US 2004.0029864A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0029864A1 MacMillan (43) Pub. Date: Feb. 12, 2004

(54) TREATMENT OF COLDS AND COUGH Related U.S. Application Data WITH A COMBINATION OF A CYCLOOXYGENASE-2 SELECTIVE (60) Provisional application No. 60/354,135, filed on Feb. INHIBITOR AND A COLDS AND COUGH 4, 2002. ACTIVE INGREDIENT AND COMPOSITIONS THEREOF Publication Classification (75) Inventor: Stephen P. MacMillan, Newtown, PA (51) Int. Cl." ...... A61K 31/55; A61K 31/415; (US) A61K 31/495 (52) U.S. Cl...... 514/217.05; 514/255.04; 514/406 Correspondence Address: Charles E. Dunlap Keenan Building (57) ABSTRACT Third Floor 1330 Lady Street Columbia, SC 29201 (US) A method for the treatment, prevention and amelioration of colds and/or cough in a Subject in need of Such treatment, (73) Assignee: Pharmacia Corporation, St. Louis, MO prevention and amelioration, comprises administering to the Subject a cyclooxygenase-2 Selective inhibitor or prodrug (21) Appl. No.: 10/357,747 thereof and one or more colds and cough active ingredient. Compositions, pharmaceutical compositions and kits for (22) Filed: Feb. 4, 2003 practicing the method are also disclosed. US 2004/0029864 A1 Feb. 12, 2004

TREATMENT OF COLDS AND COUGH WITH A 0009 Recently, significant progress has also been made COMBINATION OF A CYCLOOXYGENASE-2 in the field of inflammation, and the development of drugs SELECTIVE INHIBITOR AND A COLDS AND that show promise for the treatment of the inflammation COUGH ACTIVE INGREDIENT AND related disorders of osteoarthritis and rheumatoid arthritis. It COMPOSITIONS THEREOF has been known for Some time that many of the common non-steroidal antiinflammatory drugs (NSAIDs) modulate CROSS-REFERENCE TO RELATED PATENTS prostagiandin Synthesis by inhibition of cyclooxygenases AND PATENT APPLICATIONS that catalyze the transformation of arachidonic acid-the first Step in the prostaglandin Synthesis pathway. However, 0001. The subject matter of the present invention is the use of high doses of many common NSAIDs can produce related to and claims the benefit of co-pending and com Severe side effects that limit their therapeutic potential. monly assigned U.S. Provisional Patent Application Serial 0010. In an effort to reduce the unwanted side effects of No. 60/354,135, filed on Feb. 4, 2002, which application is common NSAIDS, it was discovered that two cyclooxyge hereby incorporated herein by reference in its entirety. nases are involved in the transformation of arachidonic acid as the first Step in the prostaglandin Synthesis pathway. BACKGROUND OF THE INVENTION These enzymes have been termed cyclooxygenase-1 (Cox 0002 (1) Field of the Invention 1) and cyclooxygenase-2 (Cox-2). See, Needleman, P. et al., J. Rheumatol., 24, Suppl.49:6-8 (1997). See, Fu, J. Y., et al., 0003. The present invention relates to the treatment of J. Biol. Chem., 265(28): 16737-40 (1990). colds and coughs, and more particularly to the treatment of 0011 Cox-1 has been shown to be a constitutively pro colds and coughs by administering to a Subject a combina duced enzyme that is involved in many of the non-inflam tion of a cyclooxygenase-2 Selective inhibitor and a colds matory regulatory functions associated with prostaglandins. and cough active ingredient. Cox-2, on the other hand, is an inducible enzyme having 0004) (2) Description of the Related Art Significant involvement in the inflammatory process. Inflam mation causes the induction of Cox-2, leading to the release 0005 The common cold is an acute viral infection of the of prostanoids, which Sensitize peripheral nociceptor termi mucous membranes of the nose and throat, often involving nals and produce localized pain hyperSensitivity. See, e.g., the Sinuses. The typical Sore throat, Sneezing, and fatigue Samad, T. A. et al., Nature, 410(6827):471-5 (2001). Many can be accompanied by body aches, headache, low fever, of the common NSAIDs are now known to be inhibitors of and chills. The congested and discharging mucous mem both Cox-1 and Cox-2. Accordingly, when administered in brane may become a fertile ground for S Secondary bacterial sufficiently high levels, these NSAIDs affect not only the infection that can spread to the larynx, bronchi, lungs, or inflammatory consequences of Cox-2 activity, but also the ears. Uncomplicated infections usually last from three to ten beneficial activities of Cox-1. days. 0012 Recently, compounds that selectively inhibit Cox-2 0006 Colds are caused by any one of up to 200 viruses to a greater extent than the activity of Cox-1 have been Such as the rhinoviruses, coronaviruses, or respiratory Syn discovered. The new Cox-2-selective inhibitors are believed cytial virus. Infection with a viral Strain conferS only a to offer advantages that include the capacity to prevent or temporary immunity to that Strain. Colds in infants and reduce inflammation while avoiding harmful Side effects young children caused by the respiratory Syncytial virus can associated with the inhibition of Cox-1. progreSS to pneumonia and other complications, and can 0013 Interestingly, for purposes of the present invention, result in death. it has been reported that isolated alkali metal and alkali-earth metal Salts of acetaminophen could be used for treatment of 0007. It is believed that there is no treatment for the mammals in need of an analgesic or antipyretic agent. U.S. common cold other than that aimed at relieving Symptoms Pat. No. 6,160,020 to Ohannesian et al. However, the and keeping the body well rested, fed, and hydrated. How purpose of the invention was to provide metal Salts of ever, many compounds have been found that are effective in acetaminophen with improved acqueous Solubility and taste. the relief of aches and pain (analgesics-usually non-Ste The acetaminophen salts could be combined with other roidal anti-inflammatory drugs, or NSAIDs), in reducing active ingredients Such as analgesics, decongestants, expec Sneezing and runny nose (antihistamines), for the Suppres torants, antituSSives, antihistamines, diuretics, gastrointesti Sion of coughs (antituSSives), for the breakup of nasal and nal agents, bronchodilators, and Sleep-inducing agents. The Sinus congestion (decongestants), and for helping clear the analgesic could be Supplied by acetylsalicylic acid (aspirin), lungs of excess mucus (expectorants). Many of these medi indomethacin, and CoX-2 inhibitorS Such as floSulide, nime cations are available commercially, and more are now being Sulide, celecoxib, 5-(4-aminosu lfonyl-3-fluorophenyl)-4- developed. cyclohexyl-2-methyloxazole, meloxicam, nambumethone, 0008 One promising area for colds medications is the and etodolac, among other compounds. However, no indi development of new antiviral agents. Older antiviral com cation was provided that the analgesic should be a Cox-2 pounds Such as aciclovir have proven to be effective against Selective inhibitor. Furthermore, the additional chemical herpesviruses, and new materials. Such as dipyridamole, reactions and Separations necessary to provide isolated metal impulsin, and pleconaril have shown promise for the pre Salts of acetaminophen, rather than the acid form of acetami vention and/or amelioration of colds. See, e.g., Jefferson, T. nophen, result in additional expense and require more com O. et al., Cochrane Database Syst. Rev., 1:3 CD002743 pleX production techniques. (2001); and Romero, J. R., Expert. Opin. Investig. Drugs, 0014 U.S. Pat. Nos. 6,271,253; 6,034.256; 6,077,850; 10(2):369-379 (2001). and 6,271,253 to Carter et al. describe the use of certain US 2004/0029864 A1 Feb. 12, 2004

substituted benzopyran Cox-2 inhibitors for the treatment of and amelioration of colds and/or cough in a Subject in need inflammation. It is also Stated that the Substituted benzopy of Such treatment, prevention and amelioration, the compo ran Cox-2 inhibitors can be used in addition to other Sition comprising a cyclooxygenase-2 Selective inhibitor, a anti-inflammatories, and in combination with opioids and colds and cough active ingredient, and a pharmaceutically other analgesics, codeine, hydrocodone, antihistamines, acceptable excipient. decongestants, diuretics and antituSSive agents. 0022. The present invention is also directed to a novel kit 0015 U.S. Pat. No. 6,303,628 to Nakao et al. describes that is Suitable for use in the treatment, prevention or certain bicycliccarbonyl indole compounds as having Cox-2 amelioration of colds and/or cough, the kit comprises a first Selective inhibitory activity, and States that these compounds dosage form comprising a colds and cough active ingredient are useful for treating Cox-2 mediated diseases-including and a Second dosage form comprising a cyclooxygenase-2 co-administration with Such other ingredients as another Selective inhibitor or prodrug thereof, in quantities which pain reliever, a potentiator, a decongestant, an antituSSive, a comprise a therapeutically effective amount of the combi prostaglandin, a diuretic, an antihistamine, anticancer nation of the compounds for the treatment, prevention, or agents, and the like. amelioration of colds and/or cough. 0016. From the foregoing, it can be seen that a need exists 0023. Among the several advantages found to be for improved treatment methods and compositions for colds achieved by the present invention, therefore, may be noted and coughs. It would also be useful if Such improved the provision of improved treatment methods and composi methods and compositions could be provided that combined tions for colds and coughs, the provision of Such improved the effectiveness of Cox-2 selective inhibitors with the methods and compositions that combined the effectiveness effectiveness of one or more compounds that are useful for of Cox-2 selective inhibitors with the effectiveness of one or ameliorating the Symptoms of colds and/or cough. More more compounds that are useful for ameliorating the Symp over, it would be useful if Such methods and compositions toms of colds and/or cough, the provision of Such methods avoided the requirement for Special forms of active ingre and compositions that avoided the requirement for Special dients, in particular, if they could be free of Such materials forms of active ingredients, the provision of Such methods as isolated metal Salts of an active ingredient-isolated and compositions that were free of Such materials as isolated metal Salts of acetaminophen as an example. metal Salts of an active ingredient, and in particular, isolated metal Salts of acetaminophen. SUMMARY OF THE INVENTION 0017 Briefly, therefore the present invention is directed DETAILED DESCRIPTION OF THE to a novel method for the treatment, prevention and ame PREFERRED EMBODIMENTS lioration of colds and/or cough in a Subject in need of Such 0024. In accordance with the present invention, it has treatment, prevention and amelioration, the method com been discovered that some or all of the symptoms of colds prising administering to the Subject a cyclooxygenase-2 and cough can be treated, prevented or ameliorated in a Selective inhibitor or prodrug thereof and one or more colds Subject in need of Such treatment, prevention or amelioration and cough active ingredient. by administering to the Subject a cyclooxygenase-2 Selective 0.018. The present invention is also directed to a novel inhibitor or prodrug thereof and one or more colds and composition for the treatment, prevention and amelioration cough active ingredient. In order to reduce the costs and of colds and/or cough in a Subject in need of Such treatment, complications of producing the novel combinations, it has prevention and amelioration, the composition comprising a been found that combinations comprising acetaminophen cyclooxygenase-2 Selective inhibitor and a colds and cough are not required to contain the isolated metal Salt of acetami active ingredient. nophen. Indeed, in combinations comprising analgesics, it has been found that it is not required that the analgesic be an 0019. The present invention is also directed to a novel isolated metal Salt of the analgesic. composition for the treatment, prevention and amelioration of colds and/or cough in a Subject in need of Such treatment, 0025. In certain embodiments, the compositions of the prevention and amelioration, the composition comprising a invention comprise one or more Cox-2 Selective inhibitors in cyclooxygenase-2 Selective inhibitor Selected from the combination with two or more colds and cough active group consisting of celecoxib, parecoxib and Valdecoxib, ingredients. and a colds and cough active ingredient Selected from the 0026. In each of the embodiments of the subject methods group consisting of chlorpheniramine, cetirzine, loratadine, and compositions, it has been found that the anti-inflamma codeine, hydrocodone, carbetapentane, dextromethorphan, tory and analgesic effects of a Cox-2 Selective inhibitor can aspirin, guaifenesin, ephedrine, ephinephrine, phenyleph be enjoyed without the adverse side effects of some other rine, phenylpropanolamine, pseudoephedrine, impulsin, ple common NSAIDs. Moreover, the novel methods and com conaril, aciclovir, and ganciclovir. positions provide the benefits of the colds and cough active 0020. The present invention is also directed to a novel ingredients that are included. composition for the treatment, prevention and amelioration 0027. One component of the combination of the present of colds and/or cough in a Subject in need of Such treatment, invention is a cycloxygenase-2 Selective inhibitor. The terms prevention and amelioration, the composition comprising a “cyclooxygenase-2 selective inhibitor', or “Cox-2 selective cyclooxygenase-2 Selective inhibitor and a combination of inhibitor', which can be used interchangeably herein, two or more colds and cough active ingredients. embrace compounds which Selectively inhibit cyclooxyge 0021. The present invention is also directed to a novel nase-2 over cyclooxygenase-1, and also include pharmaceu pharmaceutical composition for the treatment, prevention tically acceptable Salts of those compounds. US 2004/0029864 A1 Feb. 12, 2004

0028. 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 B-2 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 th O ICso value for inhibition of Cox-1, divided by the ICs value N N for inhibition of Cox-2 (Cox-1 ICs/Cox-2 ICs). A Cox-2 HN1 N \ f selective inhibitor is any inhibitor for which the ratio of Cox-1 ICso to Cox-2 ICso is greater than 1. In preferred O 21 Cl embodiments, this ratio is greater than 2, more preferably CH greater than 5, yet more preferably greater than 10, Still more preferably greater than 50, and more preferably still greater 0034. In a another embodiment of the invention the than 100. cyclooxygenase-2 Selective inhibitor is of the chromene/ chroman Structural class that is a Substituted benzopyran or 0029. As used herein, the term “ICs” refers to the a Substituted benzopyran analog, and even more preferably concentration of a compound that is required to produce Selected from the group consisting of Substituted benzothi 50% inhibition of cyclooxygenase activity. Preferred opyrans, dihydroquinolines, or dihydronaphthalenes having cyclooxygenase-2 Selective inhibitors of the present inven the Structure of any one of the compounds having a structure tion have a cyclooxygenase-2 ICso of less than about 1 uM, shown by general Formulas I, II, III, IV, V, and VI, shown more preferred of less than about 0.5 uM, and even more below, and possessing, by way of example and not limita preferred of less than about 0.2 uM. tion, the Structures disclosed in Table 1, including the 0030 Preferred cycloxoygenase-2 selective inhibitors diastereomers, enantiomers, racemates, tautomers, Salts, have a cyclooxygenase-1 ICs of greater than about 1 uM, esters, amides and prodrugs thereof. and more preferably of greater than 20 uM. Such preferred 0035 Benzopyrians that can serve as a cyclooxygenase-2 Selectivity may indicate an ability to reduce the incidence of selective inhibitor of the present invention include substi common NSAID-induced side effects. tuted benzopyran derivatives that are described in U.S. Pat. No. 6,271,253. One such class of compounds is defined by 0031. Also included within the scope of the present the general formula shown below in formulas I: invention are compounds that act as prodrugs of cyclooxy genase-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 R2 Cox-2 selective inhibitor by metabolic or simple chemical Al R1 processes within the body of the Subject. One example of a A22 N prodrug for a Cox-2 Selective inhibitor is parecoxib, which R-- A is a therapeutically effective prodrug of the tricyclic A. cyclooxygenase-2 Selective inhibitor Valdecoxib. An s X1 R3 example of a preferred Cox-2 Selective inhibitor prodrug is parecoxib Sodium. A class of prodrugs of Cox-2 inhibitors is described in U.S. Pat. No. 5,932,598. 0036) wherein X is selected from O, S, CRR and NR; 0.032 The cyclooxygenase-2 selective inhibitor of the present invention can be, for example, the Cox-2 Selective 0037 wherein R is selected from hydrido, C-C- inhibitor meloxicam, Formula B-1 (CAS registry number alkyl, (optionally Substituted phenyl)-C-C-alkyl, 71125-38-7), or a pharmaceutically acceptable salt or pro acyl and carboxy-C-C-alkyl, drug thereof. 0.038 wherein each of R and R is independently Selected from hydrido, C-C-alkyl, phenyl-C-C- alkyl, C-C-perfluoroalkyl, chloro, C-C-alkylthio, C-C-alkoxy, nitro, cyano and cyano-C-C-alkyl, OH O \ B-1 or wherein CRR forms a 3-6 membered cycloalkyl ring, 0039) wherein R' is selected from carboxyl, ami s1 N nocarbonyl, C-C-alkylsulfonylaminocarbonyl and MV C-C-alkoxycarbonyl, O O 0040 wherein R is selected from hydrido, phenyl, thie nyl, C-C-alkyl and C-C-alkenyl, 0033. In another embodiment of the invention the 0041) wherein R is selected from C-C-perfluoro cyclooxygenase-2 Selective inhibitor can be the Cox-2 Selec alkyl, chloro, C-C-alkylthio, C-C-alkoxy, nitro, tive inhibitor RS 57067, 6-5-(4-chlorobenzoyl)-1,4-dim ethyl-1H-pyrrol-2-yl)methyl-3(2H)-pyridazinone, Formula cyano and cyano-C-C-alkyl, B-2 (CAS registry number 179382-91-3), or a pharmaceu 0.042 wherein R is one or more radicals indepen tically acceptable Salt or prodrug thereof. dently Selected from hydrido, halo, C-C-alkyl, US 2004/0029864 A1 Feb. 12, 2004

C-C-alkenyl, C-C-alkynyl, halo-C-C-alkynyl, 0051) wherein R is selected from C-C-perfluoro aryl-C-C-alkyl, aryl-C-C-alkynyl, aryl-C-C- alkyl, chloro, C-C-alkylthio, C-C-alkoxy, nitro, alkenyl, C-C-alkoxy, methylenedioxy, C-C-alky cyano and cyano-C-C-alkyl; wherein R is one or lthio, C-C-alkylsulfinyl, aryloxy, arylthio, aryl more radicals independently Selected from hydrido, Sulfinyl, heteroaryloxy, C-C-alkoxy-C-C-alkyl, halo, C-C-alkyl, C-C-alkenyl, C-C-alkynyl, aryl-C-C-alkyloxy, heteroaryl-C-C-alkyloxy, halo-C-C-alkynyl, aryl-C-C-alkyl, aryl-C-C- aryl-C-C-alkoxy-C-C-alkyl, C-C-haloalkyl, alkynyl, aryl-C-C-alkenyl, C-C-alkoxy, methyl C-C-haloalkoxy, C-C-haloalkylthio, C-C-ha enedioxy, C-C-alkylthio, C-C-alkylsulfinyl, loalkylsulfinyl, C-C-haloalkylsulfonyl, C-C-(ha -O(CF)-O-, aryloxy, arylthio, arylsulfinyl, het loalkyl-1-C -hydroxyalkyl, C-C-hydroxyalkyl, eroaryloxy, C-C-alkoxy-C-C-alkyl, aryl-C-C- hydroxyimino-C-C-alkyl, C-C-alkylamino, ary alkyloxy, heteroaryl-C-C-alkyloxy, aryl-C-C- lamino, aryl-C-C-alkylamino, heteroarylamino, alkoxy-C-C-alkyl, C-C-haloalkyl, 1. 6 heteroaryl-C-C-alkylamino, nitro, cyano, amino, haloalkoxy, C-C-haloalkylthio, 1. 6 aminoSulfonyl, C-C-alkylaminoSulfonyl, arylami haloalkylsulfinyl, C-C-haloalkylsulfonyl, 1. 3. noSulfonyl, heteroarylaminoSulfonyl, aryl-C-C- (haloalkyl-C-C-hydroxyalkyl), 1 - 6 alkylaminosulfonyl, heteroaryl-C-C-alkylamino hydroxyalkyl, hydroxyimino-C-C-alkyl, C-C- Sulfonyl, heterocyclylsulfonyl, C-C-alkylsulfonyl, alkylamino, arylamino, aryl-C-C-alkylamino, aryl-C-C-alkylsulfonyl, optionally Substituted aryl, heteroarylamino, heteroaryl-C-C-alkylamino, optionally Substituted heteroaryl, aryl-C-C-alkyl nitro, cyano, amino, aminoSulfonyl, C-C-alkylami carbonyl, heteroaryl-C-C-alkylcarbonyl, het noSulfonyl, arylaminosulfonyl, heteroarylaminoSul eroarylcarbonyl, arylcarbonyl, aminocarbonyl, fonyl, aryl-C-C-alkylaminoSulfonyl, heteroaryl C-C-alkoxycarbonyl, formyl, C-C-haloalkylcar C-C-alkylaminoSulfonyl, heterocyclylsulfonyl, bonyl and C-C-alkylcarbonyl; and C-C-alkylsulfonyl, aryl-C-C-alkylsulfonyl, optionally Substituted aryl, optionally Substituted 0043 wherein the A ring atoms A, A, A and A' heteroaryl, aryl-C-C-alkylcarbonyl, heteroaryl-C- are independently Selected from carbon and nitrogen Co-alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, with the proviso that at least two of A, A, A and aminocarbonyl, C-C-alkoxycarbonyl, formyl, A" are carbon; C-C-haloalkylcarbonyl and C-C-alkylcarbonyl, 0044) or wherein R* together with ring A forms a and radical Selected from naphthyl, quinolyl, isoquinolyl, 0.052 wherein the D ring atoms D, D, D and D' quinolizinyl, quinoxalinyl and dibenzofuryl, or an are independently Selected from carbon and nitrogen isomer or pharmaceutically acceptable Salt thereof. with the proviso that at least two of D, D™, D and 0.045 Another class of benzopyran derivatives that can D" are carbon; or serve as the Cox-2 selective inhibitor of the present inven : 8 - 0 tion includes a compound having the Structure of formula II: 0053 wherein R together with ring D forms a radical Selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl, or an II isomer or pharmaceutically acceptable Salt thereof. R6 0054) Other benzopyran Cox-2 selective inhibitors useful D R5 in the practice of the present invention are described in U.S. p? 5 N Pat. Nos. 6,034,256 and 6,077.850. The general formula for these compounds is shown in formula III: R8-DS 8D 1. s X2 R7 0.055 Formula III is:

III 0046) wherein X is selected from O, S, CRR and NR; 0047 wherein R is selected from hydrido, C-C- alkyl, (optionally Substituted phenyl)-C-C-alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-C-C-alkyl, 0.048 wherein each of R and R is independently Selected from hydrido, C-C-alkyl, phenyl-C-C- alkyl, C-C-perfluoroalkyl, chloro, C-C-alkylthio, 0056 wherein X is selected from the group con C-C-alkoxy, nitro, cyano and cyano-C-C-alkyl, sisting of O or S or NR; or wherein CR R form a cyclopropyl ring; 0057 wherein R is alkyl; 0049) wherein R is selected from carboxyl, ami 0058 wherein R is selected from the group con nocarbonyl, C-C-alkylsulfonylaminocarbonyl and Sisting of H and aryl; C-C-alkoxycarbonyl, 0059) wherein R' is selected from the group con 0050 wherein R is selected from hydrido, phenyl, Sisting of carboxyl, aminocarbonyl, alkylsulfony thienyl, C-C-alkynyl and C-C-alkenyl; laminocarbonyl and alkoxycarbonyl, US 2004/0029864 A1 Feb. 12, 2004

0060) wherein R' is selected from the group consisting 0070 Formula V is: of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally Substituted with one or more radicals Selected from alky lthio, nitro and alkylsulfonyl, and 0061 wherein R' is selected from the group consisting of one or more radicals Selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralky loxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralky lamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminoSulfonyl, alkylaminoSulfonyl, arylaminosulfo 0071 wherein: nyl, heteroarylaminoSulfonyl, aralkylaminoSulfonyl, het 0072 X is selected from the group consisting of eroaralkylaminoSulfonyl, heterocycloSulfonyl, alkylsulfo O or S or NR; nyl, hydroxyarylcarbonyl, nitroaryl, optionally Substituted 0073 R is alkyl; aryl, optionally Substituted heteroaryl, aralkylcarbonyl, het eroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcar 0074) R' is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocar bonyl; or bonyl and alkoxycarbonyl, 0062) wherein R' together with ring E forms a 0075 R7 is selected from the group consisting of naphthyl radical; or an isomer or pharmaceutically haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, acceptable Salt thereof, and including the diastere wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and omers, enantiomers, racemates, tautomers, Salts, aryl each is independently optionally Substituted esters, amides and prodrugs thereof. with one or more radicals Selected from the group 0.063 A related class of compounds useful as cyclooxy consisting of alkylthio, nitro and alkylsulfonyl, genase-2 Selective inhibitors in the present invention is and described by Formulas IV and V. 0076) R' is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralky IV loxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroary lamino, heteroarylalkylamino, nitro, amino, ami noSulfonyl, alkylaminoSulfonyl, arylaminoSulfo nyl, heteroarylaminoSulfonyl, aralkylaminoSulfonyl, heteroaralkylaminoSulfo nyl, heterocycloSulfonyl, alkylsulfonyl, optionally 0.064 wherein X" is selected from O or S or NR; Substituted aryl, optionally Substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbo 0065 wherein R is alkyl; nyl, aminocarbonyl, and alkylcarbonyl, or 0.066 wherein R' is selected from carboxyl, ami wherein R' together with ring A forms a naphthyl nocarbonyl, alkylsulfonylaminocarbonyl and radical; alkoxycarbonyl, 0.077 or an isomer or pharmaceutically accept able salt thereof. 0067 wherein R' is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally Substituted 0078. The cyclooxygenase-2 selective inhibitor may also with one or more radicals Selected from alkylthio, be a compound of Formula V, wherein: nitro and alkylsulfonyl; and 0079 X is selected from the group consisting of 0068 wherein R' is one or more radicals selected from oxygen and Sulfur, hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, 0080) R' is selected from the group consisting of aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alky carboxyl, lower alkyl, lower aralkyl and lower lamino, arylamino, aralkylamino, heteroarylamino, het alkoxycarbonyl, eroarylalkylamino, nitro, amino, aminoSulfonyl, alkylami noSulfonyl, arylaminoSulfonyl, heteroarylaminoSulfonyl, 0081) R' is selected from the group consisting of aralkylaminoSulfonyl, heteroaralkylaminoSulfonyl, hetero lower haloalkyl, lower cycloalkyl and phenyl; and cycloSulfonyl, alkylsulfonyl, optionally Substituted aryl, 0082) R' is one or more radicals selected from the group optionally Substituted heteroaryl, aralkylcarbonyl, het of consisting of hydrido, halo, lower alkyl, lower alkoxy, eroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcar lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, bonyl; amino, aminoSulfonyl, lower alkylaminoSulfonyl, 5-mem bered heteroarylalkylaminosulfonyl, 6-membered het 0069 or wherein R' together with ring G forms a eroarylalkylaminoSulfonyl, lower aralkylaminosulfonyl, naphthyl radical; or an isomer or pharmaceutically 5-membered nitrogen-containing heterocycloSulfonyl, acceptable Salt thereof. 6-membered-nitrogen containing heterocycloSulfonyl, US 2004/0029864 A1 Feb. 12, 2004 lower alkylsulfonyl, optionally Substituted phenyl, lower 0098) R' is selected from the group consisting of aralkylcarbonyl, and lower alkylcarbonyl, or carboxyl, lower alkyl, lower aralkyl and lower 0.083 wherein R together with ring A forms a alkoxycarbonyl, naphthyl radical; or an isomer or pharmaceutically 0099 R7 is selected from the group consisting acceptable Salt thereof. trifluoromethyl and pentafluoroethyl; and 0084. The cyclooxygenase-2 selective inhibitor may also 0100) R' is one or more radicals selected from the group be a compound of Formula V, wherein: consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trif I0085 X is selected from the group consisting of oxygen luoromethoxy, N-phenylmethylaminosulfonyl, N-phenyl and Sulfur, ethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N- 0086) R' is carboxyl; R7 is lower haloalkyl; and dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2- 0087) R' is one or more radicals selected from the group dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, consisting of hydrido, halo, lower alkyl, lower haloalkyl, 2-methylpropylaminoSulfonyl, N-morpholinosulfonyl, lower haloalkoxy, lower alkylamino, amino, aminoSulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; or wherein R' lower alkylaminosulfonyl, 5-membered heteroarylalkylami together with ring A forms a naphthyl radical; noSulfonyl, 6-membered heteroarylalkylaminoSulfonyl, 0101 or an isomer or prodrug thereof. lower aralkylaminoSulfonyl, lower alkylsulfonyl, 6-mem bered nitrogen-containing heterocycloSulfonyl, optionally 0102) The cyclooxygenase-2 selective inhibitor of the Substituted phenyl, lower aralkylcarbonyl, and lower alky present invention can also be a compound having the lcarbonyl; or wherein R' together with ring A forms a structure of Formula VI: naphthyl radical; 0088 or an isomer or pharmaceutically acceptable VI Salt thereof. 0089. The cyclooxygenase-2 selective inhibitor may also be a compound of Formula V, wherein: 0090 X is selected from the group consisting of oxygen and Sulfur, 0091) R' is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl, 0092) R'7 is selected from the group consisting of 01.03 wherein: fluoromethyl, chloromethyl, dichloromethyl, trichlo 0104 X is selected from the group consisting of romethyl, pentafluoroethyl, heptafluoropropyl, d O and S; ifluoroethyl, difluoropropyl, dichloroethyl, dichlo ropropyl, difluoromethyl, and trifluoromethyl, and 01.05) R' is lower haloalkyl;y 0.093) R' is one or more radicals selected from the 0106) R' is selected from the group consisting of group consisting of hydrido, chloro, fluoro, bromo, hydrido, and halo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, 0107) R' is selected from the group consisting of isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropy hydrido, halo, lower alkyl, lower haloalkoxy, lower loxy, tertbutyloxy, trifluoromethyl, difluoromethyl, alkoxy, lower aralkylcarbonyl, lower dialkylamino trifluoromethoxy, amino, N,N-dimethylamino, N,N- Sulfonyl, lower alkylaminoSulfonyl, lower aralky diethylamino, N-phenylmethylaminosulfonyl, laminosulfonyl, lower heteroaralkylaminoSulfonyl, N-phenylethylaminosulfonyl, N-(2-furylmethy 5-membered nitrogen-containing heterocycloSulfo l)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl, nyl, and 6-membered nitrogen-containing heterocy aminosulfonyl, N-methylaminosulfonyl, N-ethylsul closulfonyl; fonyl, 2,2-dimethylethylaminosulfonyl, N,N-dim ethylaminosulfonyl, N-(2-methylpropyl)aminosulfo 0108) R' is selected from the group consisting of nyl, N-morpholinosulfonyl, methylsulfonyl, hydrido, lower alkyl, halo, lower alkoxy, and aryl; benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phe and nylacetyl and phenyl; or 0109) R' is selected from the group consisting of O094 WCCherein R togetherh withith ring.ring A fOS a the group consisting of hydrido, halo, lower alkyl, naphthyl radical; lower alkoxy, and aryl; 0095 or an isomer or pharmaceutically acceptable 0110 or an isomer or prodrug thereof. Salt thereof. 0111. The cyclooxygenase-2 selective inhibitor can also 0096. The cyclooxygenase-2 selective inhibitor may also be a compound of having the structure of Formula VI, be a compound of Formula V, wherein: wherein: 0097 X is selected from the group consisting of 0112 X is selected from the group consisting of O oxygen and Sulfur, and S; US 2004/0029864 A1 Feb. 12, 2004 7

0113) R' is selected from the group consisting of trifluoromethyl and pentafluoroethyl; TABLE 1-continued 0114 R’ is selected from the group consisting of Examples of Chromene Cox-2 Selective Inhibitors hydrido, chloro, and fluoro; Compound 0115) R' is selected from the group consisting of Number Structural Formula hydrido, chloro, bromo, fluoro, iodo, methyl, tert- B-6 O butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminoSulfonyl, N OH methylaminoSulfonyl, benzylaminoSulfonyl, phenyl ethylaminoSulfonyl, methylpropylaminoSulfonyl, O CF methylsulfonyl, and morpholinoSulfonyl, 0116 R22 is selected from the group consisting of 2-Trifluoromethyl-2H-naphtho2,3-bipyran3-carboxylic acid hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl; and O 0117 R is selected from the group consisting of ON C N OH hydrido, chloro, bromo, fluoro, methyl, ethyl, tert butyl, methoxy, and phenyl, O O CF 0118 or an isomer or prodrug thereof. 6-Chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1- benzopyran-3-carboxylic acid

TABLE 1. B-8 O Examples of Chromene Cox-2 Selective Inhibitors C N OH Compound Number Structural Formula B-3 O O CF Cl ON N OH (S)-6,8-Dichloro-2-(trifluoromethyl)- 2H-1-benzopyran-3-carboxylic acid

O CF B-9

6-Nitro-2-trifluoromethyl-2H-1- O benzopyran-3-carboxylic acid C S. OH B-4 O

C N OH O CF 6-Chloro-2-(trifluoromethyl)-4-phenyl-2H O CF 1-benzopyran-3-carboxylic acid

CH B-10 O O

N OH 6-Chloro-8-methyl-2-trifluoromethyl 2H-1-benzopyran-3-Carboxylic acid HO O CF

B-5 O 6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)- 2H-1-benzopyran-3-carboxylic acid C N OH B-11 O

O CF FC 1S N OH CH S CF ((S)-6-Chloro-7-(1,1-dimethylethyl)-2- (trifluoromethyl-2H-1-benzopyran-3-Carboxylic acid 2-(Trifluoromethyl)-6-(trifluoromethyl)thio 2H-1-benzothiopyran-3-carboxylic acid

US 2004/0029864 A1 Feb. 12, 2004 12

0290 r2) 6-chloro-2-trifluoromethyl-2H-1-benzothi cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalk opyran-3-carboxylic acid; enyl, aralkyl, heterocyclylalkyl, acyl, alkylthio 0291 r3) 4-5-(4-chlorophenyl)-3-(trifluoromethyl)- alkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbo 1H-pyrazol-1-ylbenzenesulfonamide; nyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, 0292 r4) 4-5-(4-methylphenyl)-3-(trifluoromethyl)- aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbo 1H-pyrazol-1-ylbenzenesulfonamide; nylalkyl, aminocarbonyl, aminocarbonylalkyl, 0293 rS) 4-5-(3-fluoro-4-methoxyphenyl)-3-(difluo alkylaminocarbonyl, N-arylaminocarbonyl, romethyl)-1H-pyrazol-1-yl)benzenesulfonamide; N-alkyl-N-arylaminocarbonyl, alkylaminocarbo nylalkyl, carboxyalkyl, alkylamino, N-arylamino, 0294 r8) 3-1-4-(methylsulfonyl)phenyl-4-trifluo N-aralkylamino, N-alkyl-N-aralkylamino, romethyl-1H-imidazol-2-ylpyridine; N-alkyl-N-arylamino, aminoalkyl, alkylami 0295 r7) 2-methyl-5-1-4-(methylsulfonyl)phenyl noalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, 4-trifluoromethyl-1H-imidazol-2-ylpyridine; N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylami 0296 r8) 4-2-(5-methylpyridin-3-yl)-4-(trifluorom noalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, ethyl)-1H-imidazol-1-ylbenzenesulfonamide; alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alky laminosulfonyl, N-arylaminosulfonyl, arylsulfo 0297 r9) 4-5-methyl-3-phenylisoxazol-4-ylbenzene nyl, N-alkyl-N-arylaminosulfonyl; Sulfonamide; 0298 r10) 4-5-hydroxymethyl-3-phenylisoxazol-4- 0308) or a prodrug thereof. ylbenzenesulfonamide; 0309. In a preferred embodiment of the invention the 0299 s1) 2-trifluoromethyl-5-(3,4-difluorophenyl)-4- cyclooxygenase-2 Selective inhibitor represented by the oxazolylbenzenesulfonamide; above Formula VII is selected from the group of com 0300 s2) 4-2-methyl-4-phenyl-5-oxazolylbenzene pounds, illustrated in Table 2, which includes celecoxib (B-18), Valdecoxib (B-19), deracoxib (B-20), rofecoxib Sulfonamide; or (B-21), etoricoxib (MK-663; B-22), JTE-522 (B-23), or a 0301 s3) 4-5-(3-fluoro-4-methoxyphenyl-2-trifluo prodrug thereof. romethyl)-4-oxazolylbenzenesulfonamide; or a phar maceutically acceptable Salt or prodrug thereof. 0310 Additional information about selected examples of the Cox-2 selective inhibitors discussed above can be found 0302) In a further preferred embodiment of the invention as follows: celecoxib (CAS RN 169590-42-5, C-2779, the cyclooxygenase inhibitor can be selected from the class SC-58653, and in U.S. Pat. No. 5,466,823); deracoxib (CAS of tricyclic cyclooxygenase-2 Selective inhibitors repre RN 169590-41-4); rofecoxib (CAS RN 162011-90-7); com sented by the general structure of formula VII: pound B-24 (U.S. Pat. No. 5,840,924); compound B-26 (WO 00/25779); and etoricoxib (CAS RN 202409-33-4, VII MK-663, SC-86218, and in WO 98/03484). TABLE 2 Examples of Tricyclic COX-2 Selective Inhibitors Compound Number Structural Formula 0303 wherein: B-18 O O 0304 Z is selected from the group consisting of V/ partially unsaturated or unsaturated heterocyclyl -S CH and partially unsaturated or unsaturated carbocy HN clic rings, 0305) R' is selected from the group consisting of N heterocyclyl, cycloalkyl, cycloalkenyl and aryl, Nf \ wherein R' is optionally substituted at a substi tutable position with one or more radicals Selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycar CF bonyl, hydroxyl, hydroxyalkyl, haloalkoxy, B-19 O. O amino, alkylamino, arylamino, nitro, alkoxyalkyl, V/ alkylsulfinyl, halo, alkoxy and alkylthio; 0306 R is selected from the group consisting of methyl or amino; and 0307 R’ is selected from the group consisting of a radical Selected from H, halo, alkyl, alkenyl, alkynyl, OXO, cyano, carboxyl, cyanoalkyl, hetero cyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, US 2004/0029864 A1 Feb. 12, 2004

TABLE 2-continued B-24 Examples of Tricyclic COX-2 Selective Inhibitors

Compound Number Structural Formula

B-2O F O.V/ O -S OCH HN 0313 A preferred form of parecoxib is sodium parecoxib. N 0314. In another embodiment of the invention, the com f \ pound ABT-963 having the formula B-25 that has been N previously described in International Publication number WO 00/24719, is another tricyclic cyclooxygenase-2 selec CHF, tive inhibitor which may be advantageously employed.

B-21 O O B-25 \/ F O OH O HC1 CO | F O O 2N

B-22 O O H3CN S \/ CH /\ HC1 21 3 O O N N 0315. In a further embodiment of the invention, the cyclooxygenase inhibitor can be Selected from the class of / \ phenylacetic acid derivative cyclooxygenase-2 Selective inhibitors represented by the general Structure of Formula C VIII:

B-23 O. O VIII \/ R2 O HN1 OO orNH s R28 R32 CH R29 R31 R30 0311. In a more preferred embodiment of the invention, the Cox-2 selective inhibitor is selected from the group 0316 wherein: consisting of celecoxib, rofecoxib and etoricoxib. 0317 R is methyl, ethyl, or propyl; 0312. In a preferred embodiment of the invention, pare coxib (See, e.g. U.S. Pat. No. 5,932,598), having the struc 0318 R is chloro or fluoro; ture shown in B-24, which is a therapeutically effective 0319 R’ is hydrogen, fluoro, or methyl; prodrug of the tricyclic cyclooxygenase-2 Selective inhibitor 0320 R is hydrogen, fluoro, chloro, methyl, valdecoxib, B-19, (See, e.g., U.S. Pat. No. 5,633,272), may ethyl, methoxy, ethoxy or hydroxy, be advantageously employed as a Source of a cyclooxyge nase inhibitor. 0321) R' is hydrogen, fluoro, or methyl; and US 2004/0029864 A1 Feb. 12, 2004 14

0322) R' is chloro, fluoro, trifluoromethyl, (0345) X is O; J is 1-oxo-inden-5-yl; R is 2-F; methyl, or ethyl, provided that R, R, R and R is 4-F; and R is 6-NHSOCH, (flosulide); R" are not all fluoro when R7 is ethyl and R is and H. 0323) A phenylacetic acid derivative cyclooxygenase-2 0346 X is O; J is cyclohexyl; R is Selective inhibitor that is described in WO 99/11605 is a 2-NHSOCH; R is 5-NO; and there is no R. compound that has the structure shown in Formula VIII, group, (NS-398); and (0347 X is S; J is 1-oxo-inden-5-yl; R is 2-F; 0324 wherein: R is 4-F; and R is 6-NSCH, Na", 0325 R7 ISis ethylethyl, (L-745337); and 0326). RandR are Chloro,h 0348 X is S; J is thiophen-2-yl; R is 4-F, there 0327) R' and R are hydrogen; and is no R' group; and R is 5-NHSOCH (RWJ 0328. RiIS methV.hyl 63556); and 0329. Another phenylacetic acid derivative cyclooxyge 0349 X is 0; J is 2-oxo-5(R)-methyl-5-(2,2,2- nase-2 Selective inhibitor is a compound that has the Struc trifluoroethyl)furan-(5H)-3-yl; R is 3-F; R is ture shown in Formula VIII, 4-F; and R is 4-(p-SOCH)C.H., (L-784512). 0330 wherein: 0350. Further information on the applications of the Cox-2 selective inhibitor N-(2-cyclohexyloxynitrophenyl) 0331) R7 is propyl; methane sulfonamide (NS-398, CAS RN 123653-11-2), 0332) R and Rare chloro; having a structure as shown in formula B-26, have been described by, for example, Yoshimi, N. et al., in Japanese J. 0333) R’ and R are methyl; and Cancer Res., 90(4):406-412 (1999); Falgueyret, J.-P. et al., 0334) R’ is ethyl. in Science Spectra, available at: http://www.gbhap.com/ Science Spectra/20-1-article.htm (06/06/2001); and Iwata, 0335) Another phenylacetic acid derivative cyclooxyge K. et al., in Jpn. J. Pharmacol., 75(2):191-194 (1997). nase-2 Selective inhibitor that is described in WO 02/20090 is a compound that is referred to as COX-189 (also termed lumiracoxib), having CAS Reg. No. 220991-20-8, and hav B-26 ing the structure shown in Formula VIII, H n 1 SOCH 0336 wherein: 0337 R-7 is methyl; 0338 R is fluoro; 0339) R is chloro; and 0340 R'R'', and R are hydrogen. NO 0341 Compounds that have a structure similar to that shown in Formula VIII, which can serve as the Cox-2 0351. An evaluation of the anti-inflammatory activity of Selective inhibitor of the present invention, are described in the cyclooxygenase-2 selective inhibitor, RWJ 63556, in a U.S. Pat. Nos. 6,310,099, 6.291523, and 5,958,978. canine model of inflammation, was described by Kirchner et 0342. Other cyclooxygenase-2 selective inhibitors that al., in J Pharmacol Exp Ther 282, 1094-1101 (1997). can be used in the present invention have the general 0352 Materials that can serve as the cyclooxygenase-2 Structure shown in formula IX, where the J group is a selective inhibitor of the present invention include diaryl carbocycle or a heterocycle. Preferred embodiments have methylidenefuran derivatives that are described in U.S. Pat. the Structure: No. 6,180,651. Such diarylmethylidenefuran derivatives have the general formula shown below in formula X:

IX

0343 wherein: 0344) X is O; J is 1-phenyl; R is 2-NHSOCH; R" is 4-NO; and there is no R group, (nime Sulide), and US 2004/0029864 A1 Feb. 12, 2004

0353 wherein: 0382 Cyclooxygenase-2 selective inhibitors that are use ful in the present invention include darbufelone (Pfizer), 0354) the rings T and M independently are: CS-502 (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 0355) a phenyl radical, 34555 (Almirall Profesfarma), S-33516 (Servier), SD8381 (Pharmacia, described in U.S. Pat. No. 6,034,256), BMS 0356) a naphthyl radical, 347070 (Bristol Myers Squibb, described in U.S. Pat. No. 0357 a radical derived from a heterocycle 6,180,651), MK-966 (Merck), L-783003 (Merck), T-614 comprising 5 to 6 members and possessing (Toyama), D-1367 (Chiroscience), L-748731 (Merck), CT3 from 1 to 4 heteroatoms, or (Atlantic Pharmaceutical), CGP-28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), 6-dioxo 0358 a radical derived from a saturated hydro 9H-purin-8-yl-cinnamic acid (GlaxoWellcome), and S-2474 carbon ring having from 3 to 7 carbon atoms, (Shionogi). 0359 at least one of the substituents Q', Q’, L' or 0383 Information about S-33516, mentioned above, can L is: be found in Current Drugs Headline News, at http://ww 0360 an -S(O), R group, in which n is an w.current-drugs.com/NEWS/Inflam1.htm, 10/04/2001, integer equal to 0, 1 or 2 and R is: where it was reported that S-33516 is a tetrahydroisoinde derivative which has ICs values of 0.1 and 0.001 mM 0361 a lower alkyl radical having 1 to 6 against cyclooxygenase-1 and cyclooxygenase-2, respec carbon atoms or tively. In human whole blood, S-33516 was reported to have 0362 a lower haloalkyl radical having 1 to 6 an EDso=0.39 mg/kg. carbon atoms, or 0384 Compounds that may act as cyclooxygenase-2 0363 an -SONH group; Selective inhibitors include multibinding compounds con taining from 2 to 10 ligands covanlently attached to one or 0364 and is located in the para position, more linkers, as described in U.S. Pat. No. 6,395,724. 0365 the others independently being: 0385 Compounds that may act as cyclooxygenase-2 0366 a hydrogen atom, inhibitors include conjugated linoleic acid that is described 0367 a halogen atom, in U.S. Pat. No. 6,077,868. 0386 Materials that can serve as a cyclooxygenase-2 0368 a lower alkyl radical having 1 to 6 selective inhibitor of the present invention include hetero carbon atoms, cyclic aromatic oxazole compounds that are described in 0369) a trifluoromethyl radical, or U.S. Pat. Nos. 5,994,381 and 6,362.209. Such heterocyclic 0370 a lower O-alkyl radical having 1 to 6 aromatic oxazole compounds have the formula shown below carbon atoms, or in formula XI: 0371 Q' and Q or L' and L are a methylene dioxy group; and XI 0372) R, R7, R and R independently are: 0373) a hydrogen atom, 0374) a halogen atom, 0375) a lower alkyl radical having 1 to 6 carbon atOmS, 0387) wherein: 0376 a lower haloalkyl radical having 1 to 6 0388 Z is an oxygenyg atom; carbon atoms, or O389 OC. O fR'' and R' isIS agrOuda group Ofof the fOrmula 1 0377 an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl, or, R44 0378) R, R-7 or R, R are an oxygen atom, or RS 0379 R, R-7 or R, R, together with the carbon atom to which they are attached, form a Saturated hydrocarbon ring having from 3 to 7 R3-OS R47 carbon atoms, 0380 or an isomer or prodrug thereof. 0381 Particular materials that are included in this family 0390 wherein: of compounds, and which can Serve as the cyclooxygenase-2 selective inhibitor in the present invention, include N-(2- 0391) R' is lower alkyl, amino or lower alky cyclohexyloxynitrophenyl)methane Sulfonamide, and (E)-4- lamino; and (4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene) 0392 R", R, R and R7 are the same or methylbenzenesulfonamide. different and each is hydrogen atom, halogen US 2004/0029864 A1 Feb. 12, 2004

atom, lower alkyl, lower alkoxy, trifluoromethyl, 0414. Materials that can serve as cyclooxygenase-2 hydroxy or amino, provided that at least one of Selective inhibitors include pyridines that are described in R", R", R" and R' is not hydrogen atom, and U.S. Pat. Nos. 6,369,275, 6,127,545, 6,130,334, 6,204,387, the other is an optionally Substituted cycloalkyl, 6,071,936, 6,001,843 and 6,040,450, and which have the an optionally Substituted heterocyclic group or an general formula described by formula XIII: optionally Substituted aryl; and

0393 R' is a lower alkyl or a halogenated lower XIII alkyl, and a pharmaceutically acceptable Salt SOR51 thereof. 0394 Cox-2 selective inhibitors that are useful in the R52 Subject method and compositions can include compounds that are described in U.S. Pat. Nos. 6,080,876 and 6,133,292, r 2 and described by formula XII: N Z4

XII O 0415 wherein: Z3 0416) R' is selected from the group consisting of: O 0417 (a) CH, 0418 (b) NH, 50 R49 R 0419 (c) NHC(O)CF, ROS 0420 (d) NHCH; 0421) Z' is a mono-, di-, or trisubstituted phenyl 0395 wherein: or pyridinyl (or the N-oxide thereof, 0422 wherein the substituents are chosen from 0396 Z is selected from the group consisting of: the group consisting of: 0397) (a) linear or branched C. alkyl, 0423 (a) hydrogen, 0398 (b) linear or branched C alkoxy, 0424) (b) halo, 0399 (c) unsubstituted, mono-, di- or tri-Sub stituted phenyl or naphthyl wherein the Sub 0425) (c) Coalkoxy, Stituents are Selected from the group consisting 0426 (d) Co. alkylthio, of: 0427 (e) CN, 04.00 (1) hydrogen, 0428 (f) Co. alkyl, 0401) (2) halo, 0429 (g) Co. fluoroalkyl, 0402 (3)C alkoxy, 0430) (h) N., 0403) (4) CN, 0431 (i) -COR, 04.04 (5) C fluoroalkyl 0432) (j) hydroxy, 0405 (6) C alkyl, 0433) (k) –C(R)(R)-OH, 0406) (7) -COH: 04:34) (I)-Calkyl-CO-R, 0407) R' is selected from the group consisting of 0435) (m) Cofluoroalkoxy, NH and CH, 0436 R is chosen from the group consisting of: 0408) R" is selected from the group consisting of: 0437 (a) halo, (b) Cigalkoxy, 04.09 C alkyl unsubstituted or substituted 0438) with C. cycloalkyl, and C cycloalkyl, 0439) (c) Co. alkylthio, 0410) R' is selected from the group consisting 0440 (d) CN, of: 0441 (e) C-6 alkyl, 0411 C alkyl unsubstituted or substituted with one, two or three fluoro atoms, and 0442 (f) C. fluoroalkyl, 0412 C. cycloalkyl; 0443) (g) N. 0413 with the proviso that R'' and Rare not the 0444 (h) -CO.R.", SC. 0445) (i) hydroxy, US 2004/0029864 A1 Feb. 12, 2004 17

0446) () –C(R)(R)-OH, 0447 (k) -Calkyl-CO-R', R71 0448 (1) C-fluoroalkoxy, R72 N 0449) (m) NO, 0450 (n) NR'R'', and R75 R73 ClA 21 R74 0451) (o) NHCOR; N N 0452) R53 R54 R55 R56 R57 R58 R59 RGO Ro1 N N R, R', are each independently chosen from the group consisting of: OÁ 2 21h 0453 (a) hydrogen, and 0454 (b) Calkyl; 0462 wherein: 0455 or RandR, RandR or R and R together with the atom to which they are attached form a saturated 0463) R' through R', identical to or different monocyclic ring of 3, 4, 5, 6, or 7 atoms. from one another, are independently a hydrogen atom, a halogen atom, a C-C lower alkyl group, 0456 Materials that can serve as the cyclooxygenase-2 a trifluoromethyl group, an alkoxy group, a selective inhibitor of the present invention include diaryl hydroxy group, a hydroxyalkyl group, a nitro benzopyran derivatives that are described in U.S. Pat. No. group, a group of a formula: S(O)NR', a group of 6,340,694. Such diarylbenzopyran derivatives have the gen a formula: NR'R'', a trifluoromethoxy group, a nitrile group a carboxyl group, an acetyl group, or eral formula shown below in formula XIV: a formyl group,

XIV 0464 wherein n, R, R and R7 have the same X8 meaning as defined by Rabove; and R64 R67 0465 R7 is a hydrogen atom, a halogen atom, a C-C lower alkyl group, a trifluoromethyl group, C N an alkoxy group, a hydroxy group, a trifluo 2 romethoxy group, a carboxyl group, or an acetyl Y--> grOup. R66 0466 Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include 1-(4- Sulfamylaryl)-3-Substituted-5-aryl-2-pyrazolines that are described in U.S. Pat. No. 6,376,519. Such 1-(4-sulfamy 0457 wherein: laryl)-3-substituted-5-aryl-2-pyrazolines have the formula 0458) X is an oxygen atom or a sulfur atom; shown below in formula XV: 0459) R' and R', identical to or different from each other, are independently a hydrogen atom, a XV halogen atom, a C-C lower alkyl group, a trif X9 luoromethyl group, an alkoxy group, a hydroxy group, a nitro group, a nitrile group, or a carboxyl N grOup, 75 N1 0460 R is a group of a formula: S(O)NR wherein n is an integer of 0-2, R is a hydrogen atom, a C-C lower alkyl group, or a group of a formula: NR'R' wherein R and R', identical to or different from each other, are independently a hydrogen atom, or a C-C lower alkyl group; SONH2 and 0461) R' is oxazolyl, benzobthienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, ben 0467 wherein: Zofuranyl, pyrazolyl, pyrazolyl Substituted with a 0468) X is selected from the group consisting of C-C lower alkyl group, indanyl, pyrazinyl, or a C-C trihalomethyl, preferably trifluoromethyl; Substituted group represented by the following C-C alkyl; and an optionally substituted or di StructureS: Substituted phenyl group of formula XVI: US 2004/0029864 A1 Feb. 12, 2004 18

0482 R" is selected from the group consisting of: XVI 0483 (a) CH, 0484 (b) NH, 0485) (c) NHC(O)CF, Ne. 0486) (d) NHCH; 0487 R and Rare independently chosen from 0469 wherein: the group consisting of: 0488 (a) hydrogen, 0470 R77 and R7 are independently selected from the group consisting of hydrogen, halogen, 0489 (b) Co alkyl; preferably chlorine, fluorine and bromine; 0490 or R and R together with the carbon to hydroxyl; nitro, C-C alkyl, preferably C-C, which they are attached form a Saturated mono alkyl, C-C alkoxy, preferably C-C alkoxy; car cyclic carbon ring of 3, 4, 5, 6 or 7 atoms. boxy; C-C trihaloalkyl, preferably trihalom ethyl, most preferably trifluoromethyl, and cyano; 0491 Formula XVIII is: 0471) Z is selected from the group consisting of Substituted and unsubstituted aryl. XVIII 0472. Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include hetero cycles that are described in U.S. Pat. No. 6,153,787. Such heterocycles have the general formulas shown below in formulas XVII and XVIII:

XVII le O HC CH

0492 X' is fluoro or chloro. 0493 Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include 2,3,5- trisubstituted pyridines that are described in U.S. Pat. No. 6,046,217. Such pyridines have the general formula shown below in formula XIX: 0473 wherein:

0474) R' is a mono-, di-, or tri-substituted C XX alkyl, or a mono-, or an unsubstituted or mono-, SOR8 di- or tri-Substituted linear or branched Coalk enyl, or an unsubstituted or mono-, di- or tri Substituted linear or branched Co alkynyl, or an R8 unsubstituted or mono-, di- or tri-Substituted C R85 R87 R89 cycloalkenyl, or an unsubstituted or mono-, di- or tri-Substituted C-12 cycloalkynyl, wherein the N x -- (C)n OR 91 Substituents are chosen from the group consisting R86 R88 R90 of: 0475 (a) halo, selected from F, Cl, Br, and I, 0494 or a pharmaceutically acceptable salt thereof, 0476) (b) OH, 0495 wherein: 0477 (c) CF, 0496 X" is selected from the group consisting of: 0478 (d) C cycloalkyl, 0497 (a) O, 0479 (e)=O, 0498 (b) S, 0480 (f) dioxolane, 0499 (c) bond; 0481 (g) CN; and 0500 n is 0 or 1; US 2004/0029864 A1 Feb. 12, 2004 19

0501) R' is selected from the group consisting of: XX 0502 (a) CH, R99 0503) (b) NH, A622A Rolf 0504 (c) NHC(O)CF; A. W 100 X. y R 0505) R' is chosen from the group consisting R102102 A X12 of: 0506 (a) halo, 0531 and pharmaceutically acceptable salts thereof 0507 (b) C alkoxy, wherein: 0508 (c) C alkylthio, 0532) -A=A A'=A- is selected from the group consisting of: 0509) (d) CN, 0510 (e) C alkyl, 0533) (a) -CH=CH-CH=CH-, 0534) (b) -CH-CH-CH-C(O), 0511 (f) C. fluoroalkyl, CH-CH-C(O)-CH-, CH 0512 (g) N., C(O)-CH-CH, -C(O)-CH-CH CH, 0513 (h)-CO, R', 0535) (c) -CH-CH-C(O)-, -CH 0514 (i) hydroxy, C(O)-CH-, -C(O)-CH-CH, 0515 (i) -C(R')(R)-OH, 0536) (d) -CH-CH-O-C(O), CH 0516 (k) –C, alkyl-CO-R', 0537) (e) -CH-CH-C(O)-O-, 0517 (1) C. fluoroalkoxy, CH s 0518) (m) NO, 05:38) 0519 (n) NR R7, 0520 (o) NHCOR; 0521) R' to R are independantly chosen 0539 (g) -N=CH-CH=CH-, from the group consisting of 0540) (h)-CH=N-CH=CH-, 0522 (a) hydrogen, 0541) (i) -CH=CH-N=CH-, 0523) (b) C alkyl; 0542) (j) -CH=CH-CH=N-, 0524) or R and R, or R and R together 0543 (k) -N=CH-CH=N-, with the atoms to which they are attached form 0544 (1) -N=CH-N=CH-, a carbocyclic ring of 3,4,5,6 or 7 atoms, or R and Rare joined to form a bond. 0545) (m) -CH=N-CH=N-, 0546) 0525. One preferred embodiment of the Cox-2 selective (n) -S-CH=N-, inhibitor of formula XIX is that wherein X is a bond. 0547) (o) -S-N=CH-, 0526. Another preferred embodiment of the Cox-2 selec 0548) (p) -N=N-NH-, tive inhibitor of formula XIX is that wherein X is 0. 0549) (q) -CH=N-S-, and 0527. Another preferred embodiment of the Cox-2 selec tive inhibitor of formula XIX is that wherein X is S. 0550) (r)-N=CH-S-; 0528. Another preferred embodiment of the Cox-2 selec 0551) R' is selected from the group consisting tive inhibitor of formula XIX is that wherein R is CH. of: 0529) Another preferred embodiment of the Cox-2 selec 0552) (a) S(O). CH, tive inhibitor of formula XIX is that wherein R is halo or 0553) (b) S(O)NH, C fluoroalkyl. 0554 (c) S(O)NHCOCF, 0530 Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include diaryl 0555) (d) S(O)(NH)CH, bicyclic heterocycles that are described in U.S. Pat. No. 6,329,421. Such diaryl bicyclic heterocycles have the gen 0556) (e) S(O)(NH)NH, eral formula shown below in formula XX: 0557) (f) S(O)(NH)NHCOCF, US 2004/0029864 A1 Feb. 12, 2004 20

0558 (g) P(O)(CH)OH, and 0589) R' and R' are the substituents residing on any position of -A=A-A’=A- and are 0559) (h) P(O)(CH)NH; Selected independently from the group consisting 0560) R' is selected from the group consisting of: of: 0590 (a) hydrogen, 0561) (a) C, alkyl, 0562 (b) C-7, cycloalkyl, 0591 (b) CF, 0563) (c) mono- or di-substituted phenyl or 0592) (c) CN, naphthyl wherein the Substituent is selected from the group consisting of: 0593) (d) C alkyl, 0564) (1) hydrogen, 0594) (e) Q3 wherein Q3 is Q', COH, C(R0)(R10')OH, 0565) (2) halo, including F, Cl, Br, I, 0566) (3) C, alkoxy, 0595) (f) -O-O", 0567 (4) C alkylthio, 0596) (g) -S-Q", and 0568 (5) CN, 0597 (h) optionally substituted: 0569 (6) CF, 0598 (1) –Cs alkyl-Q, 0570) (7) C. alkyl, 0599 (2) -O-C alkyl-Q, 0571 (8) N., 0600 (3) -S-C alkyl-Q, 0572 (9)-COH, 0601) (4) -C-3 alkyl-O-C alkyl-Q, 0573 (10)-CO-C alkyl, 0602) (5)-C alkyl-S-C alkyl-Q, 0574) (11) -C(R)(R)-OH, 0603 (6) -C alkyl-O-Q", (0575 (12) —C(R')(R')-O-C, alkyl, and 0604 (7) –Cs alkyl-S-Q", 0576) (13)–C, alkyl-CO-R'9; 0605 wherein the substituent resides on the alkyl 0577 (d) mono- or di-substituted heteroaryl chain and the Substituent is C, alkyl, and Q is wherein the heteroaryl is a monocyclic aromatic Q4, COH, C(R)(R9")OH Q is CO-C, ring of 5 atoms, said ring having one hetero alkyl, tetrazolyl-5-yl, or C(R')(R')O-C, atom which is S, O, or N, and optionally 1, 2, alkyl; or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having 0606) R', R'' and R' are each independently one hetero atom which is N, and optionally 1, 2, Selected from the group consisting of 3, or 4 additional Natoms, said Substituents are Selected from the group consisting of: 0607) (a) hydrogen, 0578 (1) hydrogen, 0608 (b) C, alkyl; or 0579 (2) halo, including fluoro, chloro, 0609) R' and R' together with the carbon to bromo and iodo, which they are attached form a saturated mono 0580 (3) C, alkyl, cyclic carbon ring of 3, 4, 5, 6 or 7 atoms, or two R" groups on the same carbon form a saturated 0581 (4) C, alkoxy, monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; 0582) (5) C alkylthio, 0610) R' is hydrogen or C alkyl; 0583 (6) CN, 0611) R' is hydrogen, C alkyl or aryl; 0584) (7) CF, 0585 (8) N., 0586) (9) –C(R)(R)-OH, and 0587 (10) —C(R')(R')-O-C, 0613) Compounds that may act as cyclooxygenase-2 alkyl; inhibitors include Salts of 5-amino or a substituted amino 1,2,3-triazole compound that are described in U.S. Pat. No. 0588 (e) benzoheteroaryl which includes the 6,239,137. The salts are of a class of compounds of formula benzo fused analogs of (d); XXI: US 2004/0029864 A1 Feb. 12, 2004 21

0619 wherein: 0620) R' is hydrogen or halogen, R'' and R' R10 XXI are each independently hydrogen, halogen, lower \ alkyl, lower alkoxy, hydroxy or lower alkanoy N loxy, R 109 N 0621) R'7 is lower haloalkyl or lower alkyl; R 108 0622 X'' is sulfur, oxygen or NH; and 0623) Z is lower alkylthio, lower alkylsulfonyl or - . Sulfamoyl; or a pharmaceutically acceptable Salt 0614 wherein: thereof. 0615 Ro8 is: 0624 Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include substi tuted derivatives of benzosulphonamides that are described A y-(R'), in U.S. Pat. No. 6,297.282. Such benzosulphonamide S. X13-(4- W derivatives have the formula shown below in formula XXIII:

=/Y(R111) XXIII R118

- . X15 S(O)n R119 0616) wherein: O O 21 nN.1 0617 p is 0 to 2; m is 0 to 4; and n is 0 to 5; X' Y N X Rk is O, S, SO, SO, CO, CHCN, CH or C=NR' R123 NH R 124 where R' is hydrogen, loweralkyl, hydroxy, low eralkoxy, amino, loweralkylamino, diloweralky lamino or cyano; and, R'' and R'' are indepen- 0625) wherein: dently halogen, cyano, trifluoromethyl, 0626 X" denotes oxygen, sulphur or NH; loweralkanoyl, nitro, loweralkyl, loweralkoxy, 0627) R' is an optionally unsaturated alkyl or carboxy, lowercarbalkoxy, trifuloromethoxy, alkyloxyalkyl group, optionally mono- or acetamido, loweralkylthio, loweralkylsulfinyl, poly Substituted or mixed Substituted by halogen, loweralkylsulfonyl, trichlorovinyl, trifluorometh alkoxy, OXO or cyano, a cycloalkyl, aryl or het ylthio, trifluoromethylsulfinyl, or trifluoromethyl eroaryl group optionally mono- or poly Substituted sulfonyl; R' is amino, mono or diloweralkyl or mixed Substituted by halogen, alkyl, CF, cyano amino, acetamido, acetimido, ureido, formamido, or alkoxy, formamido or guanidino; and R' is carbamoyl, 0628) R'' and R', independently from one cyano, carbazoyl, amidino or N-hydroxycarbam another, denote hydrogen, an optionally polyfluo oyl, wherein the loweralkyl, loweralkyl contain rised alkyl group, an aralkyl, aryl or heteroaryl ing, loweralkoxy and loweralkanoyl groups con group or a group (CH), X', or tain from 1 to 3 carbon atoms. 0629) R'' and R', together with the N- atom, denote a 3 to 7-membered, Saturated, partially or 0618. Materials that can serve as a cyclooxygenase-2 completely unsaturated heterocycle with one or Selective inhibitor of the present invention include pyrazole more heteroatoms N, O or S, which can optionally derivatives that are described in U.S. Pat. No. 6,136,831. be Substituted by Oxo, an alkyl, alkylaryl or aryl Such pyrazole derivatives have the formula shown below in group, or a group (CH), X'; formula XXII: 0630 X' denotes halogen, NO, -OR', —COR', -COR'', OCOR'', —CN, XXII CONR" OR12-CONR, R2, SR, R14 –S(O)R'', -S(O) R121, NR121 R122, -NH ea N C(O)R'', -NHS(O) R'; R115 Y-A A-R's 0631 n denotes a whole number from 0 to 6; se X14 f N 0632) R' denotes a straight-chained or branched R116 N alkyl group with 1-10 C- atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, aralkyl group, a heteroaryl or heteroaralkyl group r which can optionally be mono- or poly Substituted or mixed Substituted by halogen or alkoxy, N-X76 0633) R' denotes halogen, hydroxy, a straight chained or branched alkyl, alkoxy, acyloxy or US 2004/0029864 A1 Feb. 12, 2004 22

alkyloxycarbonyl group with 1-6 C- atoms, which can optionally be mono- or poly Substituted by halogen, NO, -OR', COR', -COR 121 0657 (r)-R7 N-CH=CH-provided R, OCO, Ric, -CN, -CONR'2 OR 12, is not -S(O)CH, –CONR'R'',-SR',-S(O)R,-S(O) R' 1 0658 (s) -CH=CH-NR-7 provided R' NR, R-NHC(O)R'', NHS(O), R2, or a is not -S(O)CH, polyfluoroalkyl group; 0659 when side b is a double bond, and sides a 0634) R'' and R', independently from one and c are single bonds, and another, denote hydrogen, alkyl, aralkyl or aryl; 0660 X-Y-Z'- is selected from the group and consisting of: 0635 m denotes a whole number from 0 to 2; 0661 (a)=CH-O-CH=, and 0636 and the pharmaceutically-acceptable salts thereof. 0662 (b)=CH-NR'7-CH=, 0637 Materials that can serve as a cyclooxygenase-2 0663 (c) =N-S-CH=, selective inhibitor of the present invention include 3-phenyl 0664) (d)=CH-S-N=, 4-(4(methylsulfonyl)phenyl)-2-(5H)-furanones that are described in U.S. Pat. No. 6,239,173. Such 3-phenyl-4- 0665 (e)=N-O-CH=, (4(methylsulfonyl)phenyl)-2-(5H)-furanones have the for 0666) (f) =CH-O-N=, mula shown below in formula XXIV: 0667 (g) =N-S-N=, 0668 (h) =N-O-N=, XXIV 0669 when sides a and c are double bonds and Side b is a Single bond; 0670) R' is selected from the group consisting of: 0671 (a) S(O), CH, 0672 (b) S(O), NH, 0673) (c) S(O), NHC(O)CF, 0674) (d) S(O)(NH)CH, 0675 (e) S(O)(NH)NH, 0638 or pharmaceutically acceptable salts thereof wherein: 0676 (f) S(O)(NH)NHC(O)CF, 0639 X 7-Y-Z'-is selected from the group 0677 (g) P(O)(CH)OH, and consisting of: 0678) (h) P(O)(CH.)NH; 0640 (a) -CH CHCH-, 0679) R' is selected from the group consisting 0641 (b) –C(O)CHCH-, of 0642 (c)-CH CHC(O), 0680 (a) Calkyl, 0643 (d) –CR' (R')-O-C(O)-, 0681 (b) C, C, Cs, C, and C7, cycloalkyl, 0682 (c) mono-, di- or tri-substituted phenyl or 0644) (e) –C(O)-O-CR' (R')–, naphthyl, 0645 (f) —CH-NR'7-CH-, 0683) wherein the Substituent is selected 0646) (g) –CR' (R')-NR'7–C(O)-, from the group consisting of: 0647 (h)-CR-CR'?' S 0684 (1) hydrogen, 0648 (i) –S-CR'?=CR'? -, 0685 (2) halo, 0649) () -S-N=CH-, 0686 (3) C alkoxy, 0650 (k) -CH=N-S-, 0687 (4) C alkylthio, 0651) (I)-N=CR' O-, 0688 (5) CN, 0652) (m) -O-CR4=N-, 0689 (6) CF, 0653) (n)-N=CR-NH-, 0690 (7) C. alkyl, 0654) (o)-N=CR-S-, and 0691 (8) N., 0655 (p) –S-CRP-N-, 0692 (9) -COH, US 2004/0029864 A1 Feb. 12, 2004 23

0693 (10) -CO-C alkyl, 0724) R'' and R'' are each independently 0694) (11) -C(R)(R)-OH, Selected from the group consisting of: 0725 (a) hydrogen, 0695) (12) –C(R')(R)-O-C alkyl, and 0726) (b) CF, 0696 (13) -C alkyl-CO-R'', 0727 (c) CN, 0697 (d) mono-, di- or tri-substituted het 0728) (d) C alkyl, eroaryl wherein the heteroaryl is a monocyclic 0729 (e) -Q, aromatic ring of 5 atoms, Said ring having one hetero atom which is S, O, or N, and optionally 0730) (f) -O-Q; 1, 2, or 3 additionally Natoms; or the heteroaryl 0731 (g) —S-Q, and is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and option 0732 (h) optionally substituted: ally 1, 2, 3, or 4 additional N atoms; said 0733 (1) –Cs alkyl-Q, Substituents are Selected from the group con Sisting of: 0734) (2)-O-Cls alkyl-Q, 0698) (1) hydrogen, 0735 (3) —S-C, alkyl-Q, 0699) (2) halo, including fluoro, chloro, 0736) (4) -C, alkyl-O-C alkyl-Q, bromo and iodo, 0737 (5)-C, alkyl-S-C, alkyl-Q, 0700) (3) Co. alkyl, 0738 (6)–Cs alkyl-O-Q, 0701 (4) Co. alkoxy, 0739 (7) –C alkyl-S-Q, 0702) (5) C alkylthio, 0740 wherein the Substituent resides on 0703) (6) CN, the alkyl and the Substituent is C alkyl, and 0741) R'2, R1, R, R and R2 are each 0704) (7) CF, independently Selected from the group consisting 0705) (8) N., of: 0706) (9) –C(R')(R)-OH, and 0742 (a) hydrogen, 0707 (10) –C(R')(R)-O-C, 0743) (b) C alkyl; alkyl, 0744 or R'' and R' or R'' and R together 0708) (e) benzoheteroaryl which includes the with the carbon to which they are attached form a benzo fused analogs of (d); Saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; 0709) R' is selected from the group consisting 0745) Q is COH, CO-C, alkyl, tetrazolyl-5- of: y1, C(R)(R')(OH), or C(R)(R)(O-C, 0710) (a) hydrogen, alkyl); 0711) (b) CF, 0746) provided that when X-Y-Z is —S-CR'= CR' then R and R'' are other than CF. 0712) (c) CN, 0747 Materials that can serve as a cyclooxygenase-2 0713) (d) C. alkyl, selective inhibitor of the present invention include bicyclic (e) hydroxyC alkyl, carbonyl indole compounds that are described in U.S. Pat. 0714) No. 6,303,628. Such bicycliccarbonyl indole compounds 0715) (f) -C(O)-C alkyl, have the formula shown below in formula XXV: 0716) (g) optionally Substituted: XXV 0717 (1) —Cls alkyl-Q, 0718) (2) —Cs alkyl-O-C alkyl-Q, 0719) (3) —Cs alkyl-S-C1s alkyl-Q, 0720) (4) -Cs alkyl-O-Q, or 0721) (5)-Cls alkyl-S-Q, 0722) wherein the Substituent resides on the alkyl and the Substituent is C alkyl, 0723) US 2004/0029864 A1 Feb. 12, 2004 24

0748 or the pharmaceutically acceptable salts to the nitrogen atom on the benzimidazole through thereof wherein a carbon atom on the heteroaryl ring; 0749) A is C, alkylene or -NR'-; 0766 X is independently selected from halo, C-C, alkyl, hydroxy, C,C, alkoxy, halo-substi 0750 Z is C(=L)R’ or SO, R: tuted C-C alkyl, hydroxy-substituted C-C, 0751) Z is CH or N; alkyl, (C-C alkoxy)C-C alkyl, halo-substituted C-C alkoxy, amino, N-(C-C alkyl)amino, N,N- 0752 Z' and Y are independently selected from di(C-C alkyl)amino, N-(C-C alkyl)aminoC -CH2-, O, S and - C alkyl, N,N-di(C-C alkyl)aminoC-C alkyl, N-(C-C alkanoyl)amonio, N-(C-C alkyl)(C- 0753) N-R'': C. alkanoyl)amino, N-(C-C alkyl)sulfonyl 0754 m is 1, 2 or 3; amino, N-(halo-substituted C-C alkyl)sulfonyl) amino, C-C alkanoyl, carboxy, (C-C, 0755) q and r are independently 0, 1 or 2; alkoxy)carbonyl, carbamoyl, N-(C-C alky 0756 X" is independently selected from halo l)aminocarbonyl, N,N-di(C-C alkyl)amino gen, C alkyl, halo-Substituted C- alkyl, carbonyl, cyano, nitro, mercapto, (C-C alky hydroxy, C alkoxy, halo-Substituted C. l)thio, (C-C, alkyl)sulfinyl, (C-C, alkoxy, C alkylthio, nitro, amino, mono- or alkyl)sulfonyl, aminosulfonyl, N-(C-C alky di-(C, alkyl)amino and cyano; l)aminosulfonyl and N,N-di(C-C alkyl)amino Sulfonyl; 0757 n is 0, 1, 2, 3 or 4; 0767 X is independently selected from halo, 0758 L is oxygen or sulfur; C-C alkyl, hydroxy, C-C alkoxy, halo-substi 0759) R' is hydrogen or C, alkyl; tuted C-C alkyl, hydroxy-substituted C-C, alkyl, (C-C alkoxy)C-C alkyl, halo-substituted 0760) R'' is hydroxy, Calkyl, halo-substituted C-C alkoxy, amino, N-(C-C alkyl)amino, N,N- Ce alkyl, Ce alkoxy, halo-Substituted C-6 di(C-C alkyl)amino, N-(C-C alkyl)aminolc alkoxy, C-7 cycloalkoxy, C-1 alkyl(C-7 C alkyl, N,N-di(C-C alkyl)aminoC-C alkyl, cycloalkoxy), -NR'R'', C alkylphenyl-O- N-(C-C alkanoyl)amino, N-(C-C alkyl)-N- or phenyl-O-, said phenyl being optionally Sub (C-C alkanoyl)amino, N-(C-C alkyl)sulfo stituted with one to five Substituents indepen nyl)amino, N-(halo-substituted C-C alkyl)sul dently selected from halogen, C alkyl, hydroxy, fonyl)amino, C-C alkanoyl, carboxy, (C-C, C. alkoxy and nitro, alkoxy)cabonyl, cabamoyl, N-(C-C alkyl) 0761) R' is C, alkyl or halo-substituted C aminocarbonyl, N,N-di(C-C alkyl)aminocar alkyl; and bonyl, N-carbomoylamino, cyano, nitro, mer capto, (C-C alkyl)thio, (C-C alkyl)sulfinyl, 0762) R' and R'' are independently selected (C-C, alkyl)sulfonyl, aminosulfonyl, IN-(C-C, from hydrogen, C. alkyl and halo-Substituted alkyl)aminosulfonyl and N,N-di(C-C alky Calkyl. l)aminosulfonyl; 0763) Materials that can serve as a cyclooxygenase-2 0768) R' is selected from hydrogen,ydrog selective inhibitor of the present invention include benzimi dazole compounds that are described in U.S. Pat. No. 0769) straight or branched C-C alkyl optionally 6,310,079. Such benzimidazole compounds have the for substituted with one to three substituent(s) mula shown below in formula XXVI: wherein said substituents are independently selected from halo hydroxy, C-C alkoxy, amino, N-(C-C alkyl)amino and N,N-di(C-C alky XXVI l)amino, N N 0770 C-C cycloalkyl optionally substituted (x) + 2 Y-CR =cR-R's with one to three substituent(s) wherein said Sub N stituents are indepently selected from halo, C-C, V alkyl, hydroxy, C-C alkoxy, amino, N-(C-C, Al 0- (X2), alkyl)amino and N,N-di(C-C alkyl)amino, 0771) C-C cycloalkenyl optionally substituted 0764) or a pharmaceutically acceptable salt thereof, with one to three substituent(s) wherein said Sub wherein: stituents are independently selected from halo, 0765 A' is heteroaryl selected from a 5-mem C-C, alkyl, hydroxy, C-C alkoxy, amino, N-(C- bered monocyclic aromatic ring having one hetero C. alkyl)amino and N,N-di(C-C alkyl)amino, atom selected from O, S and N and optionally 0772) phenyl optionally substituted with one to containing one to three N atom(s) in addition to three substituent(s) wherein said substituents are said hetero atom, or a 6-membered monocyclic independently selected from halo, C-C alkyl, aromatic ring having one N atom and optionally hydroxy, C-C alkoxy, halo-Substituted C-C, containing one to four Natom(s) in addition to alkyl, hydroxy-Substituted C-C alkyl, (C-C, said N atom; and said heteroaryl being connected alkoxy)C-C alkyl, halo-substituted C-C, US 2004/0029864 A1 Feb. 12, 2004 25

alkoxy, amino, N-(C-C alkyl)amino, N,N-di(C- 0786 wherein: C alkyl)amino, N-(C-C alkyl)aminoC-C, alkyl, N,N-di(C-C alkyl)aminoC-C alkyl, 0787 LA is oxygen or sulfur; N-(C-C alkanoyl)amino, N-C-C, alkyl)(C-C, alkanoyl)amino, N-(C-C alkyl)sulfonyamino, 0788 Y is a direct bond or C alkylidene; N-(halo-substituted C-C alkyl)sulfonyl)amino, 0789 Q is: C-C, alkanoyl carboxy, (C-C, alkoxy)carbonyl, carbomoyl, N-(C-C alkyl)aminocarbonyl, 0790 (a) C alkyl or halosubstituted C. N,N-di(C-C, alkyl)aminocarbonyl, cyano, alkyl, Said alkyl being optionally Substituted nitro, mercapto, (C-C alkyl)thio, (C-C alkyl with up to three Substituents independently )Sulfinyl, (C-C alkyl)sulfonyl, aminosulfonyl, Selected from hydroxy, C alkoxy, amino and N-(C-C, alkyl)aminolsulfonyl and N,N-di(C- mono- or di-(C. alkyl)amino, C alkyl)aminosulfonyl; and 0791 (b) C, cycloalkyl optionally substituted 0773 heteroaryl selected from: with up to three Substituents independently Selected from hydroxy, C alkyl and C. 0774 a 5-membered monocyclic aromatic ring alkoxy, having one hetero atom Selected from O, S and N and optionally containing one to three N 0792 (c) phenyl or naphthyl, said phenyl or atom(s) in addition to Said hetero atom; or a naphthyl being optionally Substituted with up to 6-membered monocyclic aromatic ring having four Substituents independently Selected from: one N atom and optionally containing one to (c-1) halo, Calkyl, halosubstituted C alkyl, hydroxy, C alkoxy, haloSubstituted C. four Natom(s) in addition to said N atom; and alkoxy, S(O), R', SO. NH, SO N(C 0775 said heteroaryl being optionally substi alkyl), amino, mono- or di-(C. alkyl)amino, tuted with one to three substituent(s) selected NHSO, R'', NHC(O)R'', CN, COH, CO from X29; (C. alkyl), C, alkyl-OH, C, alkyl-OR'", 0776 R'' and R'' are independently selected CONH, CONH(C. alkyl), CON(C. alkyl). from: and -O-Y-phenyl, Said phenyl being option ally substituted with one or two substituents 0777 hydrogen, independently Selected from halo, C. alkyl, CF, hydroxy, OR', S(O), R', amino, 0778 halo, mono- or di-(C. alkyl)amino and CN; 0779) C-C alkyl, 0793 (d) a monocyclic aromatic group of 5 0780 phenyl optionally substituted with one to atoms, Said aromatic group having one heteroa three substituent(s) wherein said substituents tom selected from O, S and N and optionally are independently Selected from halo, C-C, containing up to three Natoms in addition to alkyl, hydroxy, C-C alkoxy, amino, N-(C-C, Said heteroatom, and Said aromatic group being alkyl)amino and N,N-di(C-C alkyl)amino, substituted with up to three substitutents inde 0781 or R'' and R' can form, together with the pendently Selected from: carbon atom to which they are attached, a C-C, 0794 (d-1) halo, C alkyl, halosubstituted cycloalkyl ring; C, alkyl, hydroxy, C. alkoxy, balasubsti tuted C alkoxy, Calkyl-OH, S(O), R", 0782 m is 0, 1, 2, 3, 4 or 5; and SO. NH, SON(C. alkyl), ES). 0783) n is 0, 1, 2, 3 or 4. or di-(C. alkyl)amino, NHSO, R 143, NHC(O)R CN, COH, CO (C. alkyl), 0784. Materials that can serve as a cyclooxygenase-2 C. alkyl-OR, CONH, CONH(Calkyl), selective inhibitor of the present invention include indole CONCC alkyl), phenyl, and mono-, di- or compounds that are described in U.S. Pat. No. 6,300,363. tri-substituted phenyl wherein the substituent Such indole compounds have the formula shown below in is independently Selected from halo, CFs, formula XXVII: C, alkyl, hydroxy, C, alkoxy, OCFs, SR 143, SO CH, SO. NH, amino, Calkylamino and NHSO, R'; XXVII R 0795 (e) a monocyclic aromatic group of 6 N-R142 atoms, Said aromatic group having one heteroa L4 tom which is N and optionally containing up to N N three atoms in addition to Said heteroatom, and (xi). H Said aromatic group being Substituted with up to 2 Y3-O6 three Substituents independently Selected from the above group (d-1); 0796) R' is hydrogen or Ce alkyl optionally 0785 and the pharmaceutically acceptable salts Substituted with a Substituent Selected indepen thereof, dently from hydroxy, OR'', nitro, amino, mono US 2004/0029864 A1 Feb. 12, 2004 26

or di-(C. alkyl)amino, COH, CO (C. alkyl), lamino, di-(Calkyl)amino, CONH2, CON CONH, CONH(CO alkyl) and CONCCO H(CO alkyl), CONCCO alkyl), alkyl); OC(O)R', and phenyl optionally substi tuted with up to three Substituents indepen 0797) R-2 is: dently Selected from halo, C. alkyl, 0798) (a) hydrogen, hydroxy, OCH, CF, OCF, CN, nitro, amino, mono- or di-(C. alkyl)amino, 0799 (b) C, alkyl, COH, CO (C. alkyl) and CONH2, 0800) (c) C(O)R'', 0807 (c-5) a monocyclic aromatic group as 0801) wherein R' is selected from: defined in (d) and (e) above, said aromatic group being optionally Substituted with up to 0802 (c-1) C alkyl or Calkenyl, said three Substituents independently Selected alkyl or alkenyl being optionally Substituted from: with up to four Substituents independently selected from: (c-1-1) halo, hydroxy, OR'', 0808) (c-5-1) halo, Cs alkyl, C alkyl S(O), R', nitro, amino, mono- or di-(C. OH, hydroxy, Cs, alkoxy, CF, OCF, CN, alkyl)amino, NHSO R', COH, CO (C- nitro, S(O), R', amino, mono- or di-(C. alkyl), CONH, CONH(C. alkyl), alkyl)amino, CONH, CONH(C. alkyl), CON(C. alkyl)., OC(O)R'', thienyl, naph CONCC, alkyl)., COH and CO (C- thyl and groups of the following formulae: alkyl), and -Y-phenyl, said phenyl being optionally substituted with up to three Sub stituents independently selected halogen, C. alkyl, hydroxy, Calkoxy, CF, OCF, CN, (x22), nitro, S(O), R', amino, mono- or di-(C. y- (x22), alkyl)amino, COH, CO (C. alkyl), CONH, CONH(C. alkyl) and CONCC so-( ) s NHSO \ / s alkyl), \ / 0809 (c-6) a group of the following formula: o 22 o 22 /y-( \ /) )n s -\ / )n s (CH2) (CH2)

-N," s )--" s 0810) X* is halo, C, alkyl, hydroxy, Calkoxy, (CH2) O - (C2) halosubstitutued C, alkoxy, S(O), R', amino, -N Z, and N Z11 mono- or di-(C. alkyl)amino, NHSO R', nitro, halosubstitutued C alkyl, CN, COH, CO (C- alkyl), C alkyl-OH, C, alkylOR'', CONH, CONH(C, alkyl) or CONCC, alkyl); R'' is C. 0803 (c-2) C-2 alkyl or C-2 alkenyl, said alkyl or haloSubstituted C alkyl, alkyl or alkenyl being optionally Substituted 0811 m is 0, 1 or 2; n is 0, 1, 2 or 3; p is 1, 2, 3, 4 with five to forty-five halogen atoms, or 5; q is 2 or 3; Z is oxygen, Sulfur or NR'; and 0804) (c-3) - Y-C., cycloalkyl or 08.12) R' is hydrogen, Ce alkyl, halosubstitutued -Ys-C-7 cycloalkenyl, Said cycloalkyl or C, alkylor-Y-phenyl, said phenyl being option cycloalkenyl being optionally Substituted ally substituted with up to two substituents indepen with up to three Substituent independently dently Selected from halo, C alkyl, hydroxy, C. Selected from: alkoxy, S(O), R', amino, mono- or di-(C. alky 0805) (c-3-1) C, alkyl, hydroxy, OR'', l)amino, CF, OCF, CN and nitro; S(O) R', amino, mono- or di-(C, alky 0813 with the proviso that a group of formula l)amino, CONH, CONH(C. alkyl) and CONC, alkyl), (c-4) phenyl or naphthyl, -Y-Q is not methyl or ethyl when X* is hydrogen; Said phenyl or naphthyl being optionally Sub 0814) L' is oxygen; Stituted with up to Seven (preferably up to Seven) Substituents independently Selected 0815) R' is hydrogen; and from: 0816 R'' is acetvl.y 0806) (c-4-1) halo, Cs alkyl, C alkyl 0817 Materials that can serve as a cyclooxygenase-2 OH, hydroxy, Cls alkoxy, haloSubstituted selective inhibitor of the present invention include aryl C, alkyl, halosubstituted Cls alkoxy, CN, phenylhydrazides that are described in U.S. Pat. No. 6,077, nitro, S(O), R', SO, NH, SO. NH(C. 869. Such aryl phenylhydrazides have the formula shown alkyl), SONCC alkyl), amino, C alky below in formula XXVIII: US 2004/0029864 A1 Feb. 12, 2004 27

XXVIII XXX O

N iiN1 || N A-21 ex R153 0818 wherein: 0819 X and Y are selected from hydrogen, halogen, alkyl, nitro, amino or other oxygen and Sulfur containing functional groupS Such as R154 CO2H hydroxy, methoxy and methylsulfonyl. 0820 Materials that can serve as a cyclooxygenase-2 0829 or a pharmaceutically acceptable salt, ester or Selective inhibitor of the present invention include 2-ary tautomer thereof, loxy, 4-aryl furan-2-ones that are described in U.S. Pat. No. 0830) wherein: 6,140,515. Such 2-aryloxy, 4-aryl furan-2-ones have the formula shown below in formula XXIX: 0831) Z is Cor N; 0832) when Z' is N, R represents H or is XXIX absent, or is taken in conjunction with R" as R 146 described below:

(0833)152. when Z' is C, R' represents H and is a moiety which has the following char acteristics: 0834 (a) it is a linear chain of 3-4 atoms containing 0-2 double bonds, which can adopt an energetically stable transoid con figuration and if a double bond is present, the bond is in the trans configuration, 0821 or a pharmaceutical salt thereof, 0835 (b) it is lipophilic except for the atom bonded directly to ring A, which is either 0822 wherein: lipophilic or non-lipophilic, and 0823) R' is selected from the group consisting 0836 (c) there exists an energetically stable of SCH, -S(O). CH and -S(O)NH; configuration planar with ring A to within 0824) R' is selected from the group consisting about 15 degrees, of OR', mono or di-substituted phenyl or 0837) or R'' and R'' are taken in combination pyridyl wherein the substituents are selected from and represent a 5- or 6-membered aromatic or the group consisting of methyl, chloro and F; non-aromatic ring D fused to ring A, Said ring D 0825) R' is unsubstituted or mono or di-substi containing 0-3 heteroatoms selected from O, S and tuted phenyl or pyridyl wherein the substituents N; are Selected from the group consisting of methyl, 0838 said ring D being lipophilic except for the chloro and F; atoms attached directly to ring A, which are lipo philic or non-lipophilic, and Said ring D having 0826) R' is H, C, alkyl optionally substituted available an energetically Stable configuration pla with 1 to 3 groups of F, Cl or Br; and nar with ring A to within about 15 degrees, 0827) R' is H, C, alkyl optionally substituted 0839 said ring D further being substituted with 1 with 1 to 3 groups of F, Cl or Br, with the proviso Ra group Selected from the group consisting of: that R'' and R'' are not the same. C, alkyl, -OC, alkyl, -NHCl2 alkyl, 0828 Materials that can serve as a cyclooxygenase-2 -N(C. alkyl), —C(O)C, alkyl, -S-C, selective inhibitor of the present invention include bisaryl alkyl and -C(S)C alkyl; compounds that are described in U.S. Pat. No. 5,994,379. 0840 Y7 represents N, CH or C-OC alkyl, Such bisaryl compounds have the formula shown below in and when Z' is N, Y can also represent a car formula XXX: bonyl group; US 2004/0029864 A1 Feb. 12, 2004 28

0841 R153 represents H, Br, C1 or F; and alkyl or R'' and R' may be taken together with the depicted nitrogen to form a heteroaryl ring of 0842) R' represents H or CHs. 5-7 ring members where one or more of the ring 0843. Materials that can serve as a cyclooxygenase-2 members is nitrogen, Sulfur or oxygen where Said selective inhibitor of the present invention include 1,5- heteroaryl ring may be optionally Substituted with diarylpyrazoles that are described in U.S. Pat. No. 6,028, Cs alkyl, 202. Such 1,5-diarylpyrazoles have the formula shown 0850) R' is hydrogen, Cls alkyl, nitro, amino, below in formula X)XI: and halogen; 0851 and pharmaceutically acceptable salts XXXI thereof. 0852. Materials that can serve as a cyclooxygenase-2 A. selective inhibitor of the present invention include 2-substi tuted imidazoles that are described in U.S. Pat. No. 6,040, C. h 320. Such 2-substituted imidazoles have the formula shown R157 below in formula XXXII: N-N R160 \ c/ R161 N N s V XXXII R 156 - I n N R166 165 A S- 1. R162 Y O R N R 155 R 159 X-R R164 N 0844 wherein: 0845) R', R', R'7, and R' are indepen dently Selected from the groups consisting of 0853 wherein: hydrogen, Cs alkyl, Cs alkoxy, phenyl, halo, hydroxy, Cs alkylsulfonyl, Cs alkylthio, triha 0854) R' is phenyl, heteroaryl wherein the het loCs alkyl, amino, nitro and 2-quinolinyl eroaryl contains 5 to 6 ring atoms, or methoxy, 0855) substituted phenyl; 0846) R' is hydrogen, Cls alkyl, trihaloCs 0856 wherein the substituents are independently alkyl, phenyl, Substituted phenyl where the phenyl Selected from one or members of the group con Substitutents are halogen, Cs alkoxy, trihaloCs Sisting of Cls alkyl, halogen, nitro, trifluorom alkyl or nitro or R' is heteroaryl of 5-7 ring ethyl and nitrile; members where at least one of the ring members is nitrogen, Sulfur or oxygen; 0857) R' is phenyl, heteroaryl wherein the het 0847) R' is hydrogen, Cls alkyl, phenyl Cls eroaryl contains 5 to 6 ring atoms, alkyl, Substituted phenyl Cs alkyl where the 0858 substituted heteroaryl; phenyl Substitutents are halogen, Cs alkoxy, tri haloCs alkyl or nitro, or R' is Cls alkoxycar 0859 wherein the substituents are independently bonyl, phenoxycarbonyl, Substituted phenoxycar Selected from one or more members of the group bonyl where the phenyl Substitutents are halogen, consisting of Cls alkyl and halogen, or Substituted Cs alkoxy, trihaloCs alkyl or nitro, phenyl, 0848) R' is Co alkyl, substituted Co alkyl 0860 wherein the substituents are independently where the Substituents are halogen, trihaloCs Selected from one or members of the group con alkyl, Cs alkoxy, carboxy, Cls alkoxycarbonyl, Sisting of Cls alkyl, halogen, nitro, trifluorom amino, Cs alkylamino, diCs alkylamino, diCs ethyl and nitrile; alkylaminoCs alkylamino, Cls alkylaminoCs alkylamino or a heterocycle containing 4-8 ring 0861) R' is hydrogen, SEM, Cs alkoxycarbo atoms where one more of the ring atoms is nitro nyl, aryloxycarbonyl, arylCs alkyloxycarbonyl, gen, oxygen or Sulfur, where Said heterocycle may arylC, alkyl, phthalimidoCs alkyl, aminoCs be optionally substituted with Cs alkyl; or R' alkyl, diaminoCs alkyl, SuccinimidoCs alkyl, is phenyl, Substituted phenyl (where the phenyl C, alkylcarbonyl, arylcarbonyl, Cls alkylcarbon Substitutents are one or more of Cs alkyl, halo y1Cs alkyl, aryloxycarbonylCs alkyl, het gen, C-5 alkoxy, trihaloC1-5 alkyl or nitro), or eroarylC, alkyl where the heteroaryl contains 5 to R is heteroaryl having 5-7 ring atoms where one 6 ring atoms, or Substituted arylCs alkyl, or more atoms are nitrogen, oxygen or Sulfur, 0862 wherein the aryl Substituents are indepen fused heteroaryl where one or more 5-7 membered dently selected from one or more members of the aromatic rings are fused to the heteroaryl; or group consisting of C-5 alkyl, Cs alkoxy, halo 0849 Rol is NR3 R' where R103 and Rare gen, amino, Cs alkylamino, and diCs alky independently Selected from hydrogen and Cs lamino; US 2004/0029864 A1 Feb. 12, 2004 29

0863) R7 is (A'),-(CH)-X' wherein: 0885 wherein the phenyl substituents are inde pendently Selected from one or more members 0864 A' is sulfur or carbonyl; of the group consisting of Cls alkyl, halogen 0865 n is 0 or 1; and Cls alkoxy, 0866) q is 0-9; 0886) substituted amido, 0867) X" is selected from the group consisting 0887 wherein the carbonyl substituent is of hydrogen, hydroxy, halogen, vinyl, ethynyl, Selected from the group consisting of Cs alkyl, Cs alkyl, C-7 cycloalkyl, Cs alkoxy, phe phenyl, arylCs alkyl, thienyl, furanyl, and noxy, phenyl, arylCs alkyl, amino, Cs alky naphthyl, Substituted phenylcarbonyl, lamino, nitrile, phthalimido, amido, phenylcar 0888 wherein the phenyl substituents are inde bonyl, C1-5 alkylaminocarbonyl, pendently Selected from one or members of the phenylaminocarbonyl, arylCs alkylaminocar group consisting of C-5 alkyl, halogen and C1s bonyl, Cs alkylthio, Cs alkylsulfonyl, phe alkoxy, nylsulfonyl, 0889) substituted C alkylthio, 0868 Substituted Sulfonamido, 0890 wherein the alkyl substituent is selected 0869 wherein the sulfonyl substituent is from the group consisting of hydroxy and Selected from the group consisting of Cs alkyl, phthalimido, phenyl, araCs alkyl, thienyl, furanyl, and naphthyl; 0891 Substituted Cls alkylsulfonyl, 0870 substituted vinyl, 0892 wherein the alkyl substituent is selected from the group consisting of hydroxy and 0871 wherein the substituents are indepen phthalimido, dently selected from one or members of the group consisting of fluorine, bromine, chlorine 0893) substituted phenylsulfonyl, and iodine, 0894 wherein the phenyl substituents are inde 0872) substituted ethynyl, pendently selected from one or members of the group consisting of bromine, fluorine, chlorine, 0873 wherein the substituents are indepen Cs alkoxy and trifluoromethyl, dently selected from one or more members of the group consisting of fluorine, bromine chlo 0895 with the proviso: rine and iodine, 0896) if A' is sulfur and X* is other than 0874) substituted Cls alkyl, hydrogen, Cs alkylaminocarbonyl, pheny laminocarbonyl, arylCs alkylaminocarbo 0875 wherein the substituents are selected nyl, Cs alkylsulfonyl or phenylsulfonyl, from the group consisting of one or more Cs then q must be equal to or greater than 1; alkoxy, trihaloalkyl, phthalimido and amino, 0897 if A' is sulfur and q is 1, then X* 0876) substituted phenyl, cannot be C-2 alkyl, 0877 wherein the phenyl substituents are inde 0898 if A' is carbonyl and q is 0, then X* pendently Selected from one or more members cannot be vinyl, ethynyl, Cs alkylaminocar of the group consisting of Cls alkyl, halogen bonyl, phenylaminocarbonyl, arylCs alky and Cls alkoxy, laminocarbonyl, Cs alkylsulfonyl or phe nylsulfonyl; 0878 substituted phenoxy, 0899) if A' is carbonyl, q is 0 and X* is H, 0879 wherein the phenyl substituents are inde then R is not SEM (2-(trimethylsi pendently Selected from one or more members lyl)ethoxymethyl); of the group consisting of Cls alkyl, halogen and Cls alkoxy, 0900 if n is 0 and q is 0, then X cannot be hydrogen; 0880 Substituted Cls alkoxy, 0901 and pharmaceutically acceptable salts 0881) wherein the alkyl substituent is Selected from the group consisting of phthal thereof. imido and amino, 0902 Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include 1.3- and 0882 substituted arylCs alkyl, 2,3-diarylcycloalkano and cycloalkeno pyrazoles that are 0883 wherein the alkyl substituent is hydroxyl, described in U.S. Pat. No. 6,083,969. Such 1,3- and 2,3- diarylpyrazole compounds have the general formulas shown 0884 Substituted arylCs alkyl, below in formulas XXXIII and XXXIV: US 2004/0029864 A1 Feb. 12, 2004 30

–OCON(CH)OH, -C(COCH), di(C- C.)alkyl and di(C-C)alkoxy, VR'' XXXIII 0909) R'' is selected from the group consisting / X of hydrogen, halogen, hydroxy, carbonyl, amino, (C-C)alkyl, (C-C)alkoxy and optionally Sub Stituted carboxyphenyl, wherein Substituents on N-N the carboxyphenyl group are Selected from the \ group consisting of halogen, hydroxy, amino, (C- N C.)alkyl and (C-C)alkoxy; 0910 or R'' and R7 taken together form a A-21 moiety Selected from the group consisting of R168 -O- and VR'' XXXIV / X

N-N \ N 421 R168 0911) R'7' is selected from the group consisting of hydrogen, OH, -OCOCH, -COCH and (C- 0903 wherein: C.)alkyl, and 0904) R' and R'' are independently selected from the group consisting of hydrogen, halogen, 0912) R'' is selected from the group consisting of (C-C)alkyl, (C-C)alkoxy, nitro, amino, hydrogen, OH, -OCOCH, -COCH, (C- hydroxy, trifluoro, -S(C-C)alkyl, -SO(C- C.)alkyl, -CONH and -SO CH, with the pro C.)alkyl and -SO (C-C)alkyl, and the fused viso that moiety M is a group Selected from the group 0913) if M is a cyclohexyl group, then R'' through consisting of an optionally Substituted cyclohexyl R7 may not all be hydrogen; and and cycloheptyl group having the formulae: O914 p harmaceuticallyy acceptablep Salts, esters and pro-drug forms thereof. 0915 Materials that can serve as a cyclooxygenase-2 R173 Selective inhibitor of the present invention include esters derived from indolealkanois and novel amides derived from &T R173 indolealkylamides that are described in U.S. Pat. No. 6,306, 890. Such compounds have the general formula shown O Or R172 below in formula XXXV: R170 R172 R171 R171 R170 XXXV O 0905 wherein: ) R176 0906) R'' is selected from the group consisting (CH2)-X of hydrogen, halogen, hydroxy and carbonyl, R1 0907 or R'79 and R'7" taken together form a R178 moiety Selected from the group consisting of N -OCOCH-, –ONH(CH)COCH-, Yer -OCOCH.dbd. and -O- 0908) R'7' and R'' are independently selected from the group consisting of hydrogen, halogen, 0916 wherein: hydroxy, carbonyl, amino, (C-C)alkyl, (C- 0917 R'' is C to C alkyl, C. to C branched C.)alkoxy, =NOH, -NR7 R7, –OCH, alkyl, C. to Cs cycloalkyl, C to C. hydroxyalkyl, —OCH, CH, -OSO, NHCO, CH, =CHCO. branched C to C. hydroxyalkyl, hydroxy substi CHCH, -CHCOH, -CHCO CH, -CH tuted C to Caryl, primary, Secondary or tertiary CO CHCH, -CH CONCCH), -CHCO C, to C alkylamino, primary, Secondary or tertiary NHCH, –CHCHCO CH CH, branched C to C alkylamino, primary, Secondary US 2004/0029864 A1 Feb. 12, 2004

or tertiary C to Cs arylamino, C to C alkylcar 0929) R'' is selected from the group consisting boxylic acid, branched C to C alkylcarboxylic of alkenyl, alkoxy, alkoxyalkyl, alkoxyimi acid, C to C alkylester, branched C to C alky noalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfony lester, C to Caryl, C. to Cs arylcarboxylic acid, lalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, ary C to Cs arylester, C to Cs aryl Substituted C to lalkyl, arylalkynyl, arylhaloalkyl, C alkyl, C. to C. heterocyclic alkyl or aryl with arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, ary O, N or S in the ring, alkyl-substituted or aryl loxyhydroxyalkyl, arylcarbonylalkyl, carboxy substituted C to C. heterocyclic alkyl or aryl with alkyl, cyanoalkyl, cycloalkenyl, cycloalkenyla O, N or S in the ring, or halo-substituted versions lkyl, cycloalkyl, cycloalkylalkyl, thereof, where halo is chloro, bromo, fluoro or cycloalkylidenealkyl, haloalkenyl, haloalkoxyhy iodo; droxyalkyl, haloalkyl, haloalkynyl, heterocyclic, 0918) R'77 is C to C alkyl, C. to C. branched heterocyclic alkoxy, heterocyclic alkyl, heterocy alkyl, C. to Cs cycloalkyl, C. to Cs aryl, C. to Cs clic oxy, hydroxyalkyl, hydroxyiminoalkoxy, aryl-substituted C to C alkyl, C to Calkoxy, C -(CH), C(O)R'', -(CH), CH(OH)R'', to Ce branched alkoxy, C to Cs aryloxy, or halo -(CH), C(NORd)R', -(CH), substituted versions thereof or R'' is halo where CH NORd)R’, -(CH), CH(NRd Re)R’, halo is chloro, fluoro, bromo, or iodo; -R" R', -(CH), COCR', -(CH), 0919) R'7 is hydrogen, C to C alkyl or C, to C, [CH(CX)), (CH) R', -(CH), (CX), branched alkyl, (CH.) R', and -(CH), (CHX) (CH), Rise,188. 0920) R'' is C to C alkyl, C. to Caroyl, C. to Caryl, C. to C. heterocyclic alkyl or aryl with O, 0930) R' is selected from the group consisting N or S in the ring, C. to Cs aryl-substituted C to of hydrogen, alkenyl, alkyl, alkynyl, aryl, aryla Calkyl, alkyl-substituted or aryl-substituted C to lkyl, cycloalkenyl, cycloalkyl, haloalkenyl, Cs heterocyclic alkyl or aryl with O, N or S in the haloalkyl, haloalkynyl, heterocyclic, and hetero ring, alkyl-substituted C to Cs aroyl, or alkyl cyclic alkyl; substituted C to Caryl, or halo-substituted ver 0931) R' is selected from the group consisting sions thereof where halo is chloro, bromo, or iodo; of alkenylene, alkylene, halo-substituted alk 0921) n is 1, 2, 3, or 4; and enylene, and halo-substituted alkylene; 0922 X is O, NH, or N-R, where R is C, 0932) R' is selected from the group consisting to C alkyl or C, to Ce branched alkyl. of hydrogen, alkenyl, alkyl, alkynyl, aryl, aryla 0923) Materials that can serve as a cyclooxygenase-2 lkyl, cycloalkyl, cycloalkenyl, haloalkyl, hetero selective inhibitor of the present invention include pyridazi cyclic, and heterocyclic alkyl; none compounds that are described in U.S. Pat. No. 6,307, 0933) R' and R are independently selected from 047. Such pyridazinone compounds have the formula shown the group consisting of hydrogen, alkenyl, alkyl, below in formula XXXVI: alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl, XXXVI 0934 X is halogen; R18 N R181 2 n N1 0935 m is an integer from 0-5; R183 N X26 0936) n is an integer from 0-10; and R182 0937) p is an integer from 0-10; and 0938) R', R', and R'' are independently selected from the group consisting of hydrogen, 0924) or a pharmaceutically acceptable Salt, ester, or alkenyl, alkoxyalkyl, alkoxyiminoalkoxy, alkoxy prodrug thereof, iminoalkyl, alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, 0925) wherein: aminoalkoxy, aminoalkylcarbonyloxyalkoxy ami nocarbonylalkyl, aryl, arylalkenyl, arylalkyl, ary 0926 X is selected from the group consisting of lalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano, O, S, -NR', -NOR, and -NNR R; cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, 0927) R' is selected from the group consisting haloalkenyloxy, haloalkoxy, haloalkyl, halogen, of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, heterocyclic, hydroxyalkoxy, hydroxyimi cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, noalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, heterocyclic, and heterocyclic alkyl; nitro, phosphonatoalkoxy, Y, and Z'; 0928 R, R, and R are independently selected 0939) provided that one of R, R or R'' from the group consisting of alkyl, aryl, arylalkyl, must be Z", and further provided that only one of cycloalkyl, and cycloalkylalkyl, R182, R183, or R'' is Z1; US 2004/0029864 A1 Feb. 12, 2004 32

0940 Z' is selected from the group consisting of: 0952 D denotes a group of formula XXXVIII or XXXIX:

X28 XXXVIII S(O) / \ X27- R190 and -K X27-R 190 o N. y-r O R203 XXXIX 0941 ° is selected from the group consisting of S(O) Yi-R22 S(O), S(O)(NR'), S(O), Se(O), P(O)(OR'), M and P(O)(NR'R''); Z15 0942 X is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen; 0953) R' and R independently of each other 0943) R' is selected from the group consisting of denote hydrogen, an optionally polyfluorinated alkyl alkenyl, alkoxy, alkyl, alkylamino, alkylcarbony radical, an aralkyl, aryl or heteroaryl radical or a lamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, -NHNH, and -NCHN(R')R'; radical (CH), X'; or 0954) R' and R together with the N-atom 0944) R', R', R', and R'' are independently denote a three- to Seven-membered, Saturated, par Selected from the group consisting of hydrogen, tially or totally unsaturated heterocycle with one or alkyl, and cycloalkyl, or R'' and R' can be taken more heteroatoms N, O, or S, which may optionally together, with the nitrogen to which they are be Substituted by OXO, an alkyl, alkylaryl or aryl attached, to form a 3-6 membered ring containing 1 group or a group (CH), X’, R' denotes hydro or 2 heteroatoms Selected from the group consisting gen, an optionally polyfluorinated alkyl group, an of O, S, and NR; aralkyl, aryl or heteroaryl group or a group (CH)- 0945) Y is selected from the group consisting of X29, -OR', SR 195, C(R97)(R198)R 195, -C(O)R’, -C(O)OR', -N(R97)C(O)R 19, 0955 wherein: -NC(R97)R 19, and -N(R97)R 19, 0956 X' denotes halogen,9. NO,2 -OR', 0946) R' is selected from the group consisting of -CORCONR" –COOR365-doNR204, R', –OCO, R365, R, -CN,SR20. hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthio S(O)R’, S(O) R', NRO' R20, -NH alkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, C(O)R’9, -NHS(O), R'; Z denotes cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetero CH-, -CH-CH-, -CH-CH cyclic, heterocyclic alkyl, hydroxyalkyl, and NR' CH-, -CH-CH=CH-, -CH=CH R°09; and CH-, CH-CO-, CO-CH-, 0947) R'7, R', R', and R' are independently NHCO-, -CONH-, -NHCH-, -CH Selected from the group consisting of hydrogen, NH-, -N=CH-, -NHCH-, -CH alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, CH-NH-, -CH=CH-, >N-R', >C=O, arylalkyl, heterocyclic, and heterocyclic alkyl. >S(O); 0948 Materials that can serve as a cyclooxygenase-2 0957) R' and R' independently of each other selective inhibitor of the present invention include benzo denote hydrogen, alkyl, aralkyl or aryl; sulphonamide derivatives that are described in U.S. Pat. No. 6,004,948. Such benzosulphonamide derivatives have the 0958) n is an integer from 0 to 6; formula shown below in formula XXXVII: 0959) R' is a straight-chained or branched C alkyl group which may optionally be mono- or polysubstituted by halogen or alkoxy, or R' XXXVII denotes CF, and 0960 m denotes an integer from 0 to 2; 0961) with the proviso that A' does not represent 0 if R denotes CF; 0962 and the pharmaceutically acceptable salts thereof. 0949) herein: 0963 Cox-2 selective inhibitors that are useful in the 0950 A' denotes oxygen,yg sulphurp or NH; Subject method and compositions can include the com pounds that are described in U.S. Pat. Nos. 6,169,188, 0951) R' denotes a cycloalkyl, aryl or het 6,020,343, 5,981,576 ((methylsulfonyl)phenyl furanones); eroaryl group optionally mono- or poly Substituted U.S. Pat. No. 6,222,048 (diaryl-2-(5H)-furanones); U.S. Pat. by halogen, alkyl, CF or alkoxy; No. 6,057,319 (3,4-diaryl-2-hydroxy-2,5-dihydrofurans); US 2004/0029864 A1 Feb. 12, 2004

U.S. Pat. No. 6,046,236 (carbocyclic sulfonamides); U.S. 0971 Anticholinergics such as homatropine, may help Pat. Nos. 6,002,014 and 5,945,539 (oxazole derivatives); produce a drying effect in the nose and chest. and U.S. Pat. No. 6,359,182 (C-nitroso compounds). 0964 Cyclooxygenase-2 selective inhibitors that are use 0.972 Antiviral agents specifically or generally modulate ful in the present invention can be Supplied by any Source as the biological activity of Viruses Such as picornavirus, influ long as the cyclooxygenase-2-Selective inhibitor is pharma enza virus, herpesviruses, herpes simples, herpes Zoster, ceutically acceptable. Cyclooxygenase-2-Selective inhibi enteroviruses, varicella and rhinovirus, which are associated tors can be isolated and purified from natural Sources or can with the common cold. Examples of antiviral agents include be Synthesized. Cyclooxygenase-2-Selective inhibitors neuramimidase inhibitorS Such as Zanamivir and Oselta should be of a quality and purity that is conventional in the mivir, agents for herpesviruses Such as famciclovir, Valaci trade for use in pharmaceutical products. clovir, Valganciclovir, aciclovir and ganciclovir, interferons, 0965) Another component of the present invention is a interferon-inducers, and newer antiviral agents Such as dipy colds and cough active ingredient. It is preferred that the ridamole; ICI 130,685; impulsin; and pleconaril (VP-63843; colds and cough active ingredient is different than the 3-3,5-dimethyl-4-3-(3-methyl-5-isoxazolyl)propyloly cyclooxygenase-2 Selective inhibitor. In general, colds and phenyl-5-(trifluoromethyl)-1,2,4-oxad iazole; available cough medications can be used to relieve the cough and under the tradename PICOVIRGE) from ViroPharma and other Symptoms due to colds, influenza, or hay fever. Com Sanofi-Synthelabo). monly, two or more ingredients that have activity against the 0973 Other materials can be used along with the subject Same or different Symptoms of colds or coughs can be used combination of a Cox-2 Selective inhibitor and at least one together in a combination. AS these terms are used herein, “colds and cough active ingredient' is meant to include any colds and cough active ingredient. For example, ingredients element, compound or material, alone or in combination, Such as caffeine, potassium citrate, ascorbic acid and citric that has been used for, or has been shown to be useful for, acid can be added to the combinations, as can Such materials the prevention, treatment or amelioration of at least one as fillers, dyes, binders, adsorbents, Surfactants, and the like. Symptom commonly associated with colds or cough. 0974. One embodiment of the present invention is a Examples of general categories of colds and cough active composition that includes a cycloxygenase-2 Selective ingredients include antihistamines, decongestants, antituS inhibitor and one or more colds and cough active ingredient. Sives, expectorants, analgesics, anticholinergicS and antivi Any one of, or any combination of, the Cox-2 Selective ral agents. It should be understood that when any colds and inhibitors that are described above can be used in the cough active ingredient is referred to herein, all pharmaceu composition. Likewise, the colds and cough active ingredi tically acceptable Salts and prodrugs of the material are also ent can be Selected from an antihistamine, antituSSive, included unless Specified otherwise. analgesic, expectorant, decongestant, anticholinergic, anti 0966 Antihistamines are used to relieve or prevent the Viral agent, or a mixture of two or more thereof. Symptoms of hay fever and other types of allergy. They also help relieve Some Symptoms of the common cold, Such as 0975. In an embodiment, the colds and cough active Sneezing and runny nose. They work by preventing the ingredient comprises an antihistamine. It is preferred that the effects of histamine, which is produced by the body. Some antihistamine is Selected from the group consisting of aza examples of antihistamines are: bromodiphenhydramine, tadine, bromodiphenhydramine, brompheniramine, bro brompheniramine, carbinoxamine, chlorpheniramine, dex mpheniramine maleate, carbinoxamine, chlorpheniramine, chlorpheniramine, diphenhydramine, doxylamine, phenin deXchlorpheniramine, diphenhydramine, doxylamine, phen damine, pheniramine, phenyltoloxamine, pyrilamine, indamine, pheniramine, phenyltoloxamine, promethazine, promethazine, triprolidine, loratadine, and cetirzine. pyrilamine, triprolidine, and mixtures thereof. 0967 Decongestants, such as ephedrine, phenylephrine, 0976. In another embodiment, the colds and cough active phenylpropanolamine and pseudoephedrine, produce a nar ingredient comprises an antituSSive. In preferred embodi rowing of blood vessels. This leads to clearing of nasal ments, the antituSSive is Selected from the group consisting congestion. of codeine, dihydrocodeine, hydrocodone, hydrocodone bitartrate, hydromorphone, carbetapentane, caraminphen, 0968 Antitussives help relieve coughing. Examples of dextromethorphan, chlorphedianol, noScarpine, and mix antituSSives include those which are narcotics, Such as codeine, dihydrocodeine, hydrocodone and hydromorphone, tures thereof. or a non-narcotic, Such as carbetapentane, caramiphen, or 0977. In another embodiment, the colds and cough active dextromethorphan. It is believed that antituSSives act ingredient comprises an analgesic. It preferred embodi directly on the cough center in the brain. ments, the analgesic is Selected from the group consisting of 0969 Expectorants, such as guaifenesin, are believed to acetaminophen, aspirin, Salicylamide, Sodium Salicylate, work by loosening the mucus or phlegm in the lungs. indomethacin, ibuprofen, naproxen, flubiprofen, carprofen, Examples of other ingredients that are added as expectorants tiaprofenic acid, cicloprofen, detoprofen, ketorolac, etod include ammonium chloride, calcium iodide, iodinated glyc olac, and mixtures thereof. erol, ipecac, potassium guaiacolsulfonate, potassium iodide, 0.978. In another embodiment, the colds and cough active and Sodium citrate. ingredient comprises an expectorant. In preferred embodi 0970 Analgesics, such as acetaminophen, aspirin, and ments, the expectorant comprises guaifenesin, glyceryl guai other Salicylates, Such as Salicylamide and Sodium Salicylate, acolate, terpin hydrate, ammonium chloride, N-acety are used to help relieve the aches and pain that may occur lesteine, brom hexine, ambroXol, domiodol, 3-iodo-1,2- with the common cold. propanediol, and mixtures thereof. US 2004/0029864 A1 Feb. 12, 2004 34

0979. In another embodiment, the colds and cough active cyclovir, foScarnet, ribavarin, amantadine, rimantadine, ingredient comprises a decongestant. In preferred embodi cidofovir, or two or more of these compounds. ments, the decongestant is Selected from the group consist ing of ephedrine, ephinephrine, levodesoxyephedrine, 0982) Another embodiment of the present invention is a oxymetazoline, naphazoline, phenylephrine, phenylpro composition that includes a cycloxygenase-2 Selective panolamine, propylhexedrine, pseudoephedrine, Xylometa inhibitor and two or more different types of colds and cough Zoline, and mixtures thereof. active ingredients. The Cox-2 Selective inhibitor can be any 0980. In another embodiment, the colds and cough active one of, or any combination of, the Cox-2 Selective inhibitors ingredient comprises an anticholinergic. In preferred that are described above. The two or more different types of embodiments, the anticholinergic comprises homatropine. colds and cough active ingredients can be selected from any combination of two or more of an antihistamine, antituSSive, 0981. In another embodiment, the colds and cough active analgesic, expectorant, decongestant, anticholinergic, or an ingredient comprises an antiviral agent. In preferred antiviral agent. Preferred embodiments of the present inven embodiments, the antiviral agent comprises a neuramimi tion include a cyclooxygenase-2 Selective inhibitor in com dase inhibitor, an agent for herpesviruses, an interferon, or bination with any of the combinations of two or more colds an interferon-inducer. In more preferred embodiments, the and cough active ingredients that are shown in Table 3. antiviral agent comprises dipyridamole, ICI 130,685, impulsin, pleconaril, Zanamivir, Oseltamivir, famciclovir, 0983 Table 3: Combinations of two or more colds and Valaciclovir, Valganciclovir, aciclovir (acyclovir), ganciclo cough active ingredients and trade names of commercial Vir, idoxuridine, Vidarabine, trifluridine, penciclovir, Vala compositions that include the combination.

COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS

1. An antihistamine and an antitussive. Ambenyl Cough; bromodiphenhydramine and codeine. Ambophen; Amgenal Cough; Bromanyl: Bromotuss with Codeine: 3 chlorpheniramine and codeine. Effective Strength chlorpheniramine and dextromethorphan. Cough Formula; Primatuss Cough Mixture; Scot-Tussin DM: Tricodene Sugar Free; S-T-Forte 2: chlorpheniramine and hydrocodone. Tussionex Pennkinetic: 6 phenyltoloxamine and hydrocodone. Pentazine VC wif promethazine and codeine. Codeine: Phenergan with Codeine: Pherazine w/Codeine: Phenameth DM: promethazine and dextromethorphan. Phenergan with Dextromethorphan; Pherazine DM: Promethazine DM: Prometh wif Dextromethorphan; Tricodene: pyrilamine and codeine. An antihistamine, an antitussive, and an analgesic. 11 doxylamine, codeine and acetaminophen. 12 An antihistamine, an antitussive, and an expectorant. 13 bromodiphenhydramine, diphenhydramine, codeine, ammonium chloride and potassium guaiacolsulfonate. 14 diphenhydramine, codeine and ammonium chloride. 15 diphenhydramine, dextromethorphan and ammonium chloride. 16 pheniramine, codeine and guaifenesin. 17 Citra-Forte: pheniramine, pyrilamine, hydrocodone, potassium citrate and ascorbic acid. US 2004/0029864 A1 Feb. 12, 2004 35

-continued

COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS 18 Citra-Forte: chlorpheniramine, pheniramine, pyrilamine, phenylephrine, hydrocodone salicylamide, caffeine and ascorbic acid. 19 promethazine, codeine and potassium guaiacolsulfonate. An antihistamine, a decongestant and an antitussive. 21 brompheniramine, phenylephrine, phenylpropanolamine and codeine. 22 brompheniramine, phenylephrine, phenylpropanolamine and dextromethorphan. 23 Bromonate DC Cough; brompheniramine, phenylpropanolamine and Bromphen DC with codeine. Codeine Cough; Dimetane-DC Cough; Myphetane DC Cough; Poly-Histine-CS: 24 Dimetapp DM: brompheniramine, phenylpropanolamine and Dimetapp DM Cold & dextromethorphan. Cough; Dimetapp Maximum Strength Cold & Cough Liqui-Gels; Histinex DM: lohist DM: Liqui-Histine DM: Poly-Histine-DM: Siltapp w/ Dextromethorphan Cough & Cold; 25 Bromarest DX Cough; brompheniramine, pseudoephedrine and Bromatene DX Cough; dextromethorphan. Bromfed DM: Bromphen DX Cough; Brotane DX Cough; Dimetane-DX Cough: Myphetane DX Cough; 26 Carbinoxamine carbinoxamine, pseudoephidrine and Compound; dextromethorphan. Carbinoxamine Compound Drops; Carbodec DM: Carbodec DM Drops; Cardec DM: Cardec DM Drops; Cardec DM Pediatric; Pseudo-Car DM; Rondamine-DM Drops; Rondec-DM: Rondec-DM Drops; Sildec-DM; Sildec-DM Oral Drops; Tussafed; Tussafed Drops; 27 Rentamine Pediatric: chlorpheniramine, ephedrine, phenylephrine Rynatuss; and carbetapentane. Rynatuss Pediatric; Tri-Tannate Plus Pediatric: 28 Atuss DM: chlorpheniramine, phenylephrine and Cerose DM: dextromethorphan. Dondril; 29 Anaplex HD; chlorpheniramine, phenylephrine and Atuss HD; hydrocodone. Chlorgest-HD; ED-TLC: ED Tuss HC: Edagen-HD; Endal-HD; Endal-HD Plus: Histinex HC: Histussin HC: US 2004/0029864 A1 Feb. 12, 2004 36

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS lodal HD; lotussin HC: Med-Hist HC: Nasatuss; Para-Hist HD; Unituss HC: Vanex-HD; T-Koff chlorpheniramine, phenylephrine, phenylpropanolamine and codeine. 31 Cophene-S; chlorpheniramine, phenylephrine, Vanex Grape; phenylpropanolamine and dihydrocodeine. 32 chlorpheniramine, phenylpropanolamine and caramiphen. 33 Cheracol Plus: chlorpheniramine, phenylpropanolamine and Kophane Cough and dextromethorphan. Cold Formula: Myminicol; Snaplets-Multi; Threamine DM; Triaminicol Multi Symptom Cold and Cough Medicine; Triaminic Triaminicol; Tricodene Forte; Tricodene NN: Triminol Cough; 34 Codehist DH: chlorpheniramine, pseudoephedrine and Decohistine DH: codeine. Dihistine DH: Medahist DH: Novahistine DH Liquid; Phen hist DH wif Codeine: Ryna-C Liquid; 35 PediaCare Cough chlorpheniramine, pseudoephedrine and Cold; dextromethorphan. PediaCare Night Rest Cough-Cold Liquid; Rescon-DM: Rhinosyn-DM: Triaminic Night Time; Tussar DM: Vicks Children's NyOuil Cold/Cough Relief; Wicks Pediatric 44 M Multi-Symptom Cough & Cold; 36 Histinex PV; chlorpheniramine, pseudoephedrine and Promist HD Liquid; hydrocodone. P-V-Tussin: 37 diphenylpyraline, phenylephrine and dextromethorphan. 38 doxylamine, etafedrine and hydrocodone. 39 pheniramine, phenylephrine and dextromethorphan. 40 Rolatuss wif pheniramine, pyrilamine, phenylephrine, Hydrocodone; phenylpropanolamine and hydrocodone. Ru-Tuss with Hydrocodone Liquid; Statuss Green; 41 pyrilamine, phenylpropanolamine and codeine. 42 pheniramine, pyrilamine, phenylpropanolamine and dextromethorphan. 43 pheniramine, pyrilamine, phenylpropanolamine and hydrocodone. 44 Phenameth VC with promethazine, phenylephrine and codeine. Codeine: Phenergan VC with Codeine: Pherazine VC with Codeine: Promethazine VC wif US 2004/0029864 A1 Feb. 12, 2004 37

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS Codeine: Promethist wif Codeine: Prometh VC with Codeine: 45 promethazine, pseudoephedrine and dextromethorphan. 46 Codimal PH; pyrilamine, phenylephrine and codeine. 47 Codimal DM: pyrilamine, phenylephrine and dextromethorphan. 48 Codimal DH: pyrilamine, phenylephrine and hydrocodone. 49 Actagen-C-Cough; triprolidine, pseudoephedrine and codeine. Actifed with Codeine Cough; Allerfrin with Codeine: Aprodine with Codeine: Triacin C Cough; Triafed wif Codeine; Trifed-C Cough; 50 triprolidine, pseudoephedrine and dextromethorphan. 51 An antihistamine, a decongestant, an antitussive and an analgesic. 52 Omnicol; chlorpheniramine, phenindamine, phenylephrine, dextromethorphan, acetaminophen, salicylamide, caffeine and ascorbic acid. 53 chlorpheniramine, pheniramine, pyrilamine, phenylephrine, hydrocodone, salicylamide, caffeine and ascorbic acid. 54 Improved Sino-Tuss; chlorpheniramine, phenylephrine, dextromethorphan, acetaminophen and salicylamide. 55 Hycomine Compound; chlorpheniramine, phenylephrine, hydrocodone, acetaminophen and caffeine. 56 Alka-Seltzer Plus Flu chlorpheniramine, phenylpropanolamine, & Body Aches; dextromethorphan and acetaminophen. Comtrex Maximum Strength. Multi Symptom Liqui-Gels; Comtrex Multi Symptom Cold Reliever; Contac Severe Cold & Flu Caplets; 57 Alka-Seltzer Plus Cold chlorpheniramine, phenylpropanolamine, and Cough; dextromethorphan and aspirin. 58 chlorpheniramine, pseudoephedrine, codeine and acetaminophen. 59 Alka-Seltzer Plus Cold chlorpheniramine, pseudoephedrine, and Cough Medicine dextromethorphan and acetaminophen. Liqui-Gels; Children's Tylenol Cold Plus Cough Multi Symptom; Comtrex Nighttime; Comtrex Nighttime Maximum Strength Cold, Cough and Flu Relief; Comtrex Nighttime Maximum Strength Cold and Flu Relief; Kolephrin/DM Cough and Cold Medication: Mapap Cold Formula: TheraFlu. Flu, Cold & Cough Medicine; TheraFlu Nighttime Maximum Strength Flu, Cold & Cough; Tylenol Cold US 2004/0029864 A1 Feb. 12, 2004 38

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS Medication: Tylenol Cold Medication Caplets; Tylenol Cold Multi Symptom; Vicks 44 M Cough, Cold and Flu Relief; Vicks 44 M Cough, Cold and Fu Relief LiquidCaps; 60 Alka-Seltzer Plus doxylamine, phenylpropanolamine, Night-Time Cold; dextromethorphan and aspirin. Co-Apap; 61 Alka-Seltzer Plus doxylamine, pseudoephedrine, Night-Time Cold Liqui dextromethorphan and acetaminophen. Gels; All-Night Cold Formula: Genite: Nytcold Medicine; Robitussin Night-Time Cold Formula: Vicks NyOuil Hot Therapy; Vicks NyOuil Multi Symptom Cold/Flu LiquiCaps; Vicks NyOuil Multi Symptom Cold/Flu Relief; 62 Robitussin Night pyrilamine, pseudoephedrine, Relief; dextromethorphan and acetaminophen. 63 An antihistamine, a decongestant, an antitussive and an expectorant. 64 brompheniramine, phenylephrine, phenylpropanolamine, codeine and guaifenesin. 65 comprises brompheniramine, phenylephrine, phenylpropanolamine, hydrocodine and guaifenesin. 66 Quelidrine Cough; chlorpheniramine, ephedrine, phenylephrine, dextromethorphan, ammonium chloride and ipecac. 67 Tusquelin; orpheniramine, phenylephrine, enylpropanolamine, dextromethorphan, assium guaiacolsulfonate and ipecac. 68 Rolatuss Expectorant; orpheniramine, phenylephrine, codeine and mmonium chloride. 69 Pediacof Cough; orpheniramine, phenylephrine, codeine and Pedituss Cough; assium iodide. 70 Donatussin; orpheniramine, phenylephrine, extromethorphan and guaifenesin. 71 Father John Medicine orpheniramine, phenylephrine, Plus: extromethorphan, guaifenesin and ammonium oride. 72 Cophene-XP; orpheniramine, phenylephrine, enylpropanolamine, carbetapentane and O assium guaiacolsulfonate. 73 hlorpheniramine, phenyltoloxamine, phedrine, codeine and guaiacol carbonate. 74 hlorpheniramine, pseudoephedrine, extromethorphan and guaifenesin. 75 Prominicol Cough; heniramine, pyrilamine, phenylpropanolamine, extromethorphan and ammonium chloride. 76 Triaminic Expectorant heniramine, pyrilamine, phenylpropanolamine, DH ydrocodone and guaifenesin. 77 S-T-Forte; heniramine, phenylephrine, henylpropanolamine, hydrocodone and guaifenesin. 78 promethazine, phenylephrine, codeine and potassium guaiacolsulfonate. 79 pyrilamine, phenylephrine, hydrocodone and ammonium chloride. US 2004/0029864 A1 Feb. 12, 2004 39

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS Phanatussin; pyrilamine, phenylpropanolamine, dextromethorphan and guaifenesin. 81 triprolidine, pseudoephedrine, codeine and guaifenesin. 82 An antihistamine, a decongestant, an antitussive, an expectorant and an analgesic. 83 Tussirex: pheniramine, phenylephrine, codeine, sodium citrate, sodium salicylate and caffeine. 84 An antihistamine, a decongestant and an expectorant. 85 brompheniramine, phenylephrine, phenylpropanolamine and guaifenesin. 86 Bronkotuss chlorpheniramine, ephedrine and guaifenesin. Expectorant; 87 Donatussin Drops; chlorpheniramine, phenylephrine and guaifenesin. 88 chlorpheniramine, phenylpropanolamine and guaifenesin. 89 Lanatuss Expectorant; chlorpheniramine, phenylpropanolamine, guaifenesin, sodium citrate and citric acid. 90 chlorpheniramine, pseudoephedrine and guaifenesin. 91 Polaramine dexchlorpheniramine, pseudoephedrine and Expectorant; guaifenesin. 92 promethazine, phenylephrine and potassium guaiacolsulfonate. 93 An antihistamine, a decongestant, an expectorant and an analgesic. 94 Gelpirin-CCF; chlorpheniramine, phenylpropanolamine, guaifenesin and acetaminophen. 95 An antihistamine and an expectorant. 96 Drixoral Cough & Sore promethazine and potassium Throat Liquid Caps; guaiacolsulfonate. Tylenol Multi-Symptom Cough; 97 An antitussive and an analgesic. 98 dextromethorphan and acetaminophen. 99 An antitussive and an antichlolinergic. 1OO Codan; hydrocodone and homatropine. Hycodan; Hydromet; Hydropane; Tussigon; 101 An antitussive and an expectorant. 102 Cheracol; codeine, ammonium chloride and guaifenesin. 103 Calcidrine: codeine and calcium iodide. 104 Brontex; codeine and guaifenesin. Glydeine Cough; Guaituss A.C.; Mytussin AC; Robafen AC Cough; Robitussin A-C; Tolu-Sed Cough; Tussi-Organidin NR Liquid; Tussi-Organidin-S NR Liquid; 105 lophen-C Liquid; codeine and iodated glycerol. 106 Anti-Tuss DM dextromethorphan and guaifenesin. Expectorant; Benylin Expectorant; Cheracol D Cough; Children's Formula Cough; Diabetic Tussin DM: Extra Action Cough; Fenesin DM; Genatuss DM: Glycotuss-dM; Guaimid D.M. Liquid; Guaitussin wif Dextromethorphan; Halotussin-DM: US 2004/0029864 A1 Feb. 12, 2004 40

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS Humibid DM: Humibid DM Pediatric; lobid DM: Kolephrin GG/DM: Muco-Fen DM: Mytussin DM: Naldecon Senior DX; Phanatuss; Respa-DM: Rhinosyn-DMX Expectorant; Robafen DM: Robitussin-DM: Safe Tussin 30: Scot-Tussin Senior Clear; Silexin Cough; Siltussin-DM: Supressin DM: Supressin DM Caplets; Syracol CF; Tolu-Sed DM Touro DM: Tuss-DM; Tussi-Organidin DM NR Liquid; Tussi-Organidin DM-S NR Liquid; Uni-tussin DM: Unproco; Vicks 44E Cough & Chest Congestion; Vicks Pediatric 44E: 107 lophen DM: dextromethorphan and iodated glycerol. Tusso-DM: 108 Atuss EX: hydrocodone and guaifenesin. Codiclear DH: Co-Tuss V: Hycotuss Expectorant; Kwelcof Liquid; Pneumotussin HC: Vicodin Tuss; 109 Entuss Expectorant; hydrocodone and potassium guaiacolsulfonate. Marcof Expectorant; 110 Dilaudid Cough; hydromorphone and guaifenesin. 111 A decongestant and an antitussive. 112 phenylephrine and codeine. 113 Nalex DH: phenylephrine and hydrocodone. 114 Ordrine AT: phenylpropanolamine and caramiphen. Rescaps-D S.R.: Tuss-Ade: Tuss-Allergine Modified T.D.; Tussogest; 115 Snaplets-DM: phenylpropanolamine and dextromethorphan. Triaminic-DM Cough Relief; Tricodene Pediatric; 116 Codamine; phenylpropanolamine and hydrocodone. Codamine Pediatric Hycomine; Hycomine Pediatric; Hydromine; Hydromine Pediatric; Hydrophen; 117 Nucofed; pseudoephedrine and codeine. 118 Drixoral Cough & pseudoephedrine and dextromethorphan. Congestion Liquid Caps; Effective Strength Cough Formula with Decongestant; US 2004/0029864 A1 Feb. 12, 2004 41

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS Robitussin Maximum Strength Cold and Cough; Robitussin Pediatric Cold & Cough; Triaminic AM Non Drowsy Cough and Decongestant; Tuss-DA: Vicks 44 Cough and Cold Relief Non Drowsy LiquiCaps; Vicks 44D Cough and Head Congestion; Vicks Pediatric 44D Cough & Head Decongestion; 119 De-Tuss; pseudoephedrine and hydrocodone. Detussin Liquid; Tyrodone; 12O A decongestant, an antitussive and an analgesic. 121 Saleto-CF; phenylpropanolamine, dextromethorphan and acetaminophen. 122 Alka-Seltzer Plus Flu pseudoephedrine, dextromethorphan and & Body Aches acetaminophen. Medicine Liqui-Gels; Co-Complex DM Caplets; Comtrex Daytime Caplets; Contrex Daytime Maximum Strength Cold, Cough, and Flu Relief; Comtrex Daytime Maximum Strength Cold and Flu Relief; Comtrex Multi Symptom Maximum Strength. Non-Drowsy Caplets; Contac Cold/Flu Day Caplets; Contac Severe Cold & Flu. Non-Drowsy Caplets; Ornex Severe Cold No Drowsiness Caplets; Sudafed Severe Cold Formula: Sudafed Severe Cold Formula Caplets; TheraFlu Maximum Strength. Non-Drowsy Formula Flu, Cold & Cough Medicine; TheraFlu Maximum Strength. Non-Drowsy Formula Flu, Cold & Cough Medicine Caplets; Triaminic Sore Throat Formula: Tylenol Cold and Flu Non Crowsiness Tylenol Cold Drowsy Caplets; Tylenol Cold Medication, Non Drowsy Caplets; US 2004/0029864 A1 Feb. 12, 2004 42

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS Tylenol Maximum Strength Flu Gelcaps; Tylenol Multi-Symptom Cough with Decongestant; 123 A decongestant, an antitussive and an expectorant. 124 ephedrine, carbetapentane and guaifenesin. 125 Dexafed Cough; phenylephrine, dextromethorphan and Supressin DM Plus: guaifenesin. Tussex Cough; 126 Cophene-X; phenylephrine, phenylpropanolamine, carbetapentane and potassium guaiacolsulfonate. 127 Donatussin DC: phenylephrine, hydrocodone and guaifenesin. 128 Codegest Expectorant; phenylpropanolamine, codeine and Conex with Codeine guaifenesin. Liquid; C-Tussin Expectorant; Endal Expectorant; Naldecon-CX Adult Liquid; Statuss Expectorant; Triaminic Expectorant with Codeine: 129 Anatuss; phenylpropanolamine, dextromethorphan and GuaiCough CF; guaifenesin. Guaituss CF; Ipsatol Cough Formula for Children and Adults; Kiddy Koff: Naldecon-DX Adult Liquid; Naldecon-DX Children's Syrup; Naldecon-DX Pediatric Drops; Robafen CF; Robitussin-CF: Siltussin-CF; 130 Anatuss; phenylpropanolamine, dextromethorphan, guaifenesin and acetaminophen. 131 Deproist Exectorant pseudoephedrine, codeine and guaifenesin. with Codeine: Dihistine Expectorant; Guaituss DAC: Mytussin DAC: Novagest Expectorant w/Codeine: Novahistine Expectorant; Nucochem Expectorant; Nucochem Pediatric Expectorant; Nucofed Expectorant; Nucofed Pediatric Expectorant; Nucotuss Expectorant; Nucotuss Pediatric Expectorant; Phenhist Expectorant; Robafen. DAC: Robitussin-DAC: Ryna-CX Liquid; Tussar-2: Tussar SF: 132 Ambenyl-D pseudoephedrine, dextromethorphan and Decongestant Cough guaifenesin. Formula: Anatuss DM: Benylin Multi US 2004/0029864 A1 Feb. 12, 2004 43

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS Symptom; Concentrin; Dimacol Caplets; Dorcol Children's Cough; Novahistine DMX Liquid; PediaPressin Pediatric Drops; Primatuss Cough Mixture 4D: Rhinosyn-X; Robitussin Cold and Cough Liqui-Gels; Ru-Tuss Expectorant; Sudafed Children's Non-Drowsy Cold & Cough; Sudafed Children's Cold & Cough; 133 Cophene-XP; pseudoephedrine, hydrocodone and Detussin Expectorant; guaifenesin. Duratuss HD; Entuss-D Jr.; Med-Hist Exp; SRC Expectorant; Tussafin Expectorant; Vanex Expectorant; 134 Entuss-D; pseudoephedrine, hydrocodone and potassium Protuss-D; guaiacolsulfonate. 135 A decongestant, an antitussive, an expectorant and an analgesic. 136 phenylpropanolamine, dextromethorphan, guaifenesin and acetaminophen. 137 Comtrex Cough pseudoephedrine, dextromethorphan, Formula: guaifenesin and acetaminophen. Robitussin Cold, Cough & Flu Liqui Gels; Sudafed Cold & Cough Liquid Caps; Vicks DayOuil Multi Symptom Cold/Flu Liqui Daps; Vicks DayOuil Multi Symptom Cold/Flu Relief; 138 A decongestant and an expectorant. 139 Broncholate: ephedrine and guaifenesin. 140 KIE; ephedrine and potassium iodide. 141 Deconsal Pediatric: phenylephrine and guaifenesin. Endal; Rescon-GG: Sinupan; 142 Ami-Tex.; phenylephrine, phenylpropanolamine and Banex Liquid; guaifenesin. Contuss; Despec; Despec SF: Dura-Gest: Dura-Tex: Enomine; Entex; Entex Liquid; Norel; Sil-Tex: 143 Ami-Tex LA; phenylpropanolamine and guaifenesin. Banex-LA; Conex; Despec-SR Caplets; Dura-Vent: Entex LA; Exgest LA; US 2004/0029864 A1 Feb. 12, 2004 44

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS Guaifenex PPA 75: Guaipax; Myminic Expectorant; Naldecon-EX Children's Syrup; Naldecon-EX Pediatric Drops: Partuss LA; Phenylfenesin LA; Profen II; Profen-LA; Prominic Expectorant; Rymed-TR Caplets; Silaminic Expectorant; Sildecon-E Pediatric Drops; SINUvent; Snaplets-EX: Stamoist LA; Triaminic Expectorant; Triphenyl Expectorant; ULR-LA; Vicks DayOuil Simus Pressure and Congestion Relief Caplets; 144 Anatuss LA; pseudoephedrine and guaifenesin. Congess JR; Congess SR; Congestac Caplets; Deconsal II; Duratuss; Entex PSE; Eudal-SR; Expressin 400 Caplets; Glycofed; GP-500; Guaifed; Guaifed-PD; Guaifenex PSE 60; Guaifenex PSE 120; GuaiMAX-D; Guaitab: Guaivent: Guaivent PD; Guai-Vent/PSE; GuaiCough PE; Guaituss PE; Humibid Guaifenesin Plus: losal II; Nalex; Nalex Jr.; Nasabid: Nasatab LA; Pan Mist-JR; Respa-1": Respaire-60 SR; Respaire-120 SR; Robitussin-PE; Robitussin Severe Congestion Liqui-Gels; Ru-Tuss DE: Rymed; Rymed Liquid; Simufed Timecelles; Sinutab Non-Drying No Drowsiness Liquid Caps; Stamoist E: Sudafed Non-Drowsy Non-Drying Sinus US 2004/0029864 A1 Feb. 12, 2004

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COLDS AND COUGH ACTIVE INGREDIENT NUMBER TRADE-NAME COMBINATIONS Liquid Caps; Sudal 60/500; Sudal 120/600; Touro LA Caplets; Tuss-LA; V-Dec-M; Versacaps; Zephrex; Zephrex-LA; 145 A decongestant, an expectorant and an analgesic. 146 Fendol; phenylephrine, guaifenesin, acetaminophen, salicylamide and caffeine. 147 An antihistamine and a decongestant 148 Alerid-D cetirzine and pseudoephedrine 149 Claritin Reditabs loratadine and pseudoephedrine Claritin 24-Hour Claritin 12-Hour

0984. In an embodiment of the present method, a subject treatment of each agent by itself, while avoiding adverse in need of prevention, treatment or amelioration of a cold Side effects typically associated with alternative therapies. and/or a cough is treated by administering to the Subject a 0987 Those skilled in the art will appreciate that dosages cyclooxygenase-2 Selective inhibitor or prodrug thereof and may also be determined with guidance from Goodman & one or more colds and cough active ingredient. In one Goldman's The Pharmacological Basis of Therapeutics, embodiment, the Subject is treated with an amount of a colds Ninth Edition (1996), Appendix II, pp. 1707-1711. Further and cough active ingredient and an amount of a Cox-2 more, detailed prescribing information is available over the Selective inhibitor, where the amount of the colds and cough internet, or from the manufacturer or distributor, for each of active ingredient and the amount of the Cox-2 selective the commercial colds and cough active ingredients that are inhibitor together provide a dosage or amount of the com described in Table 3. bination that is Sufficient to constitute an effective amount of the combination. The effective amount can be a therapeutic 0988. In the present method, the amount of the colds and amount, and it can be an amount that is an effective amount cough active ingredient that is used is Such that, when for the prevention, treatment or amelioration of a cold or a administered with the cyclooxygenase-2 Selective inhibitor, cough. it is Sufficient to constitute an effective amount of the 0985. As used herein, an “effective amount’ means the combination. It is preferred that the dosage amount of the dose or effective amount to be administered to a patient and colds and cough active ingredient and the dosage amount of the frequency of administration to the Subject which is the cyclooxygenase-2 Selective inhibitor constitute a thera readily determined by one or ordinary skill in the art, by the peutically effective amount of the combination. use of known techniques and by observing results obtained 0989. It is well known that different colds and cough under analogous circumstances. The dose or effective active ingredients have different levels of potency and that amount to be administered to a patient and the frequency of recommended dosage levels vary considerably. The recom administration to the Subject can be readily determined by mended dosage level for a commercial colds and cough one of ordinary skill in the art by the use of known active ingredient can be found in the prescribing information techniques and by observing results obtained under analo that is published by the distributor as described above. gous circumstances. In determining the effective amount or dose, a number of factors are considered by the attending 0990 The frequency of dose will depend upon the half diagnostician, including but not limited to, the potency and life of the colds and cough active ingredient molecule. If the duration of action of the compounds used; the nature and colds and cough active ingredient has a short half life (e.g. Severity of the illness to be treated as well as on the Sex, age, from about 2 to 10 hours) it may be necessary to give one weight, general health and individual responsiveness of the or more doses per day. Alternatively, if the colds and cough patient to be treated, and other relevant circumstances. active ingredient has a long half-life (e.g. from about 2 to 0986 The phrase “therapeutically-effective” indicates the about 15 days) it may only be necessary to give a dosage capability of an agent to prevent, or improve the Severity of, once per day, per week, or even once every 1 or 2 months. the disorder, while avoiding adverse side effects typically A preferred dosage rate is to administer the dosage amounts asSociated with alternative therapies. The phrase “therapeu described above to a Subject once per day. tically-effective” is to be understood to be equivalent to the 0991 For the purposes of calculating and expressing a phrase “effective for the treatment, prevention, or inhibi dosage rate, all dosages that are expressed herein are cal tion', and both are intended to qualify the amount of each culated on an average amount-per-day basis irrespective of agent for use in the combination therapy which will achieve the dosage rate. For example, one 100 mg dosage of an the goal of improvement in the Severity of neurological or ingredient taken once every two days would be expressed as psychiatric disorder and the frequency of incidence over a dosage rate of 50 mg/day. Similarly, the dosage rate of an US 2004/0029864 A1 Feb. 12, 2004 46 ingredient where 50 mg is taken twice per day would be 1001 Pharmaceutically acceptable carriers include, but expressed as a dosage rate of 100 mg/day. are not limited to, physiological Saline, Ringers, phosphate Solution or buffer, buffered Saline, and other carriers known 0992 For the purposes of calculation of a dosage rate for in the art. Pharmaceutical compositions may also include the present method, the weight of an adult human is assumed Stabilizers, anti-oxidants, colorants, and diluents. Pharma to be 70 kg. ceutically acceptable carriers and additives are chosen Such 0993) The amount of Cox-2 selective inhibitor that is that Side effects from the pharmaceutical compound are used in the Subject method may be an amount that, when minimized and the performance of the compound is not administered with the colds and cough active ingredient, is canceled or inhibited to Such an extent that treatment is Sufficient to constitute an effective amount of the combina ineffective. tion. Preferably, such amount would be sufficient to provide 1002 The term “pharmacologically effective amount” a therapeutically effective amount of the combination. The shall mean that amount of a drug or pharmaceutical agent therapeutically effective amount can also be described that will elicit the biological or medical response of a tissue, herein as an amount that is effective for the prevention, System, animal or human that is being Sought by a researcher treatment or amelioration of a cold and/or a cough. or clinician. This amount can be a therapeutically effective 0994. In the present method, the amount of Cox-2 selec amount. tive inhibitor that is used in the novel method of treatment preferably ranges from about 0.01 to about 100 milligrams 1003. The term “pharmaceutically acceptable” is used per day per kilogram of body weight of the Subject (mg/ herein to mean that the modified noun is appropriate for use day kg), more preferably from about 0.1 to about 50 in a pharmaceutical product. Pharmaceutically acceptable mg/day kg, even more preferably from about 1 to about 20 cations include metallic ions and organic ions. More pre mg/day kg. ferred metallic ions, include, but are not limited to, appro priate alkali metal Salts, alkaline earth metal Salts and other 0995. When the Cox-2 selective inhibitor comprises rofe physiological acceptable metalions. Exemplary ions include coxib, it is preferred that the amount used is within a range aluminum, calcium, lithium, magnesium, potassium, Sodium of from about 0.15 to about 1.0 mg/day kg, and even more and Zinc in their usual Valences. Preferred organic ions preferably from about 0.18 to about 0.4 mg/day kg. include protonated tertiary amines and quaternary ammo nium cations, including in part, trimethylamine, diethy 0996. When the Cox-2 selective inhibitor comprises lamine, N,N'-dibenzylethylenediamine, chloroprocaine, etoricoxib, it is preferred that the amount used is within a choline, diethanolamine, ethylenediamine, meglumine range of from about 0.5 to about 5 mg/day kg, and even (N-methylglucamine) and procaine. Exemplary pharmaceu more preferably from about 0.8 to about 4 mg/day kg. tically acceptable acids include, without limitation, hydro 0997 When the Cox-2 selective inhibitor comprises cele chloric acid, hydroiodic acid, hydrobromic acid, phosphoric coxib, it is preferred that the amount used is within a range acid, Sulfuric acid, methaneSulfonic acid, acetic acid, formic of from about 1 to about 10 mg/day kg, even more prefer acid, tartaric acid, maleic acid, malic acid, citric acid, ably from about 1.4 to about 8.6 mg/day kg, and yet more isocitric acid, Succinic acid, lactic acid, gluconic acid, glu preferably from about 2 to about 3 mg/day kg. curonic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, 0998) When the Cox-2 selective inhibitor comprises and the like. parecoxib Sodium, it is preferred that the amount used is within a range of from about 0.1 to about 3 mg/day kg, and 1004) Notwithstanding the above description of certain alkali metal and alkali earth metal ions as being pharma even more preferably from about 0.3 to about 1 mg/day kg. ceutically acceptable cations, it should be recognized that it 0999 The combination of a colds and cough active is preferred that the cold and cough active ingredient of the ingredient and a Cox-2 Selective inhibitor can be Supplied in present invention be one that is free of an isolated metal Salt the form of a novel therapeutic composition that is believed of the cold and cough active ingredient. In other words, to be within the scope of the present invention. The relative when the colds and cough active ingredient is one that can amounts of each component in the therapeutic composition exist in a free acid form or in a metal Salt form, it is preferred may be varied and may be as described just above. The colds that at least Some portion of the cold and cough active and cough active ingredient and Cox-2 Selective inhibitor ingredient be present in its free acid form, rather than in an that are described above can be provided in the therapeutic isolated metal salt form. It is more preferred that when the composition So that the preferred amounts of each of the cold and cough active ingredient comprises an analgesic, the components are Supplied by a Single dosage, a single injec analgesic is free of an isolated metal Salt of the analgesic. In tion or a single capsule for example, or, by up to four, or other words, it is preferred that at least Some portion of the more, Single dosage forms. analgesic be present in its free acid form, rather than its metal salt form. It is yet more preferred that when the cold 1000 When the novel combination is supplied along with and cough active ingredient comprises acetaminophen, the a pharmaceutically acceptable carrier, a pharmaceutical acetaminophen is free of an isolated metal Salt of the composition is formed. A pharmaceutical composition of the acetaminophen. In other words, it is preferred that at least present invention is directed to a composition Suitable for Some portion of the acetaminophen be present in its free acid the prevention, treatment or amelioration of colds and/or coughs. The pharmaceutical composition comprises a phar form, rather than its metal Salt form. maceutically acceptable carrier, one or more colds and 1005. In some cases, in particular where a subject is cough active ingredient, and a cyclooxygenase-2 Selective adversely affected by acetaminophen, it is preferred that the inhibitor. novel method and compositions be free of acetaminophen. US 2004/0029864 A1 Feb. 12, 2004 47

1006. Also included in the combination of the invention cough. The Subject may be at risk due to genetic predispo are the isomeric forms and tautomers and the pharmaceuti Sition, Sedentary lifestyle, diet, exposure to disorder-causing cally-acceptable Salts of antipsychotic agents and cyclooxy agents, exposure to pathogenic agents and the like. genase-2 Selective inhibitors. Illustrative pharmaceutically acceptable Salts are prepared from formic, acetic, propionic, 1012 The subject pharmaceutical compositions may be Succinic, glycolic, gluconic, lactic, malic, tartaric, citric, administered enterally and parenterally. Parenteral adminis ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, tration includes Subcutaneous, intramuscular, intradermal, glutamic, benzoic, anthranilic, meSylic, Stearic, Salicylic, intramammary, intravenous, and other administrative meth p-hydroxybenzoic, phenylacetic, mandelic, embonic ods known in the art. Enteral administration includes Solu (pamoic), methaneSulfonic, ethaneSulfonic, benzene tion, tablets, Sustained release capsules, enteric coated cap Sulfonic, pantothenic, toluenesulfonic, 2-hydroxyethane Sules, and Syrups. When administered, the pharmaceutical Sulfonic, Sulfanilic, cyclohexylaminoSulfonic, algenic, B-hy composition may be at or near body temperature. droxybutyric, galactaric, enanthic, decanoic and 1013 The phrases “combination therapy”, “co-adminis galacturonic acids. tration”, “administration with”, or “co-therapy”, in defining 1007 Suitable pharmaceutically-acceptable base addi the use of a cyclooxygenase-2 inhibitor agent and a colds tion Salts of compounds of the present invention include and cough active ingredient, is intended to embrace admin metallic ion Salts and organic ion Salts. More preferred istration of each agent in a Sequential manner in a regimen metallic ion Salts include, but are not limited to, appropriate that will provide beneficial effects of the drug combination, alkali metal (group Ia) salts, alkaline earth metal (group IIa) and is intended as well to embrace co-administration of Salts and other physiological acceptable metal ions. Such these agents in a Substantially Simultaneous manner, Such as Salts can be made from the ions of aluminum, calcium, in a single capsule or dosage device having a fixed ratio of lithium, magnesium, potassium, Sodium and Zinc. Preferred these active agents or in multiple, Separate capsules or organic Salts can be made from tertiary amines and quater dosage devices for each agent, where the Separate capsules nary ammonium Salts, including in part, trimethylamine, or dosage devices can be taken together contemporaneously, diethylamine, N,N'-dibenzylethylenediamine, chlorop or taken within a period of time Sufficient to receive a rocaine, choline, diethanolamine, ethylenediamine, meglu beneficial effect from both of the constituent agents of the mine (N-methylglucamine) and procaine. All of the above combination. Salts can be prepared by those skilled in the art by conven 1014 Although the combination of the present invention tional means from the corresponding compound of the may include administration of a colds and cough active present invention. ingredient component and a cyclooxygenase-2 selective inhibitor component within an effective time of each respec 1008 The method and compositions of the present inven tive component, it is preferable to administer both respective tion are useful for, but not limited to, the prevention, components contemporaneously, and more preferable to inhibition, and amelioration of a cold and/or a cough in a Subject that is need of Such treatment. By way of example, administer both respective components in a single delivery the method and compositions would be useful for the dose. prevention, treatment and amelioration of runny nose, nasal 1015. In particular, the combinations of the present congestion, lung congestion, bronchial irritation, neuritis, invention can be administered orally, for example, as tablets, neuralgia, Sore throat, pain, aches, inflammation, Sneezing, coated tablets, dragees, troches, lozenges, aqueous or oily coughing, upper respiratory infections, allergic rhinitis, oti Suspensions, dispersible powders or granules, emulsions, tis, Sinusitis, coryza, itchy and watery eyes, and the like, or hard or Soft capsules, or Syrups or elixirs. Compositions any two or more of the Symptoms described above. intended for oral use may be prepared according to any 1009) The terms “treating” or “to treat” mean to alleviate method known in the art for the manufacture of pharma Symptoms, eliminate the causation either on a temporary or ceutical compositions and Such compositions may contain permanent basis, or to prevent or slow the appearance of one or more agents Selected from the group consisting of symptoms. The term “treatment” includes alleviation, elimi Sweetening agents, flavoring agents, coloring agents and nation of causation of or prevention of colds and/or cough, preserving agents in order to provide pharmaceutically or the Symptoms associated with, but not limited to those elegant and palatable preparations. Tablets contain the active disorders. Besides being useful for human treatment, these ingredient in admixture with non-toxic pharmaceutically combinations are also useful for treatment of mammals, acceptable excipients which are Suitable for the manufacture including horses, dogs, cats, rats, mice, sheep, pigs, etc. of tablets. These excipients may be, for example, inert diluents, Such as calcium carbonate, Sodium carbonate, 1010 The term “subject” for purposes of treatment lactose, calcium phosphate or Sodium phosphate, granulat includes a Subject who is in need of the prevention of, or ing and disintegrating agents, for example, maize Starch, or who has a cold or a cough. The Subject is typically an alginic acid; binding agents, for example Starch, gelatin or animal, and yet more typically is a mammal. "Mammal’, as acacia, and lubricating agents, for example magnesium that term is used herein, refers to any animal classified as a Stearate, Stearic acid or talc. The tablets may be uncoated or mammal, including humans, domestic and farm animals, they may be coated by known techniques to delay disinte and Zoo, Sports, or pet animals, Such as dogs, horses, cats, gration and adsorption in the gastrointestinal tract and cattle, etc., Preferably, the mammal is a human. thereby provide a Sustained action over a longer period. For 1011 For methods of prevention, the subject is any example, a time delay material Such as glyceryl monoStear animal Subject, and preferably is a Subject that is in need of ate or glyceryl distearate may be employed. prevention and/or treatment of a cold and/or a cough. The 1016 Formulations for oral use may also be presented as Subject may be a human Subject who is at risk for a cold or hard gelatin capsules wherein the active ingredients are US 2004/0029864 A1 Feb. 12, 2004 48 mixed with an inert Solid diluent, for example, calcium Solvent, for example as a Solution in 1,3-butanediol. Among carbonate, calcium phosphate or kaolin, or as Soft gelatin the acceptable vehicles and Solvents that may be employed capsules wherein the active ingredients are present as Such, are water, Ringer's Solution and isotonic Sodium chloride or mixed with water or an oil medium, for example, peanut Solution. In addition, Sterile, fixed oils are conventionally oil, liquid paraffin, or olive oil. employed as a Solvent or Suspending medium. For this 1017 Aqueous Suspensions can be produced that contain purpose, any bland fixed oil may be employed including the active materials in admixture with excipients Suitable for Synthetic mono- or diglycerides. In addition, n-3 polyun the manufacture of aqueous Suspensions. Such excipients Saturated fatty acids may find use in the preparation of are Suspending agents, for example, Sodium carboxymeth injectables. ylcellulose, methylcellulose, hydroxypropylmethyl-cellu 1024. The subject combination can also be administered lose, Sodium alginate, polyvinylpyrrollidone gum tragacanth by inhalation, in the form of aerosols or solutions for and gum acacia, dispersing or Wetting agents may be natu nebulizers, or rectally, in the form of Suppositories prepared rally-occurring phosphatides, for example lecithin, or con by mixing the drug with a Suitable non-irritating excipient densation products of an alkylene oxide with fatty acids, for which is Solid at ordinary temperature but liquid at the rectal example polyoxyethylene Stearate, or condensation products temperature and will therefore melt in the rectum to release of ethylene oxide with long chain aliphatic alcohols, for the drug. Such materials are cocoa butter and poly-ethylene example heptadecaethyleneoxycetanol, or condensation glycols. products of ethylene oxide with partial esters derived from fatty acids and a hexitol Such as polyoxyethylene Sorbitol 1025 The novel compositions can also be administered monooleate, or condensation products of ethylene oxide topically, in the form of creams, ointments, jellies, collyri with partial esters derived from fatty acids and hexitol ums, Solutions or Suspensions. anhydrides, for example polyoxyethylene Sorbitan 1026 Daily dosages can vary within wide limits and will monooleate. be adjusted to the individual requirements in each particular 1018. The aqueous Suspensions may also contain one or case. In general, for administration to adults, an appropriate more preservatives, for example, ethyl or n-propyl p-hy daily dosage has been described above, although the limits droxybenzoate, one or more coloring agents, one or more that were identified as being preferred may be exceeded if flavoring agents, or one or more Sweetening agents, Such as expedient. The daily dosage can be administered as a Single Sucrose or Saccharin. dosage or in divided dosages. 1019 Oily suspensions may be formulated by Suspending 1027 Various delivery systems include capsules, tablets, the active ingredients in an omega-3 fatty acid, a vegetable and gelatin capsules, for example. oil, for example arachis oil, olive oil, Sesame oil or coconut 1028. The present invention further comprises kits that oil, or in a mineral oil Such as liquid paraffin. The oily are Suitable for use in performing the methods of prevention, Suspensions may contain a thickening agent, for example treatment, or inhibition described above. In one embodi beeswax, hard paraffin or cetyl alcohol. ment, the kit contains a first dosage form comprising one or more colds and cough active ingredient in one or more of the 1020 Sweetening agents, such as those set forth above, forms identified above and a Second dosage form comprising and flavoring agents may be added to provide a palatable one or more of the cyclooxygenase-2 Selective inhibitors or oral preparation. These compositions may be preserved by prodrugs thereof identified above, in quantities Sufficient to the addition of an antioxidant Such as ascorbic acid. carry out the methods of the present invention. Preferably, 1021 Dispersible powders and granules suitable for the first dosage form and the Second dosage form together preparation of an aqueous Suspension by the addition of comprise a therapeutically effective amount of the com water provide the active ingredient in admixture with a pounds for the treatment, prevention, or amelioration of a dispersing or Wetting agent, a Suspending agent and one or cold and/or a cough. more preservatives. Suitable dispersing or wetting agents and Suspending agents are exemplified by those already 1029. The following examples describe embodiments of the invention. Other embodiments within the scope of the mentioned above. Additional excipients, for example Sweet claims herein will be apparent to one skilled in the art from ening, flavoring and coloring agents, may also be present. consideration of the Specification or practice of the invention 1022 Syrups and elixirs containing the novel combina as disclosed herein. It is intended that the Specification, tion may be formulated with Sweetening agents, for example together with the examples, be considered to be exemplary glycerol, Sorbitol or Sucrose. Such formulations may also only, with the Scope and Spirit of the invention being contain a demulcent, a preservative and flavoring and col indicated by the claims which follow the examples. In the oring agents. examples, all percentages are given on a Weight basis unless otherwise indicated. 1023 The subject combinations can also be administered parenterally, either Subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, COMPARATIVE EXAMPLE 1. in the form of Sterile injectable aqueous or olagenous 1030 This example shows the preparation of celecoxib. Suspensions. Such Suspensions may be formulated according to the known art using those Suitable dispersing of wetting 1031 Step 1: Preparation of 1-(4-methylphenyl)-4,4,4- agents and Suspending agents which have been mentioned trifluorobutane-1,3-dione. above, or other acceptable agents. The Sterile injectable 1032 Following the disclosure provided in U.S. Pat. No. preparation may also be a sterile injectable Solution or 5,760,068, 4-Methylacetophenone (5.26g, 39.2 mmol) was Suspension in a non-toxic parenterally-acceptable diluent or dissolved in 25 mL of methanol under argon and 12 mL US 2004/0029864 A1 Feb. 12, 2004 49

(52.5 mmol) sodium methoxide in methanol (25%) was 1039. If desirable, a solid carrier and other materials may added. The mixture was stirred for 5 minutes and 5.5 mL be intermixed with the therapeutic composition to form a (46.2 mmol) ethyl trifluoroacetate was added. After reflux pharmaceutical composition and the resulting pharmaceuti ing for 24 hours, the mixture was cooled to room tempera cal composition may be formed into capsules for human ture and concentrated. 100 mL 10% HCl was added and the consumption, for example, by conventional capsule-forming mixture extracted with 4x75 mL ethyl acetate. The extracts equipment, where each capsule contains can contain about were dried over MgSO, filtered and concentrated to afford the same amount of the active ingredients as each of the 8.47 g (94%) of a brown oil which was carried on without Single dose units of the liquid preparation described above. further purification. 1040. Therapeutic and pharmaceutical compositions 1033 Step 2: Preparation of 4-5-(4-methylphenyl)-3- comprising a combination of any of the cyclooxygenase-2 (trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide. Selective inhibitors and any of the Sources of cold and cough 1034) To the dione from Step 1 (4.14g, 18.0 mmol) in 75 active ingredients that are described above can be formed by mL absolute ethanol, 4.26 g (19.0 mmol) 4-Sulphonami Similar methods. dophenylhydrazine hydrochloride was added. The reaction was refluxed under argon for 24 hours. After cooling to room EXAMPLE 3 temperature and filtering, the reaction mixture was concen 1041. This illustrates the production of a composition trated to afford 6.13 g of an orange solid. The solid was containing celecoxib and aciclovir, and of a pharmaceutical recrystallized from methylene chloride/hexane to give 3.11 composition containing the combination. g (8.2 mmol, 46%) of the product as a pale yellow Solid, having a melting point (mp) of 157-159 C.; and a calcu 1042 Aciclovir (acyclovir) is available in the form of lated composition of C7H1N 02 SF, C, 53.54; H, 3.70; N, capsules, tablets and as a Suspension under the trade name 11.02. The composition that was found by analysis was: C, ZOVIRAX(R) from GlaxoSmith Kline, Research Triangle 53.17; H, 3.81; N, 10.90. Park, N.C. Celecoxib can be prepared as described in Comparative Example 1, or it can be obtained under the EXAMPLE 2 trade name CELEBREXOR from Pharmacia Corporation, Peapack, N.J. 1035. This illustrates the production of a composition containing celecoxib and the combination of an antihista 1043 A therapeutic composition of the present invention mine, a decongestant, an antituSSive and an analgesic, and of can be formed by intermixing Solid or powdered aciclovir a pharmaceutical composition containing the combination. (400 g, available as ZOVIRAX(R), from GlaxoSmithKline), and 4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol 1036 The combination of an antihistamine, a deconges 1-ylbenzenesulfonamide (200 g, as produced in Compara tant, an antituSSive and an analgesic may be Supplied by any tive Example 1, or as available from Pharmacia Corporation, one of Several commercially available preparations. One Peapack, N.J., under the tradename CELEBREX(R), in a such preparation is ALKA-SELTZER(R) PLUS LIQUI laboratory mill or mixing device Suitable for intimate mixing GELS COLD & COUGH MEDICINE, available from of powders without Substantial generation of Shear or tem Bayer Corporation, Elkhart, Ind. Each liqui-gel capsule of perature Sufficient to degrade either of the two compounds. ALKA-SELTZEROR PLUS LIOUI-GELS COLD & After mixing, the combination of aciclovir and celecoxib COUGH MEDICINE contains chlorpheniramine maleate, 2 forms a therapeutic composition that is Sufficient for the mg, pseudoephedrine hydrochloride, 30 mg. dextromethor production of about 1000 human single dose units. Each phan hydrobromide, 10 mg, and acetaminophen, 325 mg. Single dose unit contains about 400 mg of aciclovir and 1037 Celecoxib can be prepared as described in Com about 200 mg of celecoxib. parative Example 1, or it can be obtained under the trade 1044. If desirable, a solid carrier and other materials may name CELEBREXOR from Pharmacia Corporation, Peapack, be intermixed with the therapeutic composition to form a N.J. pharmaceutical composition and the resulting pharmaceuti 1038 Atherapeutic composition of the present invention cal composition may be formed into capsules for human can be formed by intermixing chlorpheniramine maleate, 2 consumption, for example, by conventional capsule-forming g; pseudoephedrine hydrochloride, 30 g, dextromethorphan equipment, where each capsule contains 400 mg of aciclovir hydrobromide, 10 g; acetaminophen, 325 g, and 4-5-(4- and 200 mg celecoxib. methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benze 1045 Alternatively, the aciclovir (preferably in the form neSulfonamide (200 g, as produced in Comparative Example of a Suspension) and the celecoxib may be dissolved or 1, or as available from Pharmacia Corporation, Peapack, Suspended into a liquid carrier, Such as, for example, normal N.J., under the tradename CELEBREX(R), in a suspension Saline Solution, to form a pharmaceutical composition Suit or Solution with a sterile pharmaceutically acceptable liquid. able for human consumption. A Single dosage of the liquid After mixing, the combination of chlorpheniramine maleate, pharmaceutical composition for human use would be a pseudoephedrine hydrochloride, dextromethorphan hydro volume sufficient to provide 400 mg of aciclovir and 200 mg bromide, acetaminophen, and celecoxib forms a therapeutic of celecoxib. composition that is Sufficient for the production of about 1000 human Single dose units. Each Single dose unit con 1046. Therapeutic and pharmaceutical compositions tains about 2 mg of chlorpheniramine maleate, 30 mg of comprising a combination of any of the cyclooxygenase-2 pseudoephedrine hydrochloride, 10 mg of dextromethor Selective inhibitors and any of the colds and cough active phan hydrobromide, 325 mg of acetaminophen and about ingredients that are described above can be formed by 200 mg of celecoxib. Similar methods. US 2004/0029864 A1 Feb. 12, 2004 50

1047 All references cited in this specification, including hydromorphone, carbetapentane, caraminphen, dex without limitation all papers, publications, patents, patent tromethorphan, chlorphedianol, noScarpine, and mixtures applications, presentations, texts, reports, manuscripts, bro thereof. chures, books, internet postings, journal articles, periodicals, 11. The method according to claim 6, wherein the colds and the like, are hereby incorporated by reference into this and cough active ingredient comprises an analgesic. Specification in their entireties. The discussion of the refer ences herein is intended merely to Summarize the assertions 12. The method according to claim 11, wherein the made by their authors and no admission is made that any analgesic is Selected from the group consisting of acetami reference constitutes prior art. Applicants reserve the right to nophen, aspirin, Salicylamide, Sodium Salicylate, indometha challenge the accuracy and pertinency of the cited refer cin, ibuprofen, naproxen, flubiprofen, carprofen, tiaprofenic CCCS. acid, cicloprofen, detoprofen, ketorolac, etodolac, and mix tures thereof. 1048. In view of the above, it will be seen that the several 13. The method according to claim 6, wherein the colds advantages of the invention are achieved and other advan and cough active ingredient comprises an expectorant. tageous results obtained. 14. The method according to claim 13, wherein the 1049. As various changes could be made in the above expectorant is Selected from the group consisting of guaifen methods and compositions without departing from the Scope esin, glycerol guaiacolate, terpin hydrate, ammonium chlo of the invention, it is intended that all matter contained in the ride, N-acetyleSteine, brom hexine, ambroXol, domiodol, above description shall be interpreted as illustrative and not 3-iodo-1,2-propanediol, and mixtures thereof. in a limiting Sense. 15. The method according to claim 6, wherein the colds What is claimed is: and cough active ingredient comprises a decongestant. 1. A method for the treatment, prevention and ameliora 16. The method according to claim 15, wherein the tion of colds and/or cough in a Subject in need of Such decongestant is Selected from the group consisting of ephe treatment, prevention and amelioration, the method com drine, ephinephrine, levodesoxyephedrine, oxymetazoline, prising administering to the Subject a cyclooxygenase-2 naphazoline, phenylephrine, phenylpropanolamine, propyl Selective inhibitor or prodrug thereof and one or more colds hexedrine, pseudoephedrine, Xylometazoline, and mixtures and cough active ingredient. thereof. 2. The method according to claim 1, except that when the 17. The method according to claim 6, wherein the colds colds and cough active ingredient is an analgesic, it is free and cough active ingredient comprises an anticholinergic. of the isolated Salt form of acetaminophen. 18. The method according to claim 17, wherein the 3. The method according to claim 1, wherein at least a anticholinergic comprises homatropine. portion of the colds and cough active ingredient is free of an isolated metal Salt form of the colds and cough active 19. The method according to claim 6, wherein the colds ingredient. and cough active ingredient comprises an antiviral agent. 4. The method according to claim 1, wherein the 20. The method according to claim 19, wherein the cyclooxygenase-2 Selective inhibitor and a colds and cough antiviral agent is Selected from the group consisting of active ingredient are administered to the Subject in combi dipyridamole, ICI 130,685, impulsin, pleconaril, Zanamivir, nation and where the amount of the cyclooxygenase-2 Oseltamivir, famciclovir, Valaciclovir, Valganciclovir, aciclo Selective inhibitor and the amount of the one or more colds Vir, ganciclovir, idoxuridine, Vidarabine, trifluridine, penci and cough active ingredient together comprise an effective clovir, Valacyclovir, foScarnet, ribavarin, amantadine, riman amount of the combination. tadine, cidofovir, and mixtures of two or more of these 5. The method according to claim 4, wherein the effective compounds. amount of the combination is a therapeutically effective 21. The method according to claim 6, wherein the colds amount for the treatment, prevention and/or amelioration of and cough active ingredient is Selected from the group colds and cough in the Subject. consisting of azatadine, bromodiphenhydramine, bromphe 6. The method according to claim 1, wherein the colds and niramine, brompheniramine maleate, carbinoxamine, chlo cough active ingredient comprises an antihistamine, antituS rpheniramine, deXchlorpheniramine, diphenhydramine, Sive, analgesic, expectorant, decongestant, anticholinergic, doxylamine, phenindamine, pheniramine, phenyltoloxam antiviral agent, or a mixture of two or more thereof. ine, promethazine, pyrilamine, triprolidine, cetirzine, lora 7. The method according to claim 6, wherein the colds and tadine, codeine, dihydrocodeine, hydrocodone, hydroc cough active ingredient comprises an antihistamine. odone bitartrate, hydromorphone, carbetapentane, 8. The method according to claim 7, wherein the antihis caraminphen, dextromethorphan, acetaminophen, aspirin, tamine is Selected from the group consisting of azatadine, Salicylamide, Sodium Salicylate, guaifenesin, ephedrine, bromodiphenhydramine, brompheniramine, bromphe ephinephrine, levodesoxyephedrine, Oxymetazoline, nap niramine maleate, carbinoxamine, chlorpheniramine, dex hazoline, phenylephrine, phenylpropanolamine, propyl chlorpheniramine, diphenhydramine, doxylamine, phenin hexedrine, pseudoephedrine, Xylometazoline, homatropine, damine, pheniramine, phenyltoloxamine, promethazine, dipyridamole, ICI 130,685, impulsin, pleconaril, Zanamivir, pyrilamine, triprolidine, cetirzine, loratadine, and mixtures Oseltamivir, famciclovir, Valaciclovir, Valganciclovir, aciclo thereof. Vir, ganciclovir, idoxuridine, Vidarabine, trifluridine, penci 9. The method according to claim 6, wherein the colds and clovir, Valacyclovir, foScarnet, ribavarin, amantadine, riman cough active ingredient comprises an antituSSive. tadine, cidofovir, and mixtures of two or more thereof. 10. The method according to claim 9, wherein the anti 22. The method according to claim 1, wherein the tussive is Selected from the group consisting of codeine, cyclooxygenase-2 Selective inhibitor or prodrug thereof has dihydrocodeine, hydrocodone, hydrocodone bitartrate, a cyclooxygenase-2 ICso of less than about 0.2 limol/L. US 2004/0029864 A1 Feb. 12, 2004

23. The method according to claim 22, wherein the 43. The method according to claim 6, wherein the one or cyclooxygenase-2 Selective inhibitor or prodrug thereof has more colds and cough active ingredient comprises a decon a cyclooxygenase-1 ICso of at least about 1 limol/L. gestant, an antituSSive, an expectorant and an analgesic. 24. The method according to claim 23, wherein the 44. The method according to claim 6, wherein the one or cyclooxygenase-2 Selective inhibitor or prodrug thereof has more colds and cough active ingredient comprises a decon a cyclooxygenase-1 ICs of at least about 10 umol/L. gestant and an expectorant. 25. The method according to claim 1, wherein the 45. The method according to claim 6, wherein the colds cyclooxygenase-2 Selective inhibitor is Selected from the and cough active ingredient comprises an antihistamine and group consisting of celecoxib, Valdecoxib, deracoxib, rofe a decongestant. coxib, etoricoxib, parecoxib, lumiracoxib, SD-8381, ABT 46. A composition for the treatment, prevention and 963, BMS-347070, and NS-398. amelioration of colds and/or cough in a Subject in need of 26. The method according to claim 25, wherein the Such treatment, prevention and amelioration, the composi cycloxygenase-2 Selective inhibitor comprises a compound tion comprising a cyclooxygenase-2 Selective inhibitor and Selected from the group consisting of celecoxib, Valdecoxib a colds and cough active ingredient. and parecoxib. 47. The composition according to claim 46, except that 27. The method according to claim 6, wherein the one or when the colds and cough active ingredient is an analgesic, more colds and cough active ingredients comprise an anti it is free of the isolated Salt form of acetaminophen. histamine and an antituSSive. 48. The composition according to claim 46, wherein at 28. The method according to claim 6, wherein the one or least a portion of the colds and cough active ingredient is more colds and cough active ingredient comprises an anti free of an isolated metal Salt form of the colds and cough histamine, an antituSSive, and an analgesic. active ingredient. 29. The method according to claim 6, wherein the one or 49. The composition according to claim 46, wherein the more colds and cough active ingredient comprises an anti colds and cough active ingredient is Selected from the group histamine, an antituSSive, and an expectorant. consisting of azatadine, bromodiphenhydramine, bromphe 30. The method according to claim 6, wherein the one or niramine, brompheniramine maleate, carbinoxamine, chlo more colds and cough active ingredient comprises an anti rpheniramine, deXchlorpheniramine, diphenhydramine, histamine, a decongestant and an antituSSive. doxylamine, phenindamine, pheniramine, phenyltoloxam 31. The method according to claim 6, wherein the one or ine, promethazine, pyrilamine, triprolidine, cetirzine, lora more colds and cough active ingredient comprises an anti tadine, codeine, dihydrocodeine, hydrocodone, hydroc histamine, a decongestant, an antituSSive and an analgesic. odone bitartrate, hydromorphone, carbetapentane, 32. The method according to claim 6, wherein the one or caraminphen, dextromethorphan, acetaminophen, aspirin, more colds and cough active ingredient comprises an anti Salicylamide, Sodium Salicylate, guaifenesin, ephedrine, histamine, a decongestant, an antituSSive and an expectorant. ephinephrine, levodesoxyephedrine, Oxymetazoline, nap 33. The method according to claim 6, wherein the one or hazoline, phenylephrine, phenylpropanolamine, propyl more colds and cough active ingredient comprises an anti hexedrine, pseudoephedrine, Xylometazoline, homatropine, histamine, a decongestant, an antituSSive, an expectorant and dipyridamole, ICI 130,685, impulsin, pleconaril, Zanamivir, an analgesic. Oseltamivir, famciclovir, Valaciclovir, Valganciclovir, aciclo 34. The method according to claim 6, wherein the one or Vir, ganciclovir, idoxuridine, Vidarabine, trifluridine, penci more colds and cough active ingredient comprises an anti clovir, Valacyclovir, foScarnet, ribavarin, amantadine, riman histamine, a decongestant and an expectorant. tadine, cidofovir, and mixtures of two or more thereof. 35. The method according to claim 6, wherein the one or 50. The composition according to claim 46, wherein the more colds and cough active ingredient comprises an anti cyclooxygenase-2 Selective inhibitor is Selected from the histamine, a decongestant, an expectorant and an analgesic. group consisting of celecoxib, Valdecoxib, deracoxib, rofe 36. The method according to claim 6, wherein the one or coxib, etoricoxib, parecoxib, lumiracoxib, SD-8381, ABT more colds and cough active ingredient comprises an anti 963, BMS-347070, NS-398, mixtures of any two or more histamine and an expectorant. thereof, and prodrugs thereof. 37. The method according to claim 6, wherein the one or 51. A composition for the treatment, prevention and more colds and cough active ingredient comprises an anti amelioration of colds and/or cough in a Subject in need of tussive and an analgesic. Such treatment, prevention and amelioration, the composi 38. The method according to claim 6, wherein the one or tion comprising a cyclooxygenase-2 Selective inhibitor more colds and cough active ingredient comprises an anti Selected from the group consisting of celecoxib, parecoxib tussive and an antichlolinergic. and Valdecoxib, and a colds and cough active ingredient 39. The method according to claim 6, wherein the one or Selected from the group consisting of chlorpheniramihe, more colds and cough active ingredient comprises an anti cetirzine, loratadine, codeine, hydrocodone, carbetapentane, tussive and an expectorant. dextromethorphan, aspirin, guaifenesin, ephedrine, ephi 40. The method according to claim 6, wherein the one or nephrine, phenylephrine, phenylpropanolamine, pseu more colds and cough active ingredient comprises a decon doephedrine, impulsin, pleconaril, aciclovir, and ganciclo gestant and an antituSSive. vir. 41. The method according to claim 6, wherein the one or 52. A composition for the treatment, prevention and more colds and cough active ingredient comprises a decon amelioration of colds and/or cough in a Subject in need of gestant, an antituSSive and an analgesic. Such treatment, prevention and amelioration, the composi 42. The method according to claim 6, wherein the one or tion comprising a cyclooxygenase-2 Selective inhibitor and more colds and cough active ingredient comprises a decon a combination of two or more colds and cough active gestant, an antituSSive and an expectorant. ingredients. US 2004/0029864 A1 Feb. 12, 2004 52

53. The composition according to claim 52, wherein the 55. The composition according to claim 54, wherein the combination of two or more colds and cough active ingre cyclooxygenase-2 Selective inhibitor is Selected from the dients comprises at least two agents Selected from the group consisting of antihistamine, antituSSive, analgesic, expecto group consisting of celecoxib, Valdecoxib, deracoxib, rofe rant, decongestant, anticholinergic, and antiviral agent. coxib, etoricoxib, parecoxib, lumiracoxib, SD-8381, ABT 54. The composition according to claim 53, wherein the 963, BMS-347070, NS-398, mixtures of any two or more combination of two or more colds and cough active ingre thereof, and prodrugs thereof. dients comprises at least two agents Selected from the group 56. A pharmaceutical composition for the treatment, pre consisting of azatadine, bromodiphenhydramine, bromphe vention and amelioration of colds and/or cough in a Subject niramine, brompheniramine maleate, carbinoxamine, chlo rpheniramine, deXchlorpheniramine, diphenhydramine, in need of Such treatment, prevention and amelioration, the doxylamine, phenindamine, pheniramine, phenyltoloxam composition comprising a cyclooxygenase-2 Selective ine, promethazine, pyrilamine, triprolidine, cetirzine, lora inhibitor, a colds and cough active ingredient, and a phar tadine, codeine, dihydrocodeine, hydrocodone, hydroc maceutically-acceptable excipient. odone bitartrate, hydromorphone, carbetapentane, 57. A kit that is suitable for use in the treatment, preven caraminphen, dextromethorphan, aspirin, Salicylamide, tion or amelioration of colds and/or cough, the kit comprises Sodium Salicylate, guaifenesin, ephedrine, ephinephrine, a first dosage form comprising a colds and cough active levodesoxyephedrine, Oxymetazoline, naphazoline, phe ingredient and a Second dosage form comprising a cyclooxy nylephrine, phenylpropanolamine, propylhexedrine, pseu doephedrine, Xylometazoline, homatropine, dipyridamole, genase-2 Selective inhibitor or prodrug thereof, in quantities ICI 130,685, impulsin, pleconaril, Zanamivir, oseltamivir, which comprise a therapeutically effective amount of the famciclovir, Valaciclovir, Valganciclovir, aciclovir, ganciclo combination of the compounds for the treatment, prevention, Vir, idoxuridine, Vidarabine, trifluridine, penciclovir, Vala or amelioration of colds and/or cough. cyclovir, foScarnet, ribavarin, amantadine, rimantadine, cidofovir, and mixtures of two or more thereof.