3 alkyl; Ci -Cβ alkoxy, preferably Ci - C3 alkoxy; carboxy; Ci -Cβ trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano; Z5 is selected from the group consisting of substituted and unsubstituted aryl.
[00096] Compounds useful as Cox-2 selective inhibitors of the present invention include heterocycles that are described in U.S. Patent No.
6,153,787. Such heterocycles have the general formulas shown below in formulas XVII and XVIII:
Figure imgf000048_0001
wherein:
R79 is a mono-, di-, or tri-substituted Ci -Cι2 alkyl, or a mono-, or an unsubstituted or mono-, di- or tri-substituted linear or branched C2 -C10 alkenyl, or an unsubstituted or mono-, di- or tri-substituted linear or branched C2 -Cιo alkynyl, or an unsubstituted or mono-, di- or tri- substituted C3 -Cι2 cycloalkenyl, or an unsubstituted or mono-, di- or tri- substituted C5 -Cι2 cycloalkynyl, wherein the substituents are chosen from the group consisting of halo selected from F, Cl, Br, and I, OH, CF3, C3 - Cβ cycloalkyl, =0,dioxolane, CN;
R80 is selected from the group consisting of CH3, NH2, NHC(0)CF3, and NHCH3;
R81 and R82 are independently chosen from the group consisting of hydrogen and Ci -C10 alkyl; or R81 and R82 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms. [00097] Formula XVIII is: XVIII
Figure imgf000049_0001
wherein X10 is fluoro or chloro.
[00098] 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:
Figure imgf000049_0002
or a pharmaceutically acceptable salt thereof, wherein:
X11 is selected from the group consisting of O, S, and a bond; n is 0 or 1 ; R83 is selected from the group consisting of CH3, NH2, and NHC(0)CF3;
R84 is chosen from the group consisting of halo, Ci -C6 alkoxy, Ci -C6 alkylthio, CN, Ci -C6 alkyl, Ci -C6 fluoroalkyl, N3, — C02 R92, hydroxyl, —
C(R93)(R94)— OH, — Ci -C6 alkyl-C02 — R95, Ci -C6 fluoroalkoxy, N02,
NR96 R97, and NHCOR98;
R85 to R89 are independently chosen from the group consisting of hydrogen and Ci -C6 alkyl; or R85 and R89, or R89 and R90 together with the atoms to which they are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R85 and R87 are joined to form a bond.
[00099] 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:
Figure imgf000050_0001
and pharmaceutically acceptable salts thereof wherein: — A5=A6 — A7=A8 — is selected from the group consisting of:
(a) — CH=CH— CH=CH— ,
(b) — CH2 — CH2 — CH2 — C(O)— , — CH2 — CH2 — C(O)— CH2 — , — CH2 — C(O)— CH2 — CH2, — C(O)— CH2 — CH2 — CH2,
(c) — CH2 — CH2 — C(O)— , — CH2 — C(O)— CH2 — , — C(O)— CH2 — CH2
(d) — CH2 — CH2 — O— C(O)— , CH2 — O— C(O)— CH2 — , — O— C(O)— CH2 — CH — , (e) — CH2 — CH2 — C(O)— O— , — CH2 — C(O)— OCH2 — , — C(O)— O— CH2 — CH2 — ,
(f) — C(R105)2 — O— C(O)— , — C(O)— 0— C(R105)2 — , — O— C(O)— C(R105)2 — , — C(R105)2 — C(O)— O— , (g) _N=CH— CH=CH— ,
(h) _CH=N— CH=CH— ,
(i) — CH=CH— N=CH— ,
G) — CH=CH— CH=N— ,
(k) _N=CH— CH=N— , (I) — N=CH— N=CH— ,
(m) — CH=N— CH=N— ,
(n) — S— CH=N— ,
(o) — S— N=CH— ,
(p) — N=N— NH— , (q) — CH=N— S— , and
(r) — N=CH— S— ;
R99 is selected from the group consisting of S(0)2CH3, S(0)2NH2,
S(0)2NHCOCF3, S(0)(NH)CH3, S(0)(NH)NH2, S(0)(NH)NHCOCF3,
P(0)(CH3)OH, and P(0)(CH3)NH2; R100 is selected from the group consisting of:
(a) Ci -C6 alkyl,
(b) C3 -C7 cycloalkyl,
(c) mono- or di-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of: (1) hydrogen, (2) halo, including F, Cl, Br, I, (3) Ci -C6 alkoxy, (4) Ci -C6 alkylthio, (5) CN, (6) CF3, (7) Ci -C6 alkyl, (8) N3, (9) — C02 H, (10) — CO2 —C1 -C4 alkyl, (11) — C(R103)(R104)— OH, (12) — C(R103)(R104)— O— Ci -C-4 alkyl, and (13) — Ci -C6 alkyl-C02 — R106;
(d) mono- or di-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1 , 2, or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1 , 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of: (1) hydrogen, (2) halo, including fluoro, chloro, bromo and iodo, (3) Ci -C6 alkyl, (4) Ci -C6 alkoxy, (5) Ci -C6 alkylthio, (6) CN, (7) CF3, (8) N3, (9) — C(R103)(R104)— OH, and (10) — C(R103)(R104)— O— Ci -C4 alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d); R101 and R102 are the substituents residing on any position of -A5=A6 — A7=A8 — and are selected independently from the group consisting of: (a) hydrogen,
(b) CF3,
(c) CN,
(d) Ci -C6 alkyl,
(e) — Q3 wherein Q3 is Q4, C02 H, C(R103)(R104)OH, (f) — O— Q4,
(g) — S— Q4, and
(h) optionally substituted: (1) — Ci -C5 alkyl-Q3, (2) — O— Ci -C5 alkyl-Q3, (3) — S— Ci -C5 alkyl-Q3, (4) — Ci -C3 alkyl-O— Cι-3 alkyl-Q3, (5) — Ci -C3 alkyl-S— Cι-3 alkyl-Q3, (6) — Ci -C5 alkyl-O— Q4, (7) — Ci -C5 alkyl-S— Q4, wherein the substituent resides on the alkyl chain and the substituent is Ci
-C3 alkyl, and Q3 is Q4, C02 H, C(R103)(R104)OH Q4 is C02 — Ci -C4 alkyl, tetrazolyl-5-yl, or C(R103)(R104)O— d -C4 alkyl;
R103, R104 and R105 are each independently selected from the group consisting of hydrogen and Ci -Cβ alkyl; or
R103 and R104 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 R105 groups on the same carbon form a saturated monocyclic carbon ring of 3,
4, 5, 6 or 7 atoms;
R106 is hydrogen or Ci -C6 alkyl;
R107 is hydrogen, Ci -C6 alkyl or aryl;
X7 is O, S, NR107, CO, C(R107)2, C(R107)(OH), — C(R107)=C(R107)— ; — C(R107)=N— ; or — N=C(R107)— .
[000100] 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:
Figure imgf000053_0001
wherein: R 08 is:
Figure imgf000054_0001
wherein: p is 0 to 2; m is 0 to 4; and n is 0 to 5;
X13 is 0, S, SO, S02, CO, CHCN, CH2 or C=NR113 where R113 is hydrogen, loweralkyl, hydroxyl, loweralkoxy, amino, loweralkylamino, diloweralkylamino or cyano;
R111 and R112 are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy, trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfmyl, or trifluoromethylsulfonyl;
R109 is amino, mono or diloweralkyl amino, acetamido, acetimido, ureido, formamido, or guanidino; and
R110 is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl; wherein the loweralkyl, loweralkyl containing, loweralkoxy and loweralkanoyl groups contain from 1 to 3 carbon atoms.
[000101] 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:
Figure imgf000055_0001
wherein:
R114 is hydrogen or halogen;
R115 and R116 are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or lower alkanoyloxy;
R117 is lower haloalkyl or lower alkyl;
X14 is sulfur, oxygen or NH; and
Z6 is lower alkylthio, lower alkylsulfonyl or sulfamoyl; or a pharmaceutically acceptable salt thereof.
[000102] 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:
XXIII
Figure imgf000055_0002
wherein:
X r15 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, CF3, cyano or alkoxy;
R119 and R 20, independently from one another, denote hydrogen, an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH2)n -X16; or R119 and R120, together with the N- atom, denote a 3 to 7-membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group, or a group (CH2)n — X16; X16 denotes halogen, N02, —OR121, —COR121, — C02 R121, — OC02 R121, — CN, — CONR121 OR122, — CONR121 R122, — SR121, — S(0)R121, — S(0)2 R121, — NR121 R122, — NHC(0)R121, — NHS(0)2 R121; n denotes a whole number from 0 to 6;
R123 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;
R124 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, N02, — OR121, — COR121, — C02 R121, — OC02 R121, — CN, —CONR121 OR122, —CONR121 R122, — SR121, — S(0)R121, — S(0)2 R121, — NR121 R122, — NHC(0)R121, — NHS(0)2 R121, or a polyfluoroalkyl group;
R121 and R122, 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.
[000103] 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:
Figure imgf000057_0001
or pharmaceutically acceptable salts thereof wherein: X17 — Y1 — Z7-is selected from the group consisting of:
(a) — CH2 CH2 CH2 — ,
(b) — C(0)CH2 CH2 — ,
(c) — CH2 CH2 C(O)— ,
(d) — CR129 (R129')— O— C(O)— ,
(e) — C(O)— O— CR129 (R129')— ,
(f) — CH2 — NR127 — CH2 — ,
(g) -CR129 (R129')_NR127 -C(O)-, (h) — CR128=CR128' — S— , (i) _S-CR128=CR128' -,
(j) _s_N=CH-
(k) — CH=N— S— ,
(I) — N=CR128 — O— ,
(m) — O— CR128 =N— ,
(n) — N=CR128 — NH— ,
(o) — N=CR128 — S— , and
(p) — S— CR128=N— ,
(q) -C(0)-NR127 -CR129 (R129')-, (r) — R127 N— CH=CH— provided R122 is not — S(0)2CH3, (s) — CH=CH— NR127 — provided R125 is not — S(0)2CH3; when side b is a double bond, and sides a and c are single bonds; and X17 — Y1 — Z7-is selected from the group consisting of: (a) =CH— O— CH=, and
(b) =CH— NR127 — CH=,
(c) =N— S— CH=,
(d) =CH— S— N=,
(e) =N— O— CH=, (f) =CH— O— N=,
(g) =N-S-N=, (h) =N— O— N=, when sides a and c are double bonds and side b is a single bond; R125 is selected from the group consisting of: (a) S(0)2 CH3,
(b) S(0)2 NH2,
(c) S(0)2 NHC(0)CF3,
(d) S(0)(NH)CH3,
(e) S(0)(NH)NH2, (f) S(0)(NH)NHC(0)CF3,
(g) P(0)(CH3)OH, and
(h) P(0)(CH3)NH2;
R126 is selected from the group consisting of
(a) Ci -C6 alkyl, (b) C3, C4, C5, C6, and C7, cycloalkyl,
(c) mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituent is selected from the group consisting of: (1) hydrogen, (2) halo, (3) Ci -C6 alkoxy, (4) Ci -C6 alkylthio, (5) CN, (6) CF3, (7) C-i -C6 alkyl, (8) N3, (9) -C02 H, (10) — C02 —C1 -C4 alkyl, (11) — C(R129)(R130)— OH, (12) — C(R129)(R130)— O— Ci -C4 alkyl, and (13) — Ci -C6 alkyl-C02 — R129 ;
(d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1 , 2, or 3 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 -C6 alkyl, (4) Ci -C6 alkoxy, (5) Ci -C6 alkylthio, (6) CN, (7) CF3, (8) N3, (9) — C(R129)(R130)— OH, and (10) — C(R129)(R130)— O— Ci -C4 alkyl; (e) benzoheteroaryl which includes the benzo fused analogs of (d);
R127 is selected from the group consisting of:
(a) hydrogen,
(b) CF3,
(c) CN, (d) Ci -C6 alkyl,
(e) hydroxyl Ci -C6 alkyl,
(f) — C(O)— Ci -C6 alkyl, (g) optionally substituted: (1) — C1 -C5 alkyl-Q5, (2) — Ci -C5 alkyl-O— Ci -C3 alkyl-Q5, (3) — Ci -C3 alkyl-S— Ci -C3 alkyl-Q5, (4) — Ci -C5 alkyl-O— Q5, or (5) — Ci -C5 alkyl-S— Q5, wherein the substituent resides on the alkyl and the substituent is Ci - C3 alkyl; (h) -Q5; R128 and R128 are each independently selected from the group consisting of:
(a) hydrogen,
(b) CF3,
(c) CN, (d) Ci -C6 alkyl,
(e) -Q5,
(f) -O-Q5;
(g) — S— Q5, and
(h) optionally substituted: (1) —Cι -C5 alkyl-Q5, (2) — O— Ci -C5 alkyl-Q5, (3) — S— Ci -C5 alkyl-Q5, (4) — Ci -C3 alkyl-O— Ci -C3 alkyl-Q5, (5) — Ci -C3 alkyl-S— Ci -C3 alkyl-Q5, (6) — Ci -C5 alkyl-O— Q5, (7) — Ci -C5 alkyl-S— Q5, wherein the substituent resides on the alkyl and the substituent is Ci - C3 alkyl, and R129, R129', R130, R131 and R132 are each independently selected from the group consisting of:
(a) hydrogen,
(b) Ci -C6 alkyl; or R129 and R130 or R131 and R132 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
Q5 is C02 H, C02 — Ci -C-4 alkyl, tetrazolyl-5-yl, C(R131)(R132)(OH), or
C(R131)(R132)(0— Ci -C4 alkyl); provided that when X— Y— Z is — S— CR128=CR128', then R 28 and R128' are other than CF3.
[000104] An exemplary phenyl heterocycle that is disclosed in U.S.
Patent No. 6,239,173 is 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(2H)- furanone.
[000105] Bicycliccarbonyl indole compounds such as those described in
U.S. Patent No. 6,303,628 are useful as Cox-2 selective inhibitors of the present invention. Such bicycliccarbonyl indole compounds have the formula shown below in formula XXV:
Figure imgf000061_0001
or the pharmaceutically acceptable salts thereof wherein:
A9 is Ci -C6 alkylene or — NR133 — ;
Z8 is C(=L3)R134, or S02 R135 ;
Z9 is CH or N;
Z10 and Y2 are independently selected from — CH2 — , O, S and — N— R133; m is 1 , 2 or 3; q and r are independently 0, 1 or 2; X1S is independently selected from halogen, Ci -C4 alkyl, halo-substituted Ci -C alkyl, hydroxyl, Ci -C4 alkoxy, halo-substituted Ci -C4 alkoxy, Ci - C4 alkylthio, nitro, amino, mono- or di-(Cι -C4 alkyl)amino and cyano; n is O, 1 , 2, 3 or 4; L3 is oxygen or sulfur;
R133 is hydrogen or C -C4 alkyl;
R134 is hydroxyl, Ci -C6 alkyl, halo-substituted Ci -C6 alkyl, Ci -C6 alkoxy, halo-substituted Ci -C6 alkoxy, C3 -C7 cycloalkoxy, Ci -C alkyl(C3 -C7 cycloalkoxy), — NR136 R137, Ci -C4 alkylphenyl-O— or phenyl-O— , said phenyl being optionally substituted with one to five substituents independently selected from halogen, Ci -C4 alkyl, hydroxyl, Ci -C4 alkoxy and nitro;
R135 is Ci -C6 alkyl or halo-substituted Ci -C6 alkyl; and
R136 and R137 are independently selected from hydrogen, Cι-6 alkyl and halo-substituted Ci -C6 alkyl.
[000106] 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:
Figure imgf000062_0001
or a pharmaceutically acceptable salt thereof, wherein:
A10 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; X20 is independently selected from halo, Ci -C alkyl, hydroxyl, Ci -C4 alkoxy, halo-substituted Ci -C alkyl, hydroxyl-substituted Ci -C alkyl, (Ci -C4 alkoxy)Cι -C4 alkyl, halo-substituted Ci -C4 alkoxy, amino, N-(Cι -C4 alkyl)amino, N, N-di(Cι -C4 alkyl)amino, [N-(Cι -C alkyl)amino]Cι -C alkyl, [N, N-di(Cι -C4 alkyl)amino]Cι -C alkyl, N-(Cι -C alkanoyl)amonio, N-(Cι -C4 alkyl)(Cι -C4 alkanoyl)amino, N-[(Cι -C4 alkyl)sulfonyl]amino,
N-[(halo-substituted Ci -C alkyl)sulfonyl]amino, Ci -C alkanoyl, carboxy, (Ci -C alkoxy)carbonyl, carbamoyl, [N-(Cι -C alkyl)amino]carbonyl, [N, N-di(Cι -C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (Ci -C4 alkyl)thio, (Ci -C4 alkyl)sulfinyl, (Ci -C alkyl)sulfonyl, aminosulfonyl, [N- (Ci -C4 alkyl)amino]sulfonyl and [N, N-di(Cι -C alkyl)amino]sulfonyl;
X21 is independently selected from halo, Ci -C4 alkyl, hydroxyl, Ci -C alkoxy, halo-substituted Ci -C4 alkyl, hydroxyl-substituted Ci -C4 alkyl, (Ci -C4 alkoxy)Cι -C alkyl, halo-substituted Ci -C4 alkoxy, amino, N-(Cι -C alkyl)amino, N, N-di(Cι -C4 alkyl)amino, [N-(Cι -C alkyl)amino]Cι -C4 alkyl, [N, N-di(Cι -C4 alkyl)amino]Cι -C4 alkyl, N-^ -C4 alkanoyl)amino,
N-(Cι -C4 alkyl)-N-(Cι -C4 alkanoyl) amino, N-[(C1 -C alkyl)sulfonyl]amino, N-[(halo-substituted Ci -C4 alkyl)sulfonyl]amino, Ci - C4 alkanoyl, carboxy, (Ci -C4 alkoxy)hydroxyl, cabamoyl, [N-(Cι -C4 alkyl) aminojcarbonyl, [N, N-di(Cι -C alkyl)amino]carbonyl, N-carbomoylamino, cyano, nitro, mercapto, (Ci -C4 alkyl)thio, (Ci -C4 alkyl)sulfinyl, (Ci -C4 alkyl)sulfonyl, aminosulfonyl, [N-(Cι -C4 alkyl)amino]sulfonyl and [N, N- di(Cι -C4 alkyl)amino]sulfonyl; R138 is selected from: hydrogen; straight or branched Ci -C4 alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxyl, Ci -C alkoxy, amino, N-(Cι -C4 alkyl)amino and N, N- di(Cι -C4 alkyl)amino;
C3 -C8 cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are indepently selected from halo, Ci -C4 alkyl, hydroxyl, Ci -C4 alkoxy, amino, N-(Cι -C alkyl)amino and N, N-di(Cι -C4 alkyl)amino;
C4 -C8 cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C4 alkyl, hydroxyl, Ci -C alkoxy, amino, N-(Cι -C4 alkyl)amino and N, N- di(Cι -C4 alkyl)amino; phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C4 alkyl, hydroxyl, Ci -C alkoxy, halo-substituted Ci -C alkyl, Dydroxyl-substituted Ci -C alkyl, (Ci -C4 alkoxy)Cι -C alkyl, halo-substituted Ci -C4 alkoxy, amino, N-(Cι -C4 alkyl)amino, N, N-di(Cι -C4 alkyl)amino, [N-(Cι -C4 alkyl)amino]Cι -C alkyl, [N, N-di(Ci -C4 alky aminojd -C4 alkyl, N-(Cι - C4 alkanoyl)amino, N-[Cι -C alkyl)(Cι -C alkanoyl)]amino, N-[(Cι -C4 alkyl)sulfony]amino, N-[(halo-substituted Ci -C4 alkyl)sulfonyl]amino, Ci - C alkanoyl, carboxy, (Ci -C4 alkoxy)carbonyl, carbomoyl, [N-(Cι -C4 alky)amino]carbonyl, [N, N-di(Cι -C alkyl)amino]carbonyl, cyano, nitro, , mercapto, (Ci -C4 alkyl)thio, (Ci -C4 alkyl)sulfinyl, (Ci -C4 alkyl)sulfonyl, aminosulfonyl, [N-(Cι -C alkyl)amino]sulfonyl and [N, N-di(Cι -C4 alkyl)amino]sulfonyl; and heteroaryl selected from: a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N 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 optionally substituted with one to three substituent(s) selected from X20 ; R139 and R140 are independently selected from: hydrogen; halo;
Ci -C4 alkyl; phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, Ci -C4 alkyl, hydroxyl,
Ci -C4 alkoxy, amino, N-(Cι -C4 alkyl)amino and N, N-di(Cι -C alkyl)amino; or R138 and R139 can form, together with the carbon atom to which they are attached, a C3 -C7 cycloalkyl ring; m is 0, 1 , 2, 3, 4 or 5; and n is O, 1 , 2, 3 or 4.
[000107] Compounds that may be employed as a Cox-2 selective inhibitor of the present invention include indole compounds that are described in U.S. Patent No. 6,300,363. Such indole compounds have the formula shown below in formula XXVII:
XXVII
Figure imgf000065_0001
and the pharmaceutically acceptable salts thereof, wherein: L4 is oxygen or sulfur; Y3 is a direct bond or Ci -C4 alkylidene; Q6 is:
(a) Ci -C6 alkyl or halosubstituted Ci -C6 alkyl, said alkyl being optionally substituted with up to three substituents independently selected from hydroxyl, Ci -C4 alkoxy, amino and mono- or di-( Ci -C4 alkyl)amino,
(b) C3 -C7 cycloalkyl optionally substituted with up to three substituents independently selected from hydroxyl, Ci -C4 alkyl and Ci -C4 alkoxy, (c) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to four substituents independently selected from: (c-1) halo, Ci -C4 alkyl, halosubstituted Ci -C4 alkyl, hydroxyl, Ci -C4 alkoxy, halosubstituted Ci -C4 alkoxy, S(0)m R143, S02 NH2, S02 N(Cι -C4 alkyl)2, amino, mono- or di-( Ci -C4 alkyl)amino, NHS02 R143, NHC(0)R143, CN, C02 H, C02 (Ci -C4 alkyl), Ci -C4 alkyl-OH, Ci -C4 alkyl-OR143, CONH2, CONH(Cι -C4 alkyl), CON(Cι -C4 alkyl)2 and — 0 — Y-phenyl, said phenyl being optionally substituted with one or two substituents independently selected from halo, Ci -C4 alkyl, CF3, hydroxyl, OR143, S(0)mR143, amino, mono- or di-( Ci -C4 alkyl)amino and CN;
(d) a monocyclic aromatic group of 5 atoms, said aromatic group having one heteroatom selected from O, S and N and optionally containing up to three N atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substitutents independently selected from: (d-1) halo, Ci -C4 alkyl, halosubstituted d -C4 alkyl, hydroxyl, Ci -C4 alkoxy, halosubstituted Ci -C4 alkoxy, Ci -C4 alkyl-OH, S(0)m R143, S02 NH2, S02 N(Cι -C4 alkyl)2, amino, mono- or di-( Ci -C4 alkyl)amino, NHS02 R143, NHC(0)R143, CN, C02 H, C02 (Ci -C4 alkyl), Ci -C4 alkyl-OR143, CONH2, CONH(Cι -C4 alkyl), CON(d -C4 alkyl)2, phenyl, and mono-, di- or tri-substituted phenyl wherein the substituent is independently selected from halo, CF3, Ci -C4 alkyl, hydroxyl, Ci - C4 alkoxy, OCF3, SR143, S02 CH3, S02 NH2, amino, Cι-4 alkylamino and NHS02 R143;
(e) a monocyclic aromatic group of 6 atoms, said aromatic group having one heteroatom which is N and optionally containing up to three atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substituents independently selected from the above group (d-1);
R141 is hydrogen or Ci -Cβ alkyl optionally substituted with a substituent selected independently from hydroxyl, OR143, nitro, amino, mono- or di-( d -C4 alkyl)amino, C02 H, C02 (Ci -C4 alkyl), CONH2, CONH(Cι -C4 alkyl) and CON(Cι -C alkyl)2 ; R142 is: (a) hydrogen, (b) Ci -C4 alkyl,
(c) C(0)R145, wherein R145 is selected from: (c-1) Ci -C22 alkyl or C2 -C22 alkenyl, said alkyl or alkenyl being optionally substituted with up to four substituents independently selected from: (c-1-1) halo, hydroxyl, OR143, S(0)m R143, nitro, amino, mono- or di-( d -C4 alkyl)amino, NHS02 R143, C02 H, C02 (Ci -C4 alkyl), CONH2, CONH(Cι -C4 alkyl), CON(Cι -C4 alkyl)2, OC(0)R143, thienyl, naphthyl and groups of the following formulas:
Figure imgf000068_0001
Figure imgf000068_0002
(c-2) Ci -C22 alkyl or C2 -C22 alkenyl, said alkyl or alkenyl being optionally substituted with five to forty-five halogen atoms, (c-3) -Y5— C3 -C7 cycloalkyl or -Y5— C3 -C7 cycloalkenyl, said cycloalkyl or cycloalkenyl being optionally substituted with up to three substituent independently selected from: (c-3-1) Ci -C4 alkyl, hydroxyl, OR143, S(0)m R143, amino, mono- or di- ( Ci -C4 alkyl)amino, CONH2, CONH(d -C4 alkyl) and CON(Cι -C4 alkyl)2, (c-4) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven (preferably up to seven) substituents independently selected from: (c-4-1) halo, Ci -C8 alkyl, Gj -C4 alkyl-OH, hydroxyl, Ci -C8 alkoxy, halosubstituted Ci -C8 alkyl, halosubstituted Ci -C8 alkoxy, CN, nitro, S(0)m R143, S02 NH2, S02 NH(d -C4 alkyl), S02 N(Cι -C4 alkyl)2, amino, Ci -C4 alkylamino, di-(Cι -C4 alkyl)amino, CONH2, CONH(Cι -C4 alkyl), CON(Cι -C4 alkyl)2, OC(0)R143, and phenyl optionally substituted with up to three substituents independently selected from halo, Ci -C4 alkyl, hydroxyl, OCH3, CF3, OCF3, CN, nitro, amino, mono- or di-(Cι -C4 alkyl)amino, C02 H, C02 (Ci -C4 alkyl) and CONH2, (c-5) a monocyclic aromatic group as defined in (d) and (e) above, said aromatic group being optionally substituted with up to three substituents independently selected from: (c-5-1) halo, Ci -C8 alkyl, Ci -C4 alkyl-OH, hydroxyl, Ci -C8 alkoxy, CF3, OCF3, CN, nitro, S(0)m R143, amino, mono- or di-( Ci -C4 alkyl)amino, CONH2, CONH(Cι -C4 alkyl), CON(Cι -C4 alkyl)2, C02 H and C02 (Ci -C4 alkyl), and — Y-phenyl, said phenyl being optionally substituted with up to three substituents independently selected halogen, Ci -C4 alkyl, hydroxyl, Ci -C4 alkoxy, CF3, OCF3, CN, nitro, S(0)m R143, amino, mono- or di-( Ci -C4 alkyl)amino, C02 H, C02 (Ci -C4 alkyl), CONH2, CONH(Cι -C4 alkyl) and CON(Cι -C4 alkyl)2, (c-6) a group of the following formula:
Figure imgf000069_0001
X22 is halo, Ci -C4 alkyl, hydroxyl, Ci -C4 alkoxy, halosubstitutued Ci -C4 alkoxy, S(0)m R143, amino, mono- or di-(Cι -C4 alkyl)amino, NHS02 R143, nitro, halosubstitutued Ci -C4 alkyl, CN, C02 H, C02 (Ci -C4 alkyl), Ci -C4 alkyl-OH, Ci -C4 alkylOR143, CONH2, CONH(Cι -C4 alkyl) or CON(Cι -C4 alkyl)2 ; R143 is Ci -C4 alkyl or halosubstituted Ci -C4 alkyl; m is 0, 1 or 2; n is 0, 1 , 2 or 3; p is 1 , 2, 3, 4 or 5; q is 2 or 3;
Z11 is oxygen, sulfur or NR144 ; and
R144 is hydrogen, Ci -C6 alkyl, halosubstitutued Ci -C4 alkyl or -Y5- phenyl, said phenyl being optionally substituted with up to two substituents independently selected from halo, Ci -C4 alkyl, hydroxyl, Ci -C4 alkoxy,
S(0)m R143, amino, mono- or di-(Cι -C4 alkyl)amino, CF3, OCF3, CN and nitro; with the proviso that a group of formula -Y5 — Q is not methyl or ethyl when
X22 is hydrogen;
L4 is oxygen;
R141 is hydrogen; and
R142 is acetyl.
[000108] Aryl phenylhydrazides that are described in U.S. Patent No.
6,077,869 can serve as Cox-2 selective inhibitors of the present invention.
Such aryl phenylhydrazides have the formula shown below in formula
XXVIII:
XXVIII
Figure imgf000070_0001
wherein:
X23 and Y6 are selected from hydrogen, halogen, alkyl, nitro, amino, hydroxy, methoxy and methylsulfonyl; or a pharmaceutically acceptable salt thereof,.
[000109] Materials that can serve as a Cox-2 selective inhibitor of the present invention include 2-aryloxy, 4-aryl furan-2-ones that are described in U.S. Patent No. 6,140,515. Such 2-aryloxy, 4-aryl furan-2-ones have the formula shown below in formula XXIX:
Figure imgf000071_0001
or a pharmaceutical salt thereof, wherein:
R146 is selected from the group consisting of SCH3, — S(0)2 CH3 and —
S(0)2 NH2 ;
R147 is selected from the group consisting of OR150, mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
R150 is unsubstituted or mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
R148 is H, Ci -C alkyl optionally substituted with 1 to 3 groups of F, Cl or
Br; and
R149 is H, Ci -C4 alkyl optionally substituted with 1 to 3 groups of F, Cl or
Br, with the proviso that R148 and R149 are not the same.
[000110] Materials that can serve as a Cox-2 selective inhibitor of the present invention include bisaryl compounds that are described in U.S.
Patent No. 5,994,379. Such bisaryl compounds have the formula shown below in formula XXX:
Figure imgf000072_0001
or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein:
Z13 is C or N; when Z13 is N, R151 represents H or is absent, or is taken in conjunction with R152 as described below: when Z13 is C, R151 represents H and R152 is a moiety which has the following characteristics:
(a) it is a linear chain of 3-4 atoms containing 0-2 double bonds, which can adopt an energetically stable transoid configuration and if a double bond is present, the bond is in the trans configuration,
(b) it is lipophilic except for the atom bonded directly to ring A, which is either lipophilic or non-lipophilic, and
(c) there exists an energetically stable configuration planar with ring A to within about 15 degrees; or R151 and R152 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 Ra group selected from the group consisting of: Ci -C2 alkyl, — OCι -C2 alkyl, — NHCi -C2 alkyl, —
N(Cι -C2 alkyl)2, — C(O) Ci -C2 alkyl, — S— Ci -C2 alkyl and — C(S) Ci -
C2 alkyl;
Y7 represents N, CH or C— OCι -C3 alkyl, and when Z13 is N, Y7 can also represent a carbonyl group;
R153 represents H, Br, Cl or F; and
R154 represents H or CH3.
[000111] 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:
Figure imgf000073_0001
wherein:
R155, R156, R157, and R158 are independently selected from the groups consisting of hydrogen, Ci -C5 alkyl, Ci -C5 alkoxy, phenyl, halo, hydroxyl,
Ci -C5 alkylsulfonyl, Ci -C5 alkylthio, trihaloCi -C5 alkyl, amino, nitro and
2-quinolinylmethoxy; R159 is hydrogen, Ci -C5 alkyl, trihaloCi -C5 alkyl, phenyl, substituted phenyl where the phenyl substitutents are halogen, d -C5 alkoxy, trihaloCi -C5 alkyl or nitro or R159 is heteroaryl of 5-7 ring members where at least one of the ring members is nitrogen, sulfur or oxygen; R160 is hydrogen, Ci -C5 alkyl, phenyl Ci -C5 alkyl, substituted phenyl Ci -
C5 alkyl where the phenyl substitutents are halogen, Ci -C5 alkoxy,' trihaloCi -C5 alkyl or nitro, or R160 is Ci -C5 alkoxycarbonyl, phenoxycarbonyl, substituted phenoxycarbonyl where the phenyl substitutents are halogen, Ci -C5 alkoxy, trihaloCi -C5 alkyl or nitro; R161 is Ci -C10 alkyl, substituted Ci -C10 alkyl where the substituents are halogen, trihaloCi -C5 alkyl, Ci -C5 alkoxy, carboxy, Ci -C5 alkoxycarbonyl, amino, Ci -C5 alkylamino, diCi -C5 alkylamino, diCi -C5 alkylaminoCi -C5 alkylamino, Ci -C5 alkylaminoCi -C5 alkylamino or a heterocycle containing 4-8 ring atoms where one more of the ring atoms is nitrogen, oxygen or sulfur, where said heterocycle may be optionally substituted with Ci -C5 alkyl; or R161 is phenyl, substituted phenyl (where the phenyl substitutents are one or more of Ci -C5 alkyl, halogen, Ci -C5 alkoxy, trihaloCi -C5 alkyl or nitro), or R161 is heteroaryl having 5-7 ring atoms where one or more atoms are nitrogen, oxygen or sulfur, fused heteroaryl where one or more 5-7 membered aromatic rings are fused to the heteroaryl; or
R161 is NR163 R164 where R163 and R164 are independently selected from hydrogen and C1.5 alkyl or R163 and R164 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 -C5 alkyl; R162 is hydrogen, Ci -C5 alkyl, nitro, amino, and halogen; and pharmaceutically acceptable salts thereof. [000112] Materials that can serve as a Cox-2 selective inhibitor of the present invention include 2-substituted imidazoles that are described in
U.S. Patent No. 6,040,320. Such 2-substituted imidazoles have the formula shown below in formula XXXII: R 166 165
R /
-R 167 XXXII
wherein:
R164 is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, or substituted phenyl; wherein the substituents are independently selected from one or members of the group consisting of C1.5 alkyl, halogen, nitro, trifluoromethyl and nitrile;
R165 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 -C5 alkyl and halogen, or substituted phenyl, wherein the substituents are independently selected from one or members of the group consisting of Ci -C5 alkyl, halogen, nitro, trifluoromethyl and nitrile;
R166 is hydrogen, 2-(trimethylsilyl)ethoxymethyl), Ci -C5 alkoxycarbonyl, aryloxycarbonyl, arylCi -C5 alkyloxycarbonyl, arylCi -C5 alkyl, phthalimidoCi -C5 alkyl, aminoCi -C5 alkyl, diaminoCi -C5 alkyl, succinimidoCi -C5 alkyl, Ci -C5 alkylcarbonyl, arylcarbonyl, Ci -C5 alkylcarbonylCi -C5 alkyl, aryloxycarbonylCi -C5 alkyl, heteroarylCi -C5 alkyl where the heteroaryl contains 5 to 6 ring atoms, or substituted arylCi -C5 alkyl, wherein the aryl substituents are independently selected from one or more members of the group consisting of Ci -C5 alkyl, Ci -C5 alkoxy, halogen, amino, Ci -C5 alkylamino, and diCi -C5 alkylamino;
R167 is (A11)„ -(CH1 -X24 wherein: A11 is sulfur or carbonyl; n is 0 or 1 ; q is 0-9;
X24 is selected from the group consisting of hydrogen, hydroxyl, halogen, vinyl, ethynyl, Ci -C5 alkyl, C3 -C7 cycloalkyl, Ci -C5 alkoxy, phenoxy, phenyl, arylCi -C5 alkyl, amino, Ci -C5 alkylamino, nitrile, phthalimido, amido, phenylcarbonyl, Ci -C5 alkylaminocarbonyl, phenylaminocarbonyl, arylCi -C5 alkylaminocarbonyl, Ci -C5 alkylthio, Ci -C5 alkylsulfonyl, phenylsulfonyl, substituted sulfonamido, wherein the sulfonyl substituent is selected from the group consisting of Ci
-C5 alkyl, phenyl, araCi -C5 alkyl, thienyl, furanyl, and naphthyl; substituted vinyl, wherein the substituents are independently selected from one or members of the group consisting of fluorine, bromine, chlorine and iodine, substituted ethynyl, wherein the substituents are independently selected from one or more members of the group consisting of fluorine, bromine chlorine and iodine, substituted Ci -C5 alkyl, wherein the substituents are selected from the group consisting of one or more Ci -C5 alkoxy, trihaloalkyl, phthalimido and amino, substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci -C5 alkyl, halogen and Ci -C5 alkoxy, substituted phenoxy, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci -C5 alkyl, halogen and Ci -C5 alkoxy, substituted Ci -C5 alkoxy, wherein the alkyl substituent is selected from the group consisting of phthalimido and amino, substituted arylCi -C5 alkyl, wherein the alkyl substituent is hydroxyl, substituted arylCi -C5 alkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci -C5 alkyl, halogen and Ci -C5 alkoxy, substituted amido, wherein the carbonyl substituent is selected from the group consisting of Ci -C5 alkyl, phenyl, arylCi -C5 alkyl, thienyl, furanyl, and naphthyl, substituted phenylcarbonyl, wherein the phenyl substituents are independently selected from one or members of the group consisting of Ci -C5 alkyl, halogen and Ci -C5 alkoxy, substituted Ci -C5 alkylthio, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido, substituted Ci -C5 alkylsulfonyl, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido, substituted phenylsulfonyl, wherein the phenyl substituents are independently selected from one or members of the group consisting of bromine, fluorine, chlorine, Ci -C5 alkoxy and trifluoromethyl, with the proviso: if A11 is sulfur and X24 is other than hydrogen, Ci -C5 alkylaminocarbonyl, phenylaminocarbonyl, arylCi -C5 alkylaminocarbonyl, Ci -C5 alkylsulfonyl or phenylsulfonyl, then q must be equal to or greater than 1 ; if A11 is sulfur and q is 1 , then X24 cannot be Ci -C2 alkyl; if A11 is carbonyl and q is 0, then X24 cannot be vinyl, ethynyl, Ci -C5 alkylaminocarbonyl, phenylaminocarbonyl, arylCi -C5 alkylaminocarbonyl,
Ci -C5 alkylsulfonyl or phenylsulfonyl; if A11 is carbonyl, q is 0 and X24 is H, then R 66 is not 2-
(trimethylsilyl)ethoxymethyl; if n is 0 and q is 0, then X24 cannot be hydrogen; and pharmaceutically acceptable salts thereof.
[000113] 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:
XXXIII
Figure imgf000078_0001
XXXIV
Figure imgf000079_0001
wherein:
R168 and R169 are independently selected from the group consisting of hydrogen, halogen, (Ci -C6)alkyl, (Ci -C6)alkoxy, nitro, amino, Dydroxyl, trifluoro, — S(Cι -C6)alkyl, — SO(Cι -C6)alkyl and — S02 (Ci -C6)alkyl; and the fused moiety M is a group selected from the group consisting of an optionally substituted cyclohexyl and cycloheptyl group having the formulae:
Figure imgf000079_0002
wherein:
R170 is selected from the group consisting of hydrogen, halogen, hydroxyl and carbonyl; or R170 and R171 taken together form a moiety selected from the group consisting of — OCOCH2 — , — ONH(CH3)COCH2 — , — OCOCH= and — 0-;
R171 and R172 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C6)alkyl, (Ci -
C6)alkoxy, =NOH, — NR174 R175, — OCH3, — OCH2 CH3, — OS02 NHC02 CH3, =CHC02 CH2 CH3, — CH2 C02 H, — CH2 C02 CH3, — CH2 C02 CH2 CH3, — CH2 CON(CH3)2, — CH2 C02 NHCH3, — CHCHC02 CH2 CH3, — OCON(CH3)OH, — C(COCH3)2, di(Cι -C6)alkyl and di(d -C6)alkoxy; R173 is selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (Ci -C6)alkyl, (Ci -C6)alkoxy and optionally substituted carboxyphenyl, wherein substituents on the carboxyphenyl group are selected from the group consisting of halogen, hydroxyl, amino, (Ci - C6)alkyl and (Ci -C6)alkoxy; or R172 and R173 taken together form a moiety selected from the group consisting of — O — and
Figure imgf000080_0001
R174 is selected from the group consisting of hydrogen, OH, — OCOCH3, — COCH3 and (Ci -C6)alkyl; and
R175 is selected from the group consisting of hydrogen, OH, — OCOCH3,
— COCH3, (Ci -C6)alkyl, — CONH2 and — S02 CH3 ; with the proviso that if M is a cyclohexyl group, then R 70 through R173 may not all be hydrogen; and pharmaceutically acceptable salts, esters and pro-drug forms thereof. [000114] 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:
Figure imgf000081_0001
wherein:
R176 is Ci -C6 alkyl, Ci -C6 branched alkyl, C4 -C8 cycloalkyl, Ci -C6 hydroxyalkyl, branched Ci -C6 hydroxyalkyl, hydroxyl substituted d -C8 aryl, primary, secondary or tertiary Ci -C6 alkylamino, primary, secondary or tertiary branched Ci -C6 alkylamino, primary, secondary or tertiary C4 - C8 arylamino, Ci -C6 alkylcarboxylic acid, branched Ci -C6 alkylcarboxylic acid, Ci -C6 alkylester, branched Ci -C6 alkylester, C4 -C8 aryl, C -C8 arylcarboxylic acid, C4 -C8 arylester, C -C8 aryl substituted Ci -C6 alkyl, C4 -C8 heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted or aryl-substituted C -C8 heterocyclic alkyl or aryl with O, N or S in the ring, or halo-substituted versions thereof, where halo is chloro, bromo, fluoro or iodo;
R177 is Ci -C6 alkyl, Ci ~C6 branched alkyl, C -C8 cycloalkyl, C4 -C8 aryl, C4 -C8 aryl-substituted Ci -Cβ alkyl, Ci -Cβ alkoxy, Ci -C6 branched alkoxy, C4 -C8 aryloxy, or halo-substituted versions thereof or R177 is halo where halo is chloro, fluoro, bromo, or iodo; R178 is hydrogen, Ci -C6 alkyl or Ci -Cβ branched alkyl; R179 is Ci -C6 alkyl, C4 -C8 aroyl, C4 -C8 aryl, C4 -C8 heterocyclic alkyl or aryl with O, N or S in the ring, C4 -C8 aryl-substituted Ci -C6 alkyl, alkyl- substituted or aryl-substituted C4 -C8 heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted C4 -C8 aroyl, or alkyl-substituted C4 -C8 aryl, or halo-substituted versions thereof where halo is chloro, bromo, or iodo; n is 1 , 2, 3, or 4; and
X25 is O, NH, or N— R180, where R180 is Ci -C6 or Ci -C6 branched alkyl. [000115] Materials that can serve as a Cox-2 selective inhibitor of the present invention include pyhdazinone compounds that are described in U.S. Patent No. 6,307,047. Such pyridazinone compounds have the formula shown below in formula XXXVI:
XXXVI
Figure imgf000082_0001
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:
X26 is selected from the group consisting of O, S, — NR185, — NORa, and - NNRb Rc ;
R185 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;
Ra, Rb, and Rc are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl; R181 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, — (CH2)n C(0)R186, — (CH2)n CH(OH)R186, — (CH2)π C(NORd)R186, — (CH2)n CH(NORd)R186, — (CH2)„ CH(NRd Re)R186, — R187
R188, -(CH2)n C≡CR188, -(CH2)n [CH(CX26 3)]m (CH2)P R188, -(CH2)n (CX26'2)m (CH2)P R188, and -(CH2)n (CHX26')m (CH2)m R188 ; R186 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;
R187 is selected from the group consisting of alkenylene, alkylene, halosubstituted alkenylene, and halo-substituted alkylene; R188 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
Rd and Re are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl; X26 is halogen; m is an integer from 0-5; n is an integer from 0-10; p is an integer from 0-10;
R182, R 83, and R184 are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy, alkoxyiminoalkyl, alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, aminoalkoxy, aminoaikylcarbonyloxyalkoxy aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, nitro, phosphonatoalkoxy, Y8, and Z14; provided that one of R182, R183, or R184 must be Z14, and further provided that only one of R182, R183, or R184 is Z14; Z14 is selected from the group consisting of:
Figure imgf000084_0001
X27 is selected from the group consisting of S(0)2, S(0)(NR191), S(O),
Se(0)2, P(0)(OR192), and P(0)(NR193 R194);
X28 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen; R190 is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, — NHNH2, and — NCHN(R191)R192 ;
R191, R192, R193, and R194 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R193 and R194 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 0, S, and NR188 ;
Y8 is selected from the group consisting of -OR195, — SR195, —
C(R197)(R198)R195, — C(0)R195, -C(0)OR195, -N(R197)C(0)R195, - NC(R197)R195, and — N(R197)R195 ;
R195 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkyl, and NR199 R200 ; and R197, R198, R199, and R200 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl. [000116] 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:
XXXVII
Figure imgf000085_0001
wherein:
A12 denotes oxygen, sulphur or NH;
R >201 denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted by halogen, alkyl, CF3 or alkoxy; D5 denotes a group of formula XXXVIII or XXXIX:
XXXVIII
Figure imgf000085_0002
or
XXXIX
Figure imgf000085_0003
R202 and R203 independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH2)n -X29; or R202 and R203 together with the N-atom denote a three- to seven- membered, saturated, partially or totally unsaturated heterocycle with one or more heteroatoms N, 0, or S, which may optionally be substituted by oxo, an alkyl, alkylaryl or aryl group or a group (CH2)n -X29, R202' denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH2)n -X29, wherein:
X29 denotes halogen, N02, —OR204, —COR204, — C02 R204, — OC02 R204,
— CN, —CONR204 OR205, —CONR204 R205, — SR204, — S(0)R204, — S(0)2
FT 20"4, — M NDR20W4 D R20u5o, /C
Figure imgf000086_0001
— M NUHSO(0V)I2 D R204. Z15 denotes -CH2 — , — CH2 -CH2 — , — CH2 -CH2 -CH2 — , — CH2 - CH=CH— , — CH=CH— CH2 — , — CH2 —CO—, — CO— CH2 — , —
NHCO— , — CONH— , — NHCH2 — , — CH2 NH— , — N=CH— — NHCH
— CH2-CH2— NH— , — CH=CH— , >N— R 20U3J, >C=0, >S(0) mi
R204 and R205 independently of each other denote hydrogen, alkyl, aralkyl or aryl; n is an integer from 0 to 6;
R206 is a straight-chained or branched Ci -C4 alkyl group which may optionally be mono- or polysubstituted by halogen or alkoxy, or R206 denotes CF3; and m denotes an integer from 0 to 2; with the proviso that A12 does not represent 0 if R206 denotes CF3; and the pharmaceutically acceptable salts thereof.
[000117] 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:
Figure imgf000087_0001
wherein:
R207 and R208 are respectively a hydrogen;
Ci -C4-alkyl substituted or not substituted by halogens;
C3 -C7-cycloalkyl;
Ci -Cδ-alkyl containing 1-3 ether bonds and/or an aryl substitute; substituted or not substituted phenyl; or substituted or not substituted five or six ring-cycled heteroaryl containing more than one hetero atoms selected from a group consisting of nitrogen, sulfur, and oxygen (wherein phenyl or heteroaryl can be one- or multi-substituted by a substituent selected from a group consisting of hydrogen, methyl, ethyl, and isopropyl).
[000118] Cox-2 selective inhibitors such as 1 H-indole derivatives described in U.S. Patent No. 6,599,929 are useful in the present invention.
Such 1 H-indole derivatives have the formula shown below in formula
XXXXI: XXXXI
Figure imgf000088_0001
wherein:
X30 is -NHS02R209 wherein R209 represents hydrogen or Ci -C3-alkyl;
Y9 is hydrogen, halogen, Ci —C3— alkyl substituted or not substituted by halogen, N02, NH2, OH, OMe, C02H, or CN; and
Q7 is C=0, C=S, or CH2.
[000119] Compounds that are useful as Cox-2 selective inhibitors of the present invention include prodrugs of Cox-2 inhibitors that are described in
U.S. Patent Nos. 6,436,967 and 6,613,790. Such prodrugs of Cox-2 inhibitors have the formula shown below in formula XXXXI I:
XXXXII
Figure imgf000088_0002
wherein:
A13 is a ring substituent selected from partially unsaturated heterocyclic, heteroaryl, cycloalkenyl and aryl, wherein A13 is unsubstituted or substituted with one or more radicals selected from alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocycloxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, araalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N- arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, -arylamino, N- aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N- arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl;
R210 is selected from heterocyclyl, cycloalkyl, cycloalkenyl, and aryl, wherein R210 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;
R211 is selected from hydrido and alkoxycarbonylalkyl; R212 is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, amino acid residue, and alkylcarbonylaminoalkylcarbonyl; provided A13 is not tetrazolium, or pyridinium; and further provided A13 is not indanone when R212 is alkyl or carboxyalkyl; further provided A13 is not thienyl, when R210 is 4-fluorophenyl, when R211 is hydrido, and when R212 is methyl or acyl; and R213 is hydrido; or a pharmaceutically-acceptable salt thereof.
[000120] Specific non-limiting examples of substituted sulfonamide prodrugs of Cox-2 inhibitors disclosed in U.S. Patent No. 6,436,967 that are useful in the present invention include: N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1- yljphen yl]sulfonyl]propanamide;
N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 - yljphen yljsulfonyljbutanamide; N-[[4-[1 ,5-dimethyl)-3-phenyl-1H-pyrazol-4-yl]phenyl]sulfonyl]acetamide;
N-[[4-(2-(3-pyridinyl)-4-(trifluoromethyl)-1 H-imidazol-1 - yl)phenyl]sulfonyl]acetamide;
N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1- yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1- yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yl]phenyl]sulfonyl]butanamide; N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yl]phenyl]sulfonyl]butanamide;
N-[[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1 - yl]phenyl]sulfonyl]acetamide;
N-[[4-[3-(3-fluorophenyl)-5-methylisoxazol-4-yl]phenyl]sulfonyl]acetamide; 2-methyl-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]propanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]benzamide;
2,2-dimethyl-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]propanamide;
N-[[4-5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]butanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]pentanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]hexanamide;
3-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]propanamide ;
2-ethoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide;
N-[[4-[5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide;
N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H pyrazol-1- yl]phenyl]sulfonyl]propanamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yl]phenyl]sulfonyl]butanamide; N-[[4-[5-(4-chlorophenyl)-3-(thfluoromethyl)-1 H-pyrazol-1 - yljphenyljsulfonyljacetamide;
N-[[4-[3-(difluoromethyl)-6-fluoro-1 ,5-dihydro-7-methoxy-
[2]benzothiopyrano [4,3-c]pyrazol-1-yl)phenyl]sulfonyl]acetamide; N-[[4-[6-fluoro-1 ,5-dihydro-7-methoxy-3-(trifluoromethyl)-[2]benzothiopyran o[4,3-c]pyrazol-1 -yljphenyljsulfonyljacetamide;
N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 - yljphenyljsulfonyljacetamide;
N-[[4-(2-methyl-4-phenyloxazol-5-yl)phenyl]sulfonyl]acetamide; methyl[[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyljamino]oxoacetate;
2-methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]acetamide;
N-[[4-[5-(difluoromethyl)-3-phenylisoxazol-4- yljphenyljsulfonyljpropanamide; ι
N-[[4-[5-(difluoromethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]butanamide;
N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]formamide;
1 , 1 -dimethylethyl-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyl]sulfonyl]carbamate; N-[[.sup.4 -(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine;
2-amino-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide;
2-(acetylamino)-N-[[4-(5-methyl-3-phenylisoxazol-4- yl)phenyljsulfonyl]acetamide; methyl 4-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-4- oxobutanoate; methyl N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]carbamate;
N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester;
N-[[4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yl)phenyl]sulfonyl]acetamide; methyl 3-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-3- oxopropanoate; 4-[5-(3-bromo-5-fluoro-4-methoxyphenyl)-2-(trifluoromethyl)oxazol-4-yl]-N- methylbenezenesulfonamide; N-(1 , 1 -dimethylethyl)-4-(5-methyl-3-phenylisoxazol-4- yl)benzenesulfonamide; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-N- methylbenzenesulfonamide;
N-methyl-4-(5-methyl-3-phenylisoxazol-4-yl)benezenesulfonamide; N-[[4-[5-(hydroxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide: N-[[4-[5-(acetoxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1 - yl)phenyl]sulfonyl]acetamide;
4-[2-(4-fluorophenyl)-1H-pyrrol-1-yl]-N-methylbenzenesulfonamide; N-[[4-(3,4-dimethyl-1 -phenyl-1 H-pyrazol-5-yl]phenyl]sulfonyl]propanamide; N-[[4-[2-(2-methylpyridin-3-yl)-4-trifluoromethylimidazol-1- yljphenyljsulfonyljpropanamide;
4-[2-(4-fluorophenyl)cyclopenten-1-yl]-N-methylbenezenesulfonamide; and N-[[4-(3-phenyl-2,3-dihydro-2-oxofuran-4-yl)phenyl]sulfonyl]propanamide. [000121] Those prodrugs disclosed in U.S. Patent No. 6,613,790 have the general formula shown above in formula XXXXII wherein: A13 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, alkylaminoalkyl, alkylsutfinyl, alkylsulfonyl, aminosulfonyl, and alkylaminosulfonyl; R210 is a phenyl group optionally substituted at a substitutable position with one or more radicals independently selected at each occurrence from the group consisting of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio;
R211 and R212 are independently selected from the group consisting of hydroxyalkyl and hydrido but at least one of R211 and R2 2 is other than hydrido; and
R213 is selected from the group consisting of hydrido and fluoro. [000122] Examples of prodrug compounds disclosed in U.S. 6,613,790 that are useful as Cox-2 inhibitors of the present invention include, but are not limited to, N-(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1 H-pyrazol-1- yljbenzenesulfonamide, N,N-bis(2-hydroxyethyl)-4-[5-(4- methylphenyl)-3-(trifluoromethyl)-1 H-pyraz ol-1 -yljbenzenesulfonamide, or pharmaceuticaly-acceptable salts thereof.
[000123] 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:
XXXXIII
Figure imgf000093_0001
wherein R ι221144 is furyl, thiazolyl or oxazolyl;
R215 is hydrogen, fluoro or ethyl; and
X31 and X32 are independently hydrogen or chloro. [000124] Heteroaryl substituted amidinyl and imidazolyl compounds such as those described in U.S. Patent No. 6,555,563 are useful as Cox-2 selective inhibitors of the present invention. Such heteroaryl substituted amidinyl and imidazolyl compounds have the formula shown below in formula XXXXIV:
XXXXIV
Figure imgf000094_0001
wherein:
Z16 is O or S,
R216 is optionally substituted aryl,
R217 is aryl optionally substituted with aminosulfonyl, and
R j218 and R 5219 cooperate to form an optionally substituted 5-membered ring.
[000125] Materials that can serve as Cox-2 selective inhibitors of the present invention include substituted hydroxamic acid derivatives that are described in U.S. Patent Nos. 6,432,999, 6,512,121 , and 6,515,014. These compounds also act as inhibitors of the lipoxygenase-5 enzyme. Such substituted hydroxamic acid derivatives have the general formulas shown below in formulas XXXXV and XXXXVI:
XXXXV
Figure imgf000094_0002
XXXXVI
Figure imgf000095_0001
[000126] Pyrazole substituted hydroxamic acid derivatives described in
U.S. Patent No. 6,432,999 have the formula shown above in formula
XXXXV, wherein: A14 is pyrazolyl optionally substituted with a substituent selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl;
Y10 is selected from lower alkenylene and lower alkynylene; ' R220 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R220 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; R221 is selected from lower alkyl and amino; and R222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof. [000127] Pyrazole substituted hydroxamic acid derivatives described in U.S. Patent No. 6,432,999 may also have the formula shown above in formula XXXXVI, wherein:
A15 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; , Y11 is selected from lower alkylene, lower alkenylene and lower alkynylene; R223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R223 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; R224 is selected from lower alkyl and amino; and , R225 is selected from hydrido, lower alkyl; or a pharmaceutically-acceptable salt thereof.
[000128] Heterocyclo substituted hydroxamic acid derivatives described in U.S. Patent No. 6,512,121 have the formula shown above in formula XXXXV, wherein: A14 is a ring substiuent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isochiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl; wherein A14 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; Y10 is lower alkylene, lower alkenylene, and lower alkynylene; R220 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R220 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; R221 is selected from lower alkyl and amino; and R222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof. [000129] 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:
A15 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; Y11 is selected from lower alkyl, lower alkenyl and lower alkynyl;
R223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R223 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, nitto, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R224 is selected from lower alkyl and amino; and R225 is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof.
[000130] Thiophene substituted hydroxamic acid derivatives described in U.S. Patent No. 6,515,014 have the formula shown above in formula XXXXV, wherein: A14 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;
Y10 is ethylene, isopropylene, propylene, butylene, lower alkenylene, and lower alkynylene; R220 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R220 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; R221 is selected from lower alkyl and amino; and
R222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically-acceptable salt thereof.
[000131] 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:
A15 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;
Y11 is selected from lower alkyl, lower alkenyl and lower alkynyl; R223 is a substituent selected from 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, wherein R223 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; R224 is selected from lower alkyl and amino; and R225 is selected from hydrido and alkyl; or a pharmaceutically-acceptable salt thereof.
[000132] 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
Figure imgf000099_0001
w ere
R226 and R227 are independently selected from the group consisting of H, halogen, Ci -Cβ alkyl, Ci -Cβ alkoxy, and Ci -Cβ alkoxy substituted by one or more fluorine atoms;
R ,22z8o is halogen, CN, CON
Figure imgf000099_0002
C02 H, C02 Ci -C6 alkyl, or
NHS02R230;
R229 is Ci -C6 alkyl or NH2 ; and
R225 and R225 are independently selected from the group consisting of H, Ci -Cβ alkyl, phenyl, phenyl substituted by one or more atoms or groups selected from the group consisting of halogen, Ci -Cβ alkyl, Ci -Cβ alkoxy, and Ci -Cβ alkoxy substituted by one or more fluorine atoms, or a pharmaceutically acceptable salt, solvate, ester, or salt or solvate of such ester thereof. [000133] 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
Figure imgf000100_0001
wherein:
X33 represents halo, hydrido, or alkyl;
Y12 represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N-acylamino)- sulfonyl, (N-alkylamino)sulfonyl, or alkylthio;
Z17 represents oxygen or sulfur atom;
R233 and R234 are selected independently from lower alkyl radicals; and R232 represents a substituted or non-substituted aromatic group of 5 to
10 atoms; or a pharmaceutically-acceptable salt thereof.
[000134] Cox-2 selective inhibitors that can be used in the present invention include 2-phenyl-1 ,2-benzisoselenazol-3(2H)-one derivatives and 2-phenylcarbomyl-phenylselenyl derivatives that are described in U.S.
Patent No. 6,492,416. Such 2-phenyl-1 ,2-benzisoselenazol-3(2H)-one derivatives and 2-phenylcarbomyl-phenylselenyl derivatives have the formulas shown below in formulas XXXXIX or XXXXIX':
XXXXIX
Figure imgf000100_0002
XXXXIX'
Figure imgf000101_0001
wherein:
R235 is a hydrogen atom or an alkyl group having 1-3 carbon atoms;
R23δ is a hydrogen atom, a hydroxyl group, an organothiol group that is bound to the selenium atom by its sulfur atom, or R235 and R236 are joined to each other by a single bond;
R237 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;
R238 and R239 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 R238 and R239 are joined to each other to form a methylenedioxy group, a salt thereof, or a hydrate thereof.
[000135] Pyrones such as those disclosed in U.S. Patent No. 6,465,509 are also useful as Cox-2 inhibitors of the present invention. These pyrone compounds have the general formula shown below in formula XXXXX:
XXXXX
Figure imgf000101_0002
wherein: X34 is selected from the group consisting of:
(a) a bond,
(b) ~(CH2)m -, wherein m 1 or 2,
(c) ~C(0)«, (d) -0-,
(e) -S-, and
(f) -N(R244)-;
R240 is selected from the group consisting of:
(a) Ci -Cio alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of: hydroxy, halo, Ci -Cι0 alkoxy, Ci -
Cio alkylthio, and CN,
(b) phenyl or naphthyl, and
(c) heteroaryl, which is comprised of a monocyclic aromatic ring of 5 atoms having one hetero atom which is S, O or N, and optionally 1 , 2, or 3 additional N atoms; or a monocyclic ring of 6 atoms having one hetero atom which is N, 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 N3 ; R241 is selected from the group consisting of
(a) Ci -Cβ alkyl, optionally substituted to its maximum with halo,
(b) NH2, and (c) NHC(0)Cι -Cio alkyl, optionally substituted to its maximum with halo;
R242 and R243 are each independently selected from the group consisting of: hydrogen, halo, and Ci -Cβ alkyl, optionally substituted to its maximum with halo; and R244 is selected from the group consisting of: hydrogen and Ci -Cβ alkyl, optionally substituted to its maximum with halo.
[000136] 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,
6-Fluoromethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenylthio-pyran-2-one, 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phenoxy-pyran-2-one, 6-Methyl-4-(4-methylsulfonyl)phenyl-3-pyridin-3-yl-pyran-2-one, 3-lsopropylthio-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one,
4-(4-Methylsulfonyl)phenyl)-3-phenylthio-6-trifluoromethyl-pyran-2-one, 3-lsopropylthio-4-(4-methylsulfonyl)phenyl-6-trifluoromethyl-pyran-2-one, 4-(4-Methylsulfonyl)phenyl-3-phenyl-6-(2,2,2-trifluoroethyl)-pyran-2-one, and 3-(3-Hydroxy-3-methylbutyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2- one.
[000137] Organically synthesized or purified from plant sources, free-B- ring flavanoids such as those described in U.S. Published Application No. 2003/0165588, are useful as Cox-2 selective inhibitors of the present invention. Such free-B-ring flavanoids have the general structure shown in formula XXXXXI:
XXXXXI
Figure imgf000103_0001
wherein:
R 246) R 24 7_ R 248 j R 249_ and R 25o are independently selected from the group consisting of: -H, -OH, -SH, -OR, -SR, -NH2, -NHR245, -N(R245)2, -N(R245)3 X35 , a carbon, oxygen, nitrogen or sulfur, glycoside of a single or a combination of multiple sugars including, aldopentoses, methyl- aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; wherein R245 is an alkyl group having between 1-10 carbon atoms; and X35 is selected from the group of pharmaceutically acceptable counter anions including, hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride and carbonate.
[000138] Heterocyclo-alkylsulfonyl pyrazoles such as those described in European Patent Application No. EP 1312367 are useful as Cox-2 selective inhibitors of the present invention. Such heterocyclo-alkylsulfonyl pyrazoles have the general formula shown below in formula XXXXXII:
XXXXXII
Figure imgf000104_0001
or a pharmaceutically acceptable salt thereof, wherein: the ring of the formula (R 55)-A-(SOmR254) is selected from the group consisting of:
Figure imgf000104_0002
Figure imgf000105_0001
m is 0, 1 or 2; X35 is >CR255 or >N;
R251 is a radical selected from the group consisting of H, N02, CN, (Ci - C6)alkyl, (Ci -C6)alkyl-S02-, (C6 -Cι0)aryl-SO2-, H-(C=0)-, (Ci -C6)alkyl- (C=0)-, (Ci -C6)alkyl-)-(C=0)-, (d -C9)heteroaryl-(C=0)-, (Ci - C9)heterocyclyl-(C=0)-, H2N-(C=0)-, (Ci -C6)alkyl-NH-(C=0)-, [(Ci - C6)alkyl]2-N-(C=0)-, [(C6 -Cι0)aryl]2-NH-(C=O)-, [(Ci -C6)alkyl]-[((Ce - Cio)aryl-N]-(C=0)-, HO-NH-(C=0)-, and (Ci -C6)alkyl-0-NH-(C=0)-; R252 is a radical selected from the group consisting of H, -N02, -CN, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-Cι0)aryl, (d- C9)heteroaryl, (d-C9)heterocyclyl, (d-Ce)alkyl-O-, (C3-C7)cycloalkyl-0-, (Ce-Cιo)aryl-O-, (Ci -C9)heteroaryl-0-, (C6 -C9)heterocyclyl-0-, H-(C=0)-, (Ci-C6)alkyl-(C=0)-, (C3-C7)cycloalkyl-(C=0)-, (C6-Cι0)aryl-(C=O)-, (d- C9)heteroaryl-(C=0)~, (d-C9)heterocyclyl-(C=0)-, (d-C6)alkyl-0-(C=0)-, (C3-C7)cycloalkyl-0-(C=0)-, (C6-Cι0)aryl-O-(C=O)-, (C C9)heteroaryl-0- (C=0)-, (Ci-C9)heterocyclyl-0-(C=0)-, (Ci-C6)alkyl-(C=0)-0-, (C3- C7)cycloalkyl-(C=0)-0-, (C6-Cio)aryl-(C=0)-0-, (Ci-C9)heteroaryl-(C=0)- 0-,
Figure imgf000105_0002
(d-C6)alkyl-(C=0)-NH-, (C3- C7)cycloalkyl-(C=0)-NH-, (Ce-Cι0aryl-(C=O)-NH-. (Ci-C9)heteroaryl-(C=0)- NH-, (Ci-C9)heterocyclyl-(C=0)-NH-, (Ci-C6)alkyl-0-(C=0)-NH-, (d- C6)alkyl-NH, [(Cι-C6)alkyl]2-N-, (C3-C7)cycloalkyl-NH-. [(C3-C7)cycloalkyl]2- N-, [(C6-Cιo)aryl]-NH-, [(C6-Cι 0)aryl]2-N-, [(Cι -C6)alkyl]-[((C6-Cιo)aryl)-N]-, [(Ci -C9)heteroaryl]-NH-, [(Cι-C9)heteroaryl]2-N-, [(Cι-C9)heterocycly]-NH-, [(Cι-C9)heterocyclyl]2-N-, H2N-(C=0)-, HO-NH-(C=0)-, (d-C6)alkyl-0-NH- (C=0)-, [(Ci-C6)alkyl]-NH-(C=0)-, [(Ci-C6)alkyl]2-N-(C=0)-, [(C3- C7)cycloalkylj-NH-(C=0)-, [(C3-C7)cycloalkyl]2-N-(C=0)-, [(C6-Cιo)aryl]-NH- (C=0)-, [(C6-Ci0aryl]2-N-(C=O)-, [(d-C 6)alkyl]-[((C6-Cιo)aryl)-N]-(C=0)-, [(Ci-C9)heteroaryl]-NH-(C=0)-, [(Ci-C9)heferoaryl]2-N-(0=0)-, [(Ci- C9)heterocyclyl]-NH-(C=0)-, (Cι-C6)alkyl-S- and (d-C6)alkyl optionally substituted by one -OH substituent or by one to four fluoro substituents; R253 is a saturated (3- to 4-membered)-heterocyclyl ring radical; or a saturated, partially saturated or aromatic (7- to 9-membered)-heterocyclyl ring radical; wherein said saturated (3- to 4-membered)-heterocyclyl ring radical orsaid saturated, partially saturated or aromatic (7- to 9-membered)- heterocyclyl ring radical; may optionally contain one to four ring heteroatoms independently selected Irom the groups consisting of -N=, -NH-, -0-. and -S-; wherein said saturated (3- to 4-membered)-heterooyclyl ring radical; or said saturated, partially saturated or aromatic (7- to 9- nembered)-heterocyclyl ring radical; may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo, -OH, -CN, -N02, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-Cι0)aryl, (C2- C9)hetorocyclyl, (Ci -C6)alkyl-0-, H-(C=0)-, (d-C6)alkyl-(C=0)-, HO- (C=0)-, (Ci-C6)alkyl-0-(C=0)-, -NH2, (d-Ce)alkyl-NH-, [(d-C6) alkyl]2-N-,
(C3-C7)cycloalkyl-NH-, (Ce-Cιo)aryl-NH-, [(Cι-C6)alkyl]-[((C6-Cιo)aryl)-N]-, (Cι-C9)heteroaryl-NH-, H2N-(C=0)-[(d-C6)alkyl]-NH-(C=0)-, [(Ci- C6)alkyl]2-N-(C=0)-, [(C6-Cιo)aryl]-NH-(C=0)-, [(Cι-C6)alkyl]-[((C6-Cιo)aryl)- N]-(C=0)-, (Cι-C6)alkyl-0-NH-(C=0)-, (d-C6)alkyl-(C=0)-HN-, (d- C6)alkyl-(C=0)-[(Cι-C6)alkyl-N]-, -SH, (d-C6)alkyl-S-,
(C1-C6)alkyl-(S=0)-, (Ci-C6)alkyl-S02- and (d-C6)alkyl optionally substituted with one to fourfluoro moieties; wherein said saturated (3- to 4-membered)-heterocyclyl ring radical; or said saturated, partially saturated or aromatic (7- to 9- membered)-heterocyclyl ring radical; may also optionally be substituted on any ring nitrogen atom by one to three substituents per ring independently selected from the group consisting of (C3-C7)cyoloalkyl, (Ce-Cιo)aryl, (C2- C9)heterocyclyl, H-(C=0)-, (d-C6)alkyl-(C=0)-, (d-C6)alkyl-0-(C=0)-, H2N-(C=0)-,
Figure imgf000107_0001
[(Cι-C6)alkyl]2-N-(C=0)-, [(C6-
Figure imgf000107_0002
[(Ci-C6)alkyl]-[((Ce-Cio)aryl)-N]-(C=0)-, (Ci -C6)alkyl- 0-NH-(C=0)-, and (Cι-C6)alkyl optionally substituted with one to four fluoro moieties;
R254 is an (Cι-C6)alkyl radical optionally substituted by one to four fluoro substituents; and
R255 is a radical selected from the group consisting of H, halo, -OH, (Cι- C6)alkyl-0-, (C2-C6)alkenyl, (C2-C6) alkynyl, (C3-C7)cycloalkyl, -CN, H- (C=0)-, (Cι-C6)alkyl-(C=0)-, (d-C6)alkyl-(C=0)-0-, HO-(C=0)-, (d-
C6)alkyl-0-(C=0)-, (d-Ce)alkyl-NH-. [(d-C6)alkyl]2-N-, (C3-C7)cycloalkyl- NH-, (Ce-Cio)aryl-NH-, [(Cι-C6)alkylj-[((C6-Cιo)aryl)-N]-, (Cι-C9)heteroaryl- NH-, H2N-(C=0)-, (Cι-C6)alkyl-NH-(C=0)-. [(d-C6)alkyl]2-N-(C=0)-, (C6-
Figure imgf000107_0003
[(Ci-C6)alkyl]-[((C6-Cio)aryl)-N]-(C=0)-, (d-Ce)alkyl-O- NH-(C=0)-, (d-Ce)alkyl-S-, and (Cι-C6)alkyl optionally substituted by one to four fluoro substituents.
[000139] 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:
XXXXXIII
Figure imgf000107_0004
wherein:
R256 represents an alkyl or -NR259 R260 group, wherein R259 and R260 each independently represents a hydrogen atom or an alkyl group;
R257 represents an alkyl, C3 -C7 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; R258 represents a methyl, hydroxymethyl, alkoxymethyl, C3 -C7 cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile, trifluoromethyl or difluoromethyl group or a CH2 - R261 group wherein R261 represents an alkyl group; and X36 represents a single bond, an oxygen atom, a sulfur atom or a methylene group; or a pharmaceutically acceptable salt thereof.
[000140] Examples of 2-phenylpyran-4-one derivatives useful in the present invention include, but are not limited to:
3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one,
3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-bromophenyl)-2-(4-methylsulfonylphenyl)-6-methylpyran-4-one, 3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(3,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(3-chloro-4-methylphenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-
4-one ,
2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one, 3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one,
3-(2-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy)pyran-4-one, 3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4- one,
3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methoxymethylpyran-4- one,
3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonylphenyl)pyran-4- one, and pharmaceutically acceptable salts thereof. [000141] Cox-2 selective inhibitors that are useful in the subject method and compositions can include the compounds that are described in U.S.
Patent No. 6,472,416 (sulfonylphenylpyrazoles); U.S. Patent No.
6,451 ,794 (2,3-diaryl-pyrazolo[1 ,5-bjpyridazines); U.S. Patent Nos.
6,169,188, 6,020,343, and 5,981 ,576 ((methylsulfonyl)phenyl furanones); U.S. Patent No. 6,222,048 (diaryl-2-(5H)-furanones); U.S. Patent No.
6,057,319 (3,4-diaryl-2-hydroxy-2,5-dihydrofurans); U.S. Patent No.
6,046,236 (carbocyclic sulfonamides); U.S. Patent Nos. 6,002,014 and
5,945,539 (oxazole derivatives); and U.S. Patent Nos. 6,359,182 and
6,538,116 (C-nitroso compounds). [000142] Examples of specific compounds that are useful as Cox-2 selective inhibitors include, without limitation: a1 ) 8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo(1 ,2- a)pyridine; a2) 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone; a3) 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-
(trifluoromethyl)pyrazole; a4) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-
(trifluoromethyl)pyrazole; a5) 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1 H-pyrazol-1 - yl)benzenesulfonamide a6) 4-(3,5-bis(4-methylphenyl)-1 H-pyrazol-1 -yl)benzenesulfonamide; a7) 4-(5-(4-chlorophenyl)-3-phenyl-1 H-pyrazol-1 - yl)benzenesulfonamide; ' aδ) 4-(3,5-bis(4-methoxyphenyl)-1 H-pyrazol-1 -yl)benzenesulfonamide; a9) 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1 H-pyrazol-1 - yl)benzenesulfonamide; a10) 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1 H-pyrazol-1 - yl)benzenesulfonamide; b1) 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1 H-pyrazol-1 - yl)benzenesulfonamide; b2) 4-(4-chloro-3,5-diphenyl-1 H-pyrazol-1 -yl)benzenesulfonamide b3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b4) 4-[5-phenyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yljbenzenesulfonamide; b5) 4-[5-(4-f luorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b6) 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b7) 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; ι b8) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b9) 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; b10) 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; d ) 4-[3-(difluoromethyl)-5-phenyl-1 H-pyrazol-1 -yljbenzenesulfonamide; c2) 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c3) 4-[3-cyano-5-(4-fluorophenyl)-1 H-pyrazol-1 -yljbenzenesulfonamide; c4) 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c6) 4-[4-chloro-5-phenyl-1 H-pyrazol-1 -yljbenzenesulfonamide; c7) 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; c8) 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1 H-pyrazol-
1 -yljbenzenesulfonamide; c9) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene; c10) 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide; d 1 ) 6-(4-f luorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene; d2) 5-(3-chloro-4-methoxyphenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene; d3) 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5- yljbenzenesulfonamide; d4) 5-(3,5-dichloro-4-methoxyphenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene; d5) 5-(3-chloro-4-fluorophenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene; d6) 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5- yljbenzenesulfonamide; d7) 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4- methylsulfonylphenyl)thiazole; d8) 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4- methylsulfonylphenyl)thiazole; d9) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole; d10) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2- trifluoromethylthiazole; e1) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole; e2) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2- benzylaminothiazole; e3) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1 - propylamino)thiazole; e4) 2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyljthiazole; e5) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2- trifluoromethylthiazole; e6) 1 -methylsulfonyl-4-[1 , 1 -dimethyl-4-(4-fluorophenyl)cyclopenta-2,4- dien-3-yl]benzene; e7) 4-[4-(4-fluorophenyl)-1 ,1-dimethylcyclopenta-2,4-dien-3- yljbenzenesulfonamide; eδ) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6- diene; e9) 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5- yljbenzenesulfonamide; e10) 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine- 3-carbonitrile; f1) 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3- carbonitrile; f2) 6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenylj-2-phenyl-pyridine-3- carbonitrile; f3) 4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; f4) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; f5) 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; f6) 3-[1 -[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazol-2- yljpyridine; f7) 2-[1 -[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H-imidazol-2- yljpyridine; f8) 2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H- imidazol-2-yl]pyridine; f9) 2-methyl-6-[1 -[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1 H- imidazol-2-yrjpyridine; f10) 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; g1) 2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-
(trifluoromethyl)-l H-imidazole; g2) 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; g3) 2-(4-chlorophenyl)-1 -[4-(methylsulfonyl)phenyl]-4-methyl-1 H- imidazole; g4) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1 H- imidazole; g5) 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenylj-
1 H-imidazole; g6) 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4- (trifluoromethyl)-l H-imidazole; g7) 1 -[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1 H- imidazole; gδ) 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenylj-4-trifluoromethyl-
1 H-imidazole; g9) 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; g10) 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-
(trifluoromethyl)-l H-imidazole; h 1 ) 4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; h2) 2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-
1 H-imidazole; h3) 4-[2-(3-methylphenyl)-4-thfluoromethyl-1 H-imidazol-1 - yljbenzenesulfonamide; h4) 1 -[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-
1 H-imidazole; h5) 4-[2-(3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1 - yljbenzenesulfonamide; h6) 4-[2-phenyl-4-trifluoromethyl-1 H-imidazol-1 -yljbenzenesulfonamide; h7) 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1 H-imidazol-1 - yljbenzenesulfonamide; hδ) 1 -allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-
(trifluoromethyl)-l H-pyrazole; h9) 4-[1 -ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1 H-pyrazol-3- yljbenzenesulfonamide; i1 ) N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-
(trifluoromethyl)-l H-pyrazol-1 -yljacetamide; i2) ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-
(trifluoromethyl)-l H-pyrazol-1 -yljacetate; i3) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)- 1 H-pyrazole; i4) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5-
(trifluoromethyl)pyrazole; i5) 1 -ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-
(trifluoromethyl)-l H-pyrazole; i6) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1 H- imidazole; i7) 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1 H- imidazole; iδ) 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine; i9) 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-
(trifluoromethyl)pyridine; ( i10) 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-
(trifluoromethyl)pyridine; j1) 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-
(trifluoromethyl)pyridine; j2) 4-[2-(3-chloro-4-methoxyphenyl)-4,5- difluorophenyljbenzenesulfonamide; j3) 1 -(4-f luorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene; j4) 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole; j5) 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide; j6) 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; j7) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesuIfonamide; jδ) 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; j9) 1 -[2-(4-fluorophenyl)cyclopenten-1 -yl]-4-(methylsulfonyl)benzene; j10) 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4- (methylsulfonyl)benzene; k1) 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; k2) 1 -[2-(2,4-dichlorophenyl)cyclopenten-1 -yl]-4-
(methylsulfonyl)benzene; k3) 1 -[2-(4-trifluoromethylphenyl)cyclopenten-1 -yl]-4- (methylsulfonyl)benzene; k4) 1 -[2-(4-methylthiophenyl)cyclopenten-1 -ylj-4-
(methylsulfonyl)benzene; k5) 1 -[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1 -yl]-4-
(methylsulfonyl)benzene; k6) 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1- yljbenzenesulfonamide; k7) 1 -[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1 -yl]-4-
(methylsulfonyl)benzene; kδ) 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1- yljbenzenesulfonamide; k9) 4-[2-(4-fluorophenyl)cyclopenten-1 -yljbenzenesulfonamide; k10) 4-[2-(4-chlorophenyl)cyclopenten-1 -yljbenzenesulfonamide;
11 ) 1 -[2-(4-methoxyphenyl)cyclopenten-1 -yl]-4-
(methylsulfonyl)benzene; 12) 1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
13) 4-[2-(3-f luoro-4-methoxyphenyl)cyclopenten-1 - yljbenzenesulfonamide;
14) 1 -[2-(3-chloro-4-methoxyphenyl)cyclopenten-1 -yl]-4- (methylsulfonyl)benzene;
15) 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
16) 4-[2-(2-methylpyridin-5-yl)cyclopenten-1 -yljbenzenesulfonamide; 17) ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyljoxazol-2-ylj-
2-benzyl-acetate;
13) 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]acetic acid; 19) 2-(tetf-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyljoxazole;
110) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenylj-2-phenyloxazole; ml) 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole; and m2) 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4- oxazolyljbenzenesulfonamide. m3) 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; m4) 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; m5) δ-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; m6) 6-chloro-7-(1 , 1 -dimethylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; m7) 6-chloro-δ-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; mδ) 2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid ; m9) 7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3- carboxy lie acid; m10) 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n1) δ-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n2) 6-trifluoromethoxy-2-thfluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n3) 5,7-dichloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n4) δ-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n5) 7,δ-dimethyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n6) 6,δ-bis(dimethyiethyl)-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; n7) 7-(1 -methylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; nδ) 7-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; n9) 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n10) 6-chloro-δ-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o1 ) 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o2) 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
03) 6,δ-dichloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid;
04) 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid;
05) 6-chloro-δ-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 06) δ-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
07) δ-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
08) 6-bromo-δ-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;
09) δ-bromo-6-fluoro-2 rifluoromethyl-2H-1 -benzopyran-3-carboxylic acid;
010) δ-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p1 ) δ-bromo-5-fluoro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; p2) 6-chloro-δ-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p3) 6-bromo-δ-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p4) 6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1 - benzopyran-3-carboxylic acid; p5) 6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid; p6) 6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid; p7) 6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; pδ) 6-[(1 , 1 -dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1 - benzopyran-3-carboxylic acid; p9) 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1 - benzopyran-3-carboxylic acid; p10) 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q1) δ-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid; q2) 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q3) 6,δ-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q4) δ-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1 -benzopyran-3- carboxylic acid; q5) 6,δ-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q6) 6-benzylsulfonyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid; q7) 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-thfluoromethyl-2H-1- benzopyran-3-carboxylic acid; qδ) 6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1 - benzopyran-3-carboxylic acid; q9) 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q10) 7-(1 ,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3- carboxylic acid; r1 ) 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulphonyl-2(5H)- fluranone; r2) 6-chloro-2-trifluoromethyl-2H-1 -benzothiopyran-3-carboxylic acid; r3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; r4) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; r5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide; r6) 3-[1 -[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H-imidazol-2- yljpyridine; r7) 2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1 H- imidazol-2-yl]pyridine; rδ) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - yljbenzenesulfonamide; r9) 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; r10) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; s1) [2-trifluoromethyl-5-(3,4-difluorophenyl)-4- oxazolyljbenzenesulfonamide; s2) 4-[2-methyl-4-phenyl-5-oxazolyljbenzenesulfonamide; or s3) 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4- oxazolyljbenzenesulfonamide; or a pharmaceutically acceptable salt or prodrug thereof.
[000143] Cox-2 inhibitors that are useful in the methods and compositions of present invention can be supplied by any source as long as the Cox-2 inhibitor is pharmaceutically acceptable. Likewise, Cox-2 inhibitors that are useful in the compositions and methods of present invention can by synthesized, for example, according to the description in
Example 1. Several Cox-2 inhibitors that are suitable for use with the compositions and methods of the present invention may be synthesized by the methods described in, for example, U.S. Patent No. 5,466,323 to
Talley, et al. Cox-2 inhibitors can also be isolated and purified from natural sources. Cox-2 inhibitors should be of a quality and purity that is conventional in the trade for use in pharmaceutical products. [000144] Preferred Cox-2 selective inhibitor compounds are those compounds selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS 57067, T-614, BMS-347070 (Bristol Meyers Squibb, described in U.S. Patent No. 6,180,651), JTE-522 (Japan Tabacco), S-2474 (Shionogi),
SVT-2016, CT-3 (Atlantic Pharmaceutical), ABT-963 (Abbott), SC-58125 (GD Searle), nimesulide, flosulide, NS-396 (Taisho Pharmaceutical), L- 745337 (Merck), RWJ-63556, L-734512 (Merck), darbufelone (Pfizer), CS- 502 (Sankyo), LAS-34475 (Almirall Prodesfarma), LAS-34555 (Almirall Prodesfarma), S-33516 (Servier), SD-δ331 (Pharmacia, described in U.S.
Patent No. 6,0340256), MK-966 (Merck), L-733003 (Merck), T-614 (Toyama), D-1376 (Chiroscience), L-743731 (Merck), CGP-23233 (Novartis), BF-369 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), prodrugs of any of them, and mixtures thereof. [000145] More preferred is that the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, prodrugs of any of them, and mixtures thereof. [000146] Even more preferred still is that the Cox-2 selective inhibitor is celecoxib.
[000147] In one embodiment of the present invention, the Cox-2 selective inhibitor is administered from about 0.1 mg per kg to about 25 mg per kg subject body weight. [000148] In one embodiment of the present invention, the Cox-2 selective inhibitor is administered from about 0.5 mg per kg to about 10 mg per kg subject body weight.
[000149] For purposes of calculating dosages, it is assumed that the weight of a normal human adult subject is 70 kilograms. [000150] An optional component of the present invention is a conventional anti-diabetic agent. As used herein, the term "conventional anti-diabetic agent" refers to any compound or combination of compounds that is capable of controlling glucose metabolism and, ultimately, blood glucose levels in a subject suffering from diabetes. Examples of preferred classes of conventional anti-diabetic agents that are suitable for use in the present invention are listed in Table 3 and include, but are not limited to, insulin, insulin analogs, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglinitides, and biguanides.
[000151] In one embodiment, the anti-diabetic agent is an insulin or insulin analog selected from the group consisting of insulin, insulin human, buffered insulin human, insulin zinc, insulin human zinc, prompt insulin zinc, extended insulin zinc, extended insulin human zinc, isophane insulin, isophane insulin human, isophane insulin human and insulin human, insulin glargine, insulin aspart, insulin lispro, and mixtures thereof. [000152] In another embodiment, the anti-diabetic agent is a sulfonylurea selected from the group consisting of acetohexamide, chlorpropamide, gliclazide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide, and mixtures thereof.
[000153] In another embodiment, the anti-diabetic agent is an alpha- glucosidase inhibitor selected from the group consisting of acarbose, migitol, and mixtures thereof. [000154] In one embodiment, the anti-diabetic agent is a thiazolidinedione selected from the group consisting of ciglitazone, englitazone, troglitazone, pioglitazone, rosiglitazone, and mixtures thereof. [000155] In another embodiment, the anti-diabetic agent is a meglinitide selected from the group consisting of repaglinide, nateglimide, and mixtures thereof. [000156] In another embodiment, the anti-diabetic agent is a biguanide selected from the group consisting of buformin, metformin, phenformin, and mixtures thereof
[000157] The amount of the anti-diabetic agent utilized in the present invention is dependent on the specific anti-diabetic agent selected. Therapeutically effective amounts of various anti-diabetic agents that are useful in the present method and composition are listed in Table 3.
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[000158] The combination of a Cox-2 inhibitor and an anti-diabetic agent can be supplied in the form of a novel therapeutic composition that is believed to be within the scope of the present invention. [000159] The combination of a Cox-2 inhibitor and an anti-diabetic agent can be provided in a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition. Examples of 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. In one embodiment, the Cox-2 inhibitor and the conventional anti-diabetic agent are administered to a subject together in one pharmaceutical carrier. In another embodiment, they are administered separately.
[000160] The pharmaceutical compositions may be administered enterally and parenterally. 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. When administered, the pharmaceutical composition may be at or near body temperature. [000161] In particular, the combinations of the present invention can be administered topically into the eye in the form of liquid drops. Eye drops can be formulated to contain a suitable amout of the active agents along with various formulatory ingredients, such as antimicrobial preservatives and tonicity agents. Examples of suitable antimicrobial preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, and other agents equally well-known to those skilled in the art. Such preservatives, if utilized, will typically be employed in an amount between about 0.001% and about 1.0% by weight. Examples of suitable agents which may be used to adjust the tonicity or osmolality of the formulations include: sodium chloride, potassium chloride, mannitol, dextrose, glycerin, and propylene glycol. Such agents, if utilized, will typically be employed in an amount between about 0.1% and about 10.0% by weight. [000162] The present therapeutic and pharmaceutical compositions can be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, gels and erodible solid ocular inserts.
[000163] The subject method of administering a Cox-2 inhibitor alone or in combination with a conventional anti-diabetic agent and compositions comprising the same can also be administered parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrastemally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions.
[000164] Aqueous suspensions can be produced that contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally- occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
[000165] 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. [000166] 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. [000167] 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, n-3 polyunsaturated fatty acids may find use in the preparation of injectables. [000168] Insulins and insulin analogues cannot be taken orally, but must be administered subcutaneously to avoid breakdown in the gastrointestinal tract. Therefore, when the anti-diabetic agent of the present invention is an insulin or insulin analog, the preferred administration of the composition would be by subcutaneously administered sterile injectable solution as described above.
[000169] When the conventional anti-diabetic agent used in the present invention is one that is administered orally, then oral (intra-gastric) is a 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. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, maize starch, or alginic- acid, binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
[000170] 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.
[000171] 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.
[000172] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
[000173] Syrups and elixirs containing the Cox-2 inhibitor alone or in combination with the conventional anti-diabetic agent may be formulated with sweetening agents, for example glycerol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
[000174] Administration can also be by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature, but liquid at the rectal temperature and will therefore, melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. [000175] Also encompassed by the present invention is buccal or "sub- lingual" administration, which includes lozenges or a chewable gum comprising the compounds, set forth herein. The compounds can be deposited in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compounds in an inert base such as gelatin and glycerin or sucrose and acacia. [000176] Other methods for administration of the Cox-2 inhibitor compound and the conventional anti-diabetic agent include dermal patches that release the medicaments directly into a subject's skin. [000177] Topical delivery systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, collyriums, solutions or suspensions.
[000178] The solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition. Such co-solvents include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art.
Typically, such co-solvents are employed at a level of from 0.01% to 2% by weight. [000179] A penetration enhancer is an agent used to increase the permeability of the skin to an active agent to increase the rate at which the drug diffuses through the skin and enters the tissues and bloodstream. Thus, in one embodiment of the present invention, a penetration enhancer may be added to a Cox-2 inhibitor topical composition or a Cox-2 inhibitor and conventional anti-diabetic agent topical composition. [000180] Examples of penetration enhancers suitable for use with the compositions of the present invention include: alcohols, such as ethanol and isopropanol; polyols, such as n-alkanols, limonene, terpenes, dioxolane, propylene glycol, ethylene glycol, other glycols, and glycerol; sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformamide, methyl dodecyl sulfoxide, dimethylacetamide; esters, such as isopropyl myristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate, and capric/caprylic triglycerides; ketones; amides, such as acetamides; oleates, such as triolein; various surfactants, such as sodium lauryl sulfate; various alkanoic acids, such as caprylic acid; lactam compounds, such as azone; alkanols, such as oleyl alcohol; dialkylamino acetates, and admixtures thereof. [000181] The above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. See e.g. Gennaro, A. R., Remington: The Science and Practice of Pharmacy, 20th Edition, (Lippincott, Williams and Wilkins), 2000; Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, ef al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999. [000182] The present invention further comprises kits that are suitable for use in performing the methods of treatment described above. In one embodiment, 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 an anti-diabetic agent, in amounts which comprise a therapeutically effective combination for the prevention or treatment of diabetic retinopathy. Preferably, the first dosage form and the second dosage form together comprise a therapeutically effective amount of the compounds for the prevention or treatment of diabetes-related ocular disorders.
[000183] The following examples describe embodiments of the invention. Other embodiments within the scope of the claims herein will be apparent to one skilled in the art from consideration of the specification or practice of the invention as disclosed herein. It is intended that the specification, together with the examples, be considered to be exemplary only, with the scope and spirit of the invention being indicated by the claims which follow the examples. In the examples, all percentages are given on a weight basis unless otherwise indicated. EXAMPLE 1
[000184] This example shows the preparation of celecoxib.
[000185] Step 1 : Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-
1 ,3-dione.
[000186] Following the disclosure provided in U.S. Patent No. 5,760,068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10% HCl was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS0 , filtered and concentrated to afford 8.47 g (94%) of a brown oil which was carried on without further purification. [000187] Step 2: Preparation of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1 H-pyrazol-1 -yljbenzenesulfonamide.
[000188] To the dione from Step 1 (4.14 g, 18.0 mmol) in 75 mL absolute ethanol, 4.26 g (19.0 mmol) 4-sulphonamidophenylhydrazine hydrochloride was added. The reaction was refluxed under argon for 24 hours. After cooling to room temperature and filtering, the reaction mixture was concentrated to afford 6.13 g of an orange solid. The solid was recrystallized from methylene chloride/hexane to give 3.11 g (8.2 mmol, 46%) of the product as a pale yellow solid, having a melting point (mp) of
157°-159°C; and a calculated composition of C17 H14 N3 02 SF3 ; C, 53.54; H, 3.70; N, 11.02. The composition that was found by analysis was: C, 53.17; H, 3.81 ; N, 10.90. EXAMPLE 2
[000189] This example illustrates the production of a composition containing celecoxib and insulin, and of a pharmaceutical composition containing the combination. [000190] Insulin may be supplied by any one of several commercially available preparations, such as Humulin® N, available from Eli Lilly and
Company, Indianapolis, IN. Humulin® N is supplied at a concentration of 100 units per milliliter.
[000191] Celecoxib can be prepared as described in Example 1 or, alternatively, can be obtained under the trade name CELEBREX® from Pharmacia Corporation, Peapack, NJ.
[000192] A therapeutic composition of the present invention can be produced by intermixing the insulin suspension (50 ml supplied by Eli Lilly and Company as Humulin® N, at a concentration of 100 units/ml); and 4- [5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide (20 g, as produced in Example 1 , or as available from Pharmacia Corporation, Peapack, NJ, under the trade name CELEBREX®), in a suspension or solution with a sterile pharmaceutically acceptable liquid. [000193] After mixing, the combination of insulin and celecoxib forms a therapeutic composition that is sufficient for the production of 100 human single dose units suitable for a subject requiring a normal dose of insulin of 50 units. Each dose contains 50 units of insulin and 200 mg of celecoxib. EXAMPLE 3 [000194] This example illustrates the production of a composition containing celecoxib and the sulfonylurea drug glipizide, and of a pharmaceutical composition containing the combination.
[000195] Glipizide can be supplied by any commercial preparations, such as GLUCOTROL®. GLUCOTROL® is supplied in the form of tablets by Pfizer, Inc, New York, NY. [000196] Celecoxib can be prepared as described in Example 1 or, alternatively, can be obtained under the trade name CELEBREX® from
Pharmacia Corporation, Peapack, NJ.
[000197] A therapeutic composition of the present invention can be produced by intermixing solid or powdered glipizide (500 mg, available as GLUCOTROL® from Pfizer, Inc.); and 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-l H-pyrazol-1 -yljbenzenesulfonamide (200 g, as produced in Example 1 , or as available from Pharmacia Corporation, Peapack, NJ, under the trade name 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. [000198] After mixing, the combination of glipizide and celecoxib forms a therapeutic composition that is sufficient for the production of 1000 human single dose unit, each dose containing 5 mg of glipizide and 200 mg of celecoxib.
[000199] All references cited in this specification, including without limitation all papers, publications, patents, patent applications, presentations, texts, reports, manuscripts, brochures, books, internet postings, journal articles, periodicals, and the like, are hereby incorporated by reference into this specification in their entireties. The discussion of the references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pertinency of the cited references.
[000200] In view of the above, it will be seen that the several advantages of the invention are achieved and other advantageous results obtained. [000201] As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense

Claims

WHAT IS CLAIMED IS: 1. A method for preventing or treating diabetes-associated ocular disorders in a subject comprising administering to the subject a Cox-2 inhibitor.
2. The method according to claim 1 , comprising administering to the subject a therapeutic amount of a Cox-2 inhibitor.
3. The method according to claim 1 , wherein the subject is one that is in need of the prevention or treatment of a diabetes-associated ocular disorder.
4. The method according to claim 1 , wherein the Cox-2 inhibitor comprises a non-steroidal anti-inflammatory drug.
5. The method according to claim 4, wherein the Cox-2 inhibitor comprises at least one compound that is selected from the group consisting of ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenec, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acetyl salicylic acid, indometacin, piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone, mefenamic acid, tolfenamic acid, diflunisal, podophyllotoxin derivatives, acemetacin, droxicam, floctafenine, oxyphenbutazone, phenylbutazone, proglumetacin, acemetacin, fentiazac, clidanac, oxipinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flufenisal, sudoxicam, etodolac, piprofen, salicylic acid, choline magnesium trisalicylate, salicylate, benorylate, fentiazac, clopinac, feprazone, isoxicam and 2-fluoro-a-methyl[1 ,1'-biphenyl]-4-acetic acid, 4- (nitrooxy)butyl ester.
6. The method according to claim 1 , wherein the Cox-2 inhibitor comprises a Cox-2 selective inhibitor.
7. The method according to claim 6, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS 57067, T-614, BMS- 347070, JTE-522, S-2474, SVT-2016, CT-3, ABT-963, SC-58125, nimesulide, flosulide, NS-398, L-745337, RWJ-63556, L-784512, darbufelone, CS-502, LAS-34475, LAS-34555, S-33516, SD-8381, MK- 966, L-783003, T-614, D-1376, L-748731 , CGP-28238, BF-389, GR- 253035, prodrugs of any of them, and mixtures thereof.
8. The method according to claim 6, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, prodrugs of any of them, and mixtures thereof.
9. The method according to claim 6, wherein the Cox-2 selective inhibitor comprises celecoxib.
10. The method according to claim 6, wherein the Cox-2 selective inhibitor is a chromene Cox-2 selective inhibitor.
11. The method according to claim 10, wherein the chromene Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of:
6-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,
6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid,
7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-bromo-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,
8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,
7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid,
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-[(dimethylaminό)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-[(1 ,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid, 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid,
6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
7-(1 , 1 -dimethylethyl)-2-pentafluoroethyl-2H-1 -benzopyran-3-carboxylic acid,
6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid.
6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
(S)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
(S)-6-chloro-7-(1 ,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3- carboxylic acid,
6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
(S)-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-formyl-2-(trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid,
6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6-chloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,
(S)-6-chloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,
6,8-dichloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,
7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
5,6-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
2,6-bis(trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid,
5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6-iodo-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,
6-bromo-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,
6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid,
6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid, and mixtures thereof.
12. The method according to claim 10, wherein the chromene Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of (S)-6-chloro-7-(1 ,1-dimethylethyl)-2- (trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, (2S)-6,8-dimethyl-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-6-chloro-8-methyI-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-8-ethyl-6- (trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)- 6,8-dichloro-2-(trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid, (2S)-6- chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and mixtures thereof.
13. The method according to claim 1 , wherein the diabetes- associated ocular disorder is diabetic retinopathy.
14. A method for preventing or treating diabetes-associated ocular disorders in a subject comprising administering to the subject a Cox-2 inhibitor and a conventional anti-diabetic agent.
15. The method according to claim 14, comprising administering to the subject an amount of a Cox-2 inhibitor and an amount of a conventional anti-diabetic agent wherein the amount of the Cox-2 inhibitor and the amount of the anti-diabetic agent together comprise a therapeutic amount.
16. The method according to claim 14, wherein the subject is one that is in need of the prevention or treatment of a diabetes-associated ocular disorder.
17. The method according to claim 14, wherein the Cox-2 inhibitor comprises a non-steroidal anti-inflammatory drug.
18. The method according to claim 17, wherein the Cox-2 inhibitor comprises at least one compound that is selected from the group consisting of ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenec, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acetyl salicylic acid, indometacin, piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone, mefenamic acid, tolfenamic acid, diflunisal, podophyllotoxin derivatives, acemetacin, droxicam, floctafenine, oxyphenbutazone, phenylbutazone, proglumetacin, acemetacin, fentiazac, clidanac, oxipinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flufenisal, sudoxicam, etodolac, piprofen, salicylic acid, choline magnesium trisalicylate, salicylate, benorylate, fentiazac, clopinac, feprazone, isoxicam and 2-fluoro-a-methyl[1 ,1'-biphenyl]-4-acetic acid, 4- (nitrooxy)butyl ester.
19. The method according to claim 14, wherein the Cox-2 inhibitor comprises a Cox-2 selective inhibitor.
20. The method according to claim 19, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS 57067, T-614, BMS- 347070, JTE-522, S-2474, SVT-2016, CT-3, ABT-963, SC-58125, nimesulide, flosulide, NS-398, L-745337, RWJ-63556, L-784512, darbufelone, CS-502, LAS-34475, LAS-34555, S-33516, SD-8381 , MK- 966, L-783003, T-614, D-1376, L-748731 , CGP-28238, BF-389, GR- 253035, prodrugs of any of them, and mixtures thereof.
21. The method according to claim 19, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, prodrugs of any of them, and mixtures thereof.
22. The method according to claim 19, wherein the Cox-2 selective inhibitor comprises celecoxib.
23. The method according to claim 19, wherein the Cox-2 selective inhibitor comprises a chromene Cox-2 selective inhibitor.
24. The method according to claim 23, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of:
6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chIoro-7-methyl-2-trifluoromethyi-2H-1-benzopyran-3-carboxylic acid, 8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6-chloro-7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid,
7-(1 , 1 -dimethylethyl)-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,
6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-chloro-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,
6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,
7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
7-phenyl-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,
6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
2-trifluoromethyl-3H-naptho[2,1 -b]pyran-3-carboxylic acid,
6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-[(1 ,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid, 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid,
6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3- carboxylic acid,
6-iodo-2-trifluoromethyl-2H-1 -benzopyran-3-carboxylic acid,
7-(1 , 1 -dimethylethyl)-2-pentafluoroethyl-2H-1 -benzopyran-3-carboxylic acid,
6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid.
6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
(S)-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-chloro-7-(1 , 1 -dimethylethyl)-2-trif luoromethyl-2H-1 -benzopyran-3- carboxylic acid,
(S)-6-chloro-7-(1 ,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3- carboxylic acid,
6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
(S)-6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6-(difluoromethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6-chloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,
(S)-6-chloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid, 6,8-dichloro-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,
7-(1 ,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid,
5,6-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
2,6-bis(trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid,
5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid,
6-iodo-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,
6-bromo-1 ,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid,
6-chloro-7-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid,
6,8-dichloro-2-trifluoromethyl-2H-1 -benzothiopyran-3-carboxylic acid, and mixtures thereof.
25. The method according to claim 23, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of (S)-6-chloro-7-(1 ,1-dimethylethyl)-2- (trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid, (2S)-6,8-dimethyl-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-6-chloro-8-methyl-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-8-ethyl-6- (trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)- 6,8-dichloro-2-(trifluoromethyl)-2H-1 -benzopyran-3-carboxylic acid, (2S)-6- chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and mixtures thereof.
26. The method according to claim 14, wherein the conventional anti-diabetic agent comprises at least one compound that is selected from the group consisting of insulin or insulin analogs, sulfonylureas, alpha- glucosidase inhibitors, thiazolidinediones, meglinitides, biguanides, and mixtures thereof.
27. The method according to claim 26, wherein the insulin or insulin analog comprises at least one compound that is selected from the group consisting of insulin regular, insulin glargine, insulin aspart, insulin lispro, insulin lente, insulin ultralente, insulin isophane, insulin protamine, and mixtures thereof.
28. The method according to claim 26, wherein the sulfonylurea comprises at least one compound that is selected from the group consisting of acetohexamide, chlorpropamide, gliclazide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide, and mixtures thereof.
29. The method according to claim 26, wherein the alpha- glucosidase inhibitor comprises at least one compound that is selected from the group consisting of acarbose, migitol, and mixtures thereof.
30. The method according to claim 26, wherein the thiazolidinedione comprises at least one compound that is selected from the group consisiting of ciglitizone, englitazone, troglitazone, pioglitazone, rosiglitizone, and mixtures thereof.
31. The method according to claim 20, wherein the meglinitide comprises at least one compound that is selected from the group consisting of repaglinide, nateglimide, and mixtures thereof.
32. The method according to claim 26, wherein the biguanide comprises at least one compound that is selected from the group consisting of buformin, metformin, phenformin, and mixtures thereof.
33. The method according to claim 14, wherein the diabetes- associated ocular disease is diabetic retinopathy.
34. A therapeutic composition comprising at least one Cox-2 inhibitor and at least one anti-diabetic agent.
35. The therapeutic composition according to claim 34, wherein a single dosage includes an amount of a Cox-2 inhibitor and an amount of a conventional anti-diabetic agent which together comprises a therapeutic amount.
36. The therapeutic composition according to claim 34, wherein the Cox-2 inhibitor comprises a Cox-2-selective inhibitor.
37. The therapeutic composition according to claim 36, wherein the Cox-2 selective inhibitor comprises at least one compound that is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, etoricoxib, RS 57067, T-614, BMS-347070, JTE-522, S-2474, SVT-2016, CT-3, ABT-963, SC-58125, nimesulide, flosulide, NS-398, L-745337, RWJ-63556, L- 784512, darbufelone, CS-502, LAS-34475, LAS-34555, S-33516, SD- 8381 , MK-966, L-783003, T-614, D-1376, L-748731 , CGP-28238, BF-389, GR-253035, prodrugs of any of them, and mixtures thereof.
38. The therapeutic composition according to claim 36, wherein the Cox-2 selective inhibitor comprises celecoxib.
39. The therapeutic composition according to claim 34, wherein the conventional anti-diabetic agent comprises at least one compound that is selected from the group consisting of insulin, insulin analogs, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglinitides, biguanides, and mixtures thereof.
40. The therapeutic composition according to claim 34, wherein the conventional anti-diabetic agent comprises at least one compound that is selected from the group consisting of insulin, insulin regular, insulin glargine, insulin aspart, insulin lispro, insulin lente, insulin ultralente, insulin isophane, insulin protamine, acetohexamide, chlorpropamide, gliclazide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide, acarbose, migitol, ciglitizone, englitazone, troglitazone, pioglitazone, rosiglitizone, repaglinide, nateglimide, buformin, metformin, phenformin, and mixtures thereof.
41. A pharmaceutical composition comprising a Cox-2 inhibitor, an anti-diabetic agent, and a pharmaceutically-acceptable excipient.
42. A kit that is suitable for the prevention or treatment of diabetic retinopathy, the kit comprising a first dosage form comprising a Cox-2 inhibitor and a second dosage comprising an anti-diabetic agent, in amounts which comprise a therapeutically effective combination of the compounds for the prevention or treatment of the diabetic retinopathy.
PCT/US2004/039330 2003-11-18 2004-11-18 Cox-2 inhibitors for the treatment or prevention of diabetes-related ocular disorders Ceased WO2005049014A1 (en)

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