Patent Publication Number: US-2005143360-A1

Title: Method of using a cyclooxygenase-2 inhibitor and sex steroids as a combination therapy for the treatment and prevention of dismenorrhea

Description:
BACKGROUND OF THE INVENTION  
      1. Field of the Invention  
      The present invention relates to methods for the treatment and prevention of dysmenorrhea in a woman using a combination of a cyclooxygenase-2 inhibitor and sex steroids.  
      2. Description of the Related Art  
      In women, the menstrual cycle involves a complex series of hormonal changes. A consequence of these hormonal changes is the growth of the uterine lining (referred to as the endometrium). In the absence of pregnancy, the endometrium is shed in a process called menstruation. This process involves the release of prostaglandins, which cause contractions of the smooth muscle in the uterus. In some women, these contractions cause substantial pain, dysmenorrhea, which interferes with their daily activities.  
      The time at which menstruation occurs varies in that it can not be predicted with certainty in any one woman. The variability in the onset of menstrual cycles is dependent upon many variables including the individual woman, her age and underlying medical and psychosocial conditions. This makes it difficult to predict the onset of menses. Non-steroidal anti-inflammatory agents (NSAIDs) that inhibit prostaglandin synthesis are effective in reducing dysmenorrhea (Lundstrom, V., et al.  Acta Obstet. Gynecol. Scand. Suppl.,  113, 83-85 (1983)). They are most effective when administered prior to the onset of menstrual pain by 24-48 hours. Since predicting the precise timing of menstruation is difficult, attempts to maximize efficacy by initiating treatment prior to menses may result in several days of unnecessary medication.  
      The use of orally active contraceptives, composed of estrogen and progestin components, has been reported to reduce the intensity of the pain of dysmenorrhea (Nabrink, M. et al.  Contraception,  42, 275-283 (1990)).  
      The vast majority of oral contraceptives consist of a combination of a progestin sex steroid and an estrogen sex steroid. These sex steroids are administered concurrently for 21 days followed by either a 7 day pill free interval or by the administration of a placebo for 7 days in each 28 day cycle. Numerous regimens have been developed in which the progestin/estrogen combination is administered either as a fixed dosage combination (monophasic) or as a biphasic or a triphasic regimen in which the dosage of the combination is varied either once or twice throughout the menstrual cycle. Kuhl has reviewed the current state of hormonal contraception ( Handb. Exp. Pharmacol.,  135/II, 363-407 (1999)). Various oral contraceptive combinations are listed in WO 98/04265. Most current oral contraceptives give good menstrual cycle control (Thorneycroft, I.  Am. J. Obstet. Gynecol.,  180 (2, Pt. 2), S280-S287 (1999)).  
      When good relief of dysmenorrhea is not obtained through the use of oral contraceptives, a nonsteroidal anti-inflammatory drug can be added as treatment (Deligeoroglou, E.  Annals of the New York Academy of Science,  900, 237-244 (2000)).  
      Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of anti-inflammatory drug discovery. However, common non-steroidal anti-inflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life-threatening ulcers, which limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long-term therapy is involved.  
      Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named “cyclooxygenase II (COX II)” or “prostaglandin G/H synthase II”) provides a viable target of inhibition that more effectively reduces inflammation and produces fewer and less drastic side effects.  
      U.S. Pat. No. 5,466,823 discloses pyrazolyl cyclooxygenase-2 inhibitors useful in treating inflammation and inflammation-related disorders, including menstrual cramps.  
      U.S. Pat. No. 5,932,598 discloses prodrugs of cyclooxygenase-2 inhibitors useful in treating inflammation and inflammation-related disorders, including menstrual cramps.  
      Morrison et al. describe a study where the cyclooxygenase-2 inhibitor, rofecoxib, is used to treat primary dysmenorrhea ( Obstet. Gynecol.,  94(4), 504-508 (1999)).  
      Compounds that selectively inhibit cyclooxygenase-2 and are useful in treating menstrual cramps have also been described in the following individual publications. 
          U.S. Pat. No. 5,521,207.     U.S. Pat. No. 5,633,272.        

      The various classes of compounds that are selective inhibitors of cyclooxygenase-2 have been reviewed by J. Talley in  Prog. Med. Chem.,  36, 201-234 (1999). Compounds that selectively inhibit cyclooxygenase-2 have also been described in the following individual publications. 
          U.S. Pat. No. 5,380,738.     U.S. Pat. No. 5,344,991.     U.S. Pat. No. 5,393,790.     U.S. Pat. No. 5,434,178.     U.S. Pat. No. 5,474,995.     U.S. Pat. No. 5,510,368.     WO 96/06840.     WO 96/03388.     WO 96/03387.     WO 96/19469.     WO 96/25405.     WO 95/15316.     WO 94/15932.     WO 94/27980.     WO 95/00501.     WO 94/13635.     WO 94/20480.     WO 94/26731.        

      The combination of NSAIDs and oral contraceptives has been used in cases where neither treatment alone was effective in treating primary dysmenorrhea (Coco, A.,  American Family Physician,  60(2), 489-496 (1999)).  
      U.S. Pat. No. 5,811,416 discloses the combination of an endothelin antagonist and/or an endothelin synthase inhibitor with at least one of a progestin, an estrogen, a combination of a progestin and estrogen, a cyclooxygenase inhibitor, a nitric oxide donor or a nitric oxide substrate for the treatment of menstrual disorders including dysmenorrhea.  
      U.S. Pat. No. 5,912,006 discloses the combination of an omega fatty acid and a cyclooxygenase inhibitor for the reduction or alleviation of uterine or vaginal pain associated with the onset of menstruation.  
      However, a combination therapy method for the treatment and prevention of dysmenorrhea comprising a COX-2 inhibitor and sex steroids has not been previously described.  
     BRIEF SUMMARY OF THE INVENTION  
      To address the continuing need to find safe and effective agents for the prophylaxis and treatment of dysmenorrhea, combination therapies of therapeutic agents are now reported.  
      Among its several embodiments, the present invention provides a therapeutic combination of a cyclooxygenase-2 inhibitor compound source and an amount of sex steroid compounds, wherein the compounds together comprise a dysmenorrhea-effective amount of the compounds.  
      In another embodiment, the cyclooxygenase-2 inhibitor compound source is a cyclooxygenase-2 inhibitor compound.  
      In yet another embodiment, the present invention provides a combination therapy method for the treatment or prophylaxis of dysmenorrhea in a patient in need thereof comprising the use of an amount of a cyclooxygenase-2 inhibitor compound and an amount of a sex steroid, wherein the amounts of the cyclooxygenase-2 inhibitor compound and the sex steroid compound together comprise a dysmenorrhea-effective amount of the compounds.  
      The invention involves the preventive management of painful uterine cramps, dysmenorrhea, in women. A key improvement over existing technologies is that moderate to severe pain is not experienced prior to initiating treatment, but that it can be preempted, providing a much more satisfactory outcome. Another advantage is that by employing this regimen, lower doses of analgesic medication may be required. There should also be an advantage of a reduced blood loss compared with existing treatments.  
      Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
      The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.  
      The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.  
      Definitions  
      The following definitions are provided in order to aid the reader in understanding the detailed description of the present invention.  
      The phrase “cyclooxygenase-2 inhibitor” or “COX-2 inhibitor” or “cyclooxygenase-II inhibitor” includes agents that specifically inhibit a class of enzymes, cyclooxygenase-2, with less significant inhibition of cyclooxygenase-1.  
      Preferably, it includes compounds that have a cyclooxygenase-2 IC 50  of less than about 0.2 μM, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase-1 IC 50  of greater than about 1 μM, and more preferably of greater than 10 μM.  
      The phrase “sex steroids” includes both estrogen and progestin steroid compounds.  
      The phrase “combination therapy” (or “co-therapy”) embraces the administration of a cyclooxygenase-2 inhibitor and a sex steroid as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). “Combination therapy” generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. “Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies.  
      The phrase “therapeutically effective” is intended to qualify the combined amount of inhibitors in the combination therapy. This combined amount will achieve the goal of reducing or eliminating dysmenorrhea.  
      “Therapeutic compound” means a compound useful in the prophylaxis or treatment of dysmenorrhea.  
      The term “comprising” means “including the following elements but not excluding others.” 
      The term “hydrido” denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (—CH 2 —) radical. Where used, either alone or within other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl” and “hydroxyalkyl”, the term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms.  
      Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.  
      The term “alkenyl” embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.  
      The term “alkynyl” denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are “lower alkynyl” radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.  
      The terms “alkenyl”, “lower alkenyl”, embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.  
      The term “cycloalkyl” embraces saturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkenyl” embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl.  
      The term “halo” means halogens such as fluorine, chlorine, bromine or iodine. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. “Lower haloalkyl” embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.  
      The term “hydroxyalkyl” embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.  
      The terms “alkoxy” and “alkyloxy” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term “alkoxyalkyl” embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. More preferred haloalkoxy radicals are “lower haloalkoxy” radicals having one to six carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.  
      The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.  
      The term “heterocyclo” embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclo radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclo radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.  
      The term “heteroaryl” embraces unsaturated heterocyclo radicals. Examples of unsaturated heterocyclo radicals, also termed “heteroaryl” radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclo group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6 membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclo group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic: group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclo group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term also embraces radicals where heterocyclo radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, benzopyran, and the like. The terms benzopyran and chromene are interchangeable. Said “heterocyclo group” may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.  
      The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term “alkylthioalkyl” embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are “lower alkylthioalkyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl.  
      The term “alkylsulfinyl” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent —S(═O)-radical. More preferred alkylsulfinyl radicals are “lower alkylsulfinyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.  
      The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO 2 —. “Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.  
      The terms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl” denote NH 2 O 2 S—.  
      The term “acyl” denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl.  
      The term “carbonyl”, whether used alone or with other terms, such as “alkoxycarbonyl”, denotes —(C═O)—. The term “aroyl” embraces aryl radicals with a carbonyl radical as defined above. Examples of aroyl include benzoyl, naphthoyl, and the like and the aryl in said aroyl may be additionally substituted.  
      The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —CO 2 H. The term “carboxyalkyl” embraces alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term “alkoxycarbonyl” means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are “lower alkoxycarbonyl” radicals with alkyl portions having 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.  
      The terms “alkylcarbonyl”, “arylcarbonyl” and “aralkylcarbonyl” include radicals having alkyl, aryl and aralkyl radicals, as defined above, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl.  
      The term “aralkyl” embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.  
      The terms benzyl and phenylmethyl are interchangeable.  
      The term “heterocycloalkyl” embraces saturated and partially unsaturated heterocyclo-substituted alkyl radicals, such as pyrrolidinylmethyl, and heteroarylsubstituted alkyl radicals, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.  
      The term “aralkoxy” embraces aralkyl radicals attached through an oxygen atom to other radicals. The term “aralkoxyalkyl” embraces aralkoxy radicals attached through an oxygen atom to an alkyl radical. The term “aralkylthio” embraces aralkyl radicals attached to a sulfur atom. The term “aralkylthioalkyl” embraces aralkylthio radicals attached through a sulfur atom to an alkyl radical.  
      The term “aminoalkyl” embraces alkyl radicals substituted with one or more amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term “alkylamino” denotes amino groups that have been substituted with one or two alkyl radicals. Preferred are “lower N-alkylamino” radicals having alkyl portions having 1 to 6 carbon atoms. Suitable lower alkylamino may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term “arylamino” denotes amino groups that have been substituted with one or two aryl radicals, such as N-phenylamino. The “arylamino” radicals may be further substituted on the aryl ring portion of the radical. The term “aralkylamino” embraces aralkyl radicals attached through an amino nitrogen atom to other radicals. The terms “N-arylaminoalkyl” and “N-aryl-N-alkylaminoalkyl” denote amino groups which have been substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having the amino group attached to an alkyl radical. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl.  
      The term “aminocarbonyl” denotes an amide group of the formula —C(═O)NH 2 . The term “alkylaminocarbonyl” denotes an aminocarbonyl group that has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” and “lower N,N-dialkylaminocarbonyl” radicals with lower alkyl portions as defined above. The term “aminocarbonylalkyl” denotes a carbonylalkyl group that has been substituted with an amino radical on the carbonyl carbon atom.  
      The term “alkylaminoalkyl” embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical. The term “aryloxyalkyl” embraces radicals having an aryl radical attached to an alkyl radical through a divalent oxygen atom. The term “arylthioalkyl” embraces radicals having an aryl radical attached to an alkyl radical through a divalent sulfur atom.  
     Combinations  
      The methods and combinations of the present invention provide one or more benefits. Combinations of COX-2 inhibitors with the compounds, compositions, agents and therapies of the present invention are useful in treating and preventing dysmenorrhea. Preferably, the COX-2 inhibitors and the compounds, compositions, agents and therapies of the present invention are administered in combination at a low dose, that is, at a dose lower than has been conventionally used in clinical situations.  
      The combinations of the present invention will have a number of uses. For example, through dosage adjustment and medical monitoring, the individual dosages of the therapeutic compounds used in the combinations of the present invention will be lower than are typical for dosages of the therapeutic compounds when used in monotherapy. The dosage lowering will provide advantages including reduction of side effects of the individual therapeutic compounds when compared to the monotherapy. In addition, fewer side effects of the combination therapy compared with the monotherapies will lead to greater patient compliance with therapy regimens.  
      Alternatively, the methods and combination of the present invention can also maximize the therapeutic effect at higher doses.  
      When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.  
      This new method of treatment for moderate to severe dysmenorrhea is superior to existing therapies, by reason of having the following characteristics. It inhibits the increased prostaglandin production induced by the complex series of hormonal changes characteristic of the menstrual cycle. The inhibition of prostaglandin synthesis occurs reproducibly 24-48 hours prior to initiation of menstruation. For safety reasons, it targets only the increased prostaglandin synthesis, which occurs immediately prior to menses, and not constitutive prostaglandin synthesis that may negatively impact other processes such as renal function.  
      The COX-2 enzyme, which is responsible for prostaglandin synthesis, has been demonstrated in the endometrium and myometrium of the uterus in women. The tissue distribution of COX-2 is significantly different from COX-1 in the endometrium. Therefore one would expect differences in the effects of COX-2 inhibitors compared to COX-1 inhibitors.  
      Among its several embodiments, the present invention provides a therapeutic combination of a cyclooxygenase-2 inhibitor compound source and a sex steroid compound, wherein the compounds together comprise a dysmenorrhea-effective amount of the compounds.  
      In another embodiment, the cyclooxygenase-2 inhibitor compound source is a cyclooxygenase-2 inhibitor compound.  
      In yet another embodiment, the cyclooxygenase-2 inhibitor compound source is a prodrug of a COX-2 inhibitor. Nonlimiting examples of COX-2 inhibitors that may be used in the present invention are identified in Table 1 below.  
               TABLE NO. 1                          Cyclooxygenase-2 Inhibitors                                 Trade/                   Research       Compound   Name   Reference   Dosage               1,5-Diphenyl-3-substituted       WO           pyrazoles       97/13755           radicicol   WO               96/25928.               Kwon et al               (Cancer               Res (1992)               52 6296)           GB-           02283745           TP-72   Cancer Res               1998 58 4               717-723       1-(4-chlorobenzoyl)-3-[4-(4-   A-183827.0       fluoro-phenyl)thiazol-2-       ylMethyl]-5-methoxy-2-       methylindole           GR-253035       4-(4-cyclohexyl-2-   JTE-522   JP 9052882       methyloxazol-5-yl)-2-       fluorobenzenesulfonamide       5-chloro-3-(4-       (methylsulfonyl)phenyl)-2-       (methyl-5-pyridinyl)-pyridine       2-(3,5-difluoro-phenyl)-3-4-       (methylsulfonyl)-phenyl)-2-       cyclopenten-1-one           L-768277           L-783003           MK-966;   U.S. Pat. No.   12.5-100            VIOXX ®   5968974   mg po       indomethacin-derived       WO   200       indolalkanoic acid       96/374679   mg/kg/day       1-Methylsulfonyl-4-[1,1-       WO       dimethyl-4-(4-       95/30656.       fluorophenyl)cyclopenta-2,4-       WO       dien-3-yl]benzene       95/30652.               WO               96/38418.               WO               96/38442.       4,4-dimethyl-2-phenyl-3-[4-       (methylsulfonyl)phenyl]cyclo-       butenone       2-(4-methoxyphenyl)-4-       EP 799823       methyl-1-(4-       sulfamoylphenyl)-pyrrole       N-[5-(4-   RWJ-63556       fluoro)phenoxy]thiophene-2-       methanesulfon-amide       5(E)-(3,5-di-tert-butyl-4-   S-2474   EP 595546       hydroxy)benzylidene-2-ethyl-       1,2-isothiazolidine-1,1-       dioxide       3-formylamino-7-   T-614   DE       methylsulfonylamino-6-       38/34204       phenoxy-4H-1-benzopyran-4-       one       Benzenesulfonamide, 4-(5-(4-   celecoxib   U.S. Pat. No.       methylphenyl)-3-       5466823       (trifluoromethyl)-1H-       pyrazol-1-yl)-       CS 502   (Sankyo)       MK 633   (Merck)           meloxicam   U.S. Pat. No.   15-30               4233299   mg/day           nimesulide   U.S. Pat. No.               3840597                  
 
      The following references listed in Table No. 2 below, hereby individually incorporated by reference, describe various COX-2 inhibitors suitable for use in the present invention described herein, and processes for their manufacture.  
               TABLE NO. 2                       COX-2 Inhibitor References                                                WO 99/30721   WO 99/30729   U.S. Pat. No.   WO 98/15528               5760068       WO 99/25695   WO 99/24404   WO 99/23087   FR 27/71005       EP 921119   FR 27/70131   WO 99/18960   WO 99/15505       WO 99/15503   WO 99/14205   WO 99/14195   WO 99/14194       WO 99/13799   GB 23/30833   U.S. Pat. No.   WO 99/12930               5859036       WO 99/11605   WO 99/10332   WO 99/10331   WO 99/09988       U.S. Pat. No.   WO 99/05104   U.S. Pat. No.   WO 98/47890       5869524       5859257       WO 98/47871   U.S. Pat. No.   U.S. Pat. No.   WO 98/45294           5830911   5824699       WO 98/43966   WO 98/41511   WO 98/41864   WO 98/41516       WO 98/37235   EP 86/3134   JP 10/175861   U.S. Pat. No.                   5776967       WO 98/29382   WO 98/25896   ZA 97/04806   EP 84/6,689       WO 98/21195   GB 23/19772   WO 98/11080   WO 98/06715       WO 98/06708   WO 98/07425   WO 98/04527   WO 98/03484       FR 27/51966   WO 97/38986   WO 97/46524   WO 97/44027       WO 97/34882   U.S. Pat. No.   WO 97/37984   U.S. Pat. No.           5681842       5686460       WO 97/36863   WO 97/40012   WO 97/36497   WO 97/29776       WO 97/29775   WO 97/29774   WO 97/28121   WO 97/28120       WO 97/27181   WO 95/11883   WO 97/14691   WO 97/13755       WO 97/13755   CA 21/80624   WO 97/11701   WO 96/41645       WO 96/41626   WO 96/41625   WO 96/38418   WO 96/37467       WO 96/37469   WO 96/36623   WO 96/36617   WO 96/31509       WO 96/25405   WO 96/24584   WO 96/23786   WO 96/19469       WO 96/16934   WO 96/13483   WO 96/03385   U.S. Pat. No.                   5510368       WO 96/09304   WO 96/06840   WO 96/06840   WO 96/03387       WO 95/21817   GB 22/83745   WO 94/27980   WO 94/26731       WO 94/20480   WO 94/13635   FR 27/70,131   U.S. Pat. No.                   5859036       WO 99/01131   WO 99/01455   WO 99/01452   WO 99/01130       WO 98/57966   WO 98/53814   WO 98/53818   WO 98/53817       WO 98/47890   U.S. Pat. No.   U.S. Pat. No.   WO 98/22101           5830911   5776967       DE 19/753463   WO 98/21195   WO 98/16227   U.S. Pat. No.                   5733909       WO 98/05639   WO 97/44028   WO 97/44027   WO 97/40012       WO 97/38986   U.S. Pat. No.   WO 97/34882   WO 97/16435           5677318       WO 97/03678   WO 97/03667   WO 96/36623   WO 96/31509       WO 96/25928   WO 96/06840   WO 96/21667   WO 96/19469       U.S. Pat. No.   WO 96/09304   GB 22/83745   WO 96/03392       5510368       WO 94/25431   WO 94/20480   WO 94/13635   JP 09052882       GB 22/94879   WO 95/15316   WO 95/15315   WO 96/03388       WO 96/24585   U.S. Pat. No.   WO 95/00501   U.S. Pat. No.           5344991       5968974       U.S. Pat. No.   U.S. Pat. No.       5945539   5994381                  
 
      Three classes of cyclooxygenase-2 inhibitors are reviewed by J. Carter in  Exp. Opin. Ther. Patents,  8(1), 21-29 (1997): methanesulfonanilides, tricyclics and structurally modified non-selective cyclooxygenase inhibitors. Methanesulfonanilides are a class of selective cyclooxygenase-2 inhibitors, of which NS-398, flosulide and nimesulide are example members.  
      A preferred class of tricyclic cyclooxygenase-2 inhibitors comprises compounds of formula (1)  
                 
          wherein A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;     wherein n is 0 or 1;     wherein X is O or S;     wherein R 1  is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R 1  is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;     wherein R 2  is methyl, amino or aminocarbonylalkyl; and     wherein R 3  is one or more radicals selected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl, wherein R 3  is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; or a pharmaceutically-acceptable salt thereof.        

      Preferred COX-2 inhibitors are tricyclic COX-2 inhibitors wherein the A ring is selected from the heterocyclyl groups of pyrazolyl, furanonyl, isoxazolyl, pyridinyl and pyridazinonyl.  
      More preferred COX-2 inhibitors that may be used in the present invention include, but are not limited to:  
                 
      JTE-522, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide;  
                 
    5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(2-methyl-5-pyridinyl)pyridine;  
                 
    2-(3,5-difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one;  
                 
    celecoxib, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide;  
                 
    rofecoxib, 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone;  
                 
    valdecoxib, 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide;  
                 
    parecoxib, N-[[4-(5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide;  
                 
    4-[5-(4-chorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzenesulfonamide;  
                 
    N-(2,3-dihydro-1,1-dioxido-6-phenoxy-1,2-benzisothiazol-5-yl)methanesulfonamide;  
                 
    6-[[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]methyl]-3(2H)-pyridazinone;  
                 
    N-(4-nitro-2-phenoxyphenyl)methanesulfonamide;  
                 
    3-(3,4-difluorophenoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-2 (5H)-furanone;  
                 
    N-[6-[(2,4-difluorophenyl)thio]-2,3-dihydro-1-oxo-1H-inden-5-yl]methanesulfonamide;  
                 
    3-(4-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-2 (3H)-oxazolone;  
                 
    4-[3-(4-fluorophenyl)-2,3-dihydro-2-oxo-4-oxazolyl]benzenesulfonamide;  
                 
    3-[4-(methylsulfonyl)phenyl]-2-phenyl-2-cyclopenten-1-one;  
                 
    4-(2-methyl-4-phenyl-5-oxazolyl)benzenesulfonamide;  
                 
    3-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2(3H)-oxazolone;  
                 
    5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole;  
                 
    4-(5-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;  
                 
    4-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;  
                 
    4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
                 
    NS-398, N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide;  
                 
    N-[6-(2,4-difluorophenoxy)-2,3-dihydro-1-oxo-1H-inden-5-yl]methanesulfonamide;  
                 
    3-(4-chlorophenoxy)-4-[(methylsulfonyl)amino]benzenesulfonamide;  
                 
    3-(4-fluorophenoxy)-4-[(methylsulfonyl)amino]benzenesulfonamide;  
                 
    3-[(1-methyl-1H-imidazol-2-yl)thio]-4 [(methylsulfonyl)amino]benzenesulfonamide;  
                 
    5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-3-phenoxy-2(5H)-furanone;  
                 
    N-[6-[(4-ethyl-2-thiazolyl)thio)-1,3-dihydro-1-oxo-5-isobenzofuranyl]methanesulfonamide;  
                 
    3-[(2,4-dichlorophenyl)thio]-4-[(methylsulfonyl)amino]benzenesulfonamide;  
                 
    1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]cyclopenten-1-yl]benzene;  
                 
    4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
                 
    3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;  
                 
    4-[2-(3-pyridinyll)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
                 
    4-[5-(hydroxymethyl)-3-phenylisoxazol-4-yl]benzenesulfonamide;  
                 
    4-[3-(4-chlorophenyl)-2,3-dihydro-2-oxo-4-oxazolyl]benzenesulfonamide;  
                 
    4-[5-(difluoromethyl)-3-phenylisoxazol-4-yl]benzenesulfonamide;  
                 
    [1,1′:2′,1″-terphenyl]-4-sulfonamide;  
                 
    4-(methylsulfonyl)-1,1′,2],1″-terphenyl;  
                 
    4-(2-phenyl-3-pyridinyl)benzenesulfonamide;  
                 
    N-(2,3-dihydro-1,1-dioxido-6-phenoxy-1,2-benzisothiazol-5-yl)methanesulfonamide; and  
                 
    N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]methanesulfonamide;  
                 
    4-[4-methyl-1-[4-(methylthio)phenyl]-1H-pyrrol-2-yl]benzenesulfonamide;  
                 
    4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide;  
                 
    deracoxib, 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
                 
    MK-663, etoricoxib, 5-chloro-6′-methyl-3-[4-(methylsulfonyl)phenyl]-2,3′-bipyridine;  
                 
    DuP 697, 5-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene;  
                 
    ABT-963, 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;  
                 
    6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
                 
    6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
                 
    (2S)-6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;  
                 
    (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;  
                 
    2-trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylic acid;  
                 
    6-chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;  
                 
    (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, ethyl ester;  
                 
    6-chloro-2-(trifluoromethyl)-4-phenyl-2H-1-benzopyran-3-carboxylic acid;  
                 
    6-(4-hydroxybenzoyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;  
                 
    2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylic acid;  
                 
    (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, sodium salt;  
                 
    6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;  
                 
    6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;  
                 
    (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxamide;  
                 
    6,7-difluoro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;  
                 
    6-chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3-quinolinecarboxylic acid;  
                 
    6-chloro-2-(trifluoromethyl)-1,2-dihydro[1,8]naphthyridine-3-carboxylic acid;  
                 
    6,8-dichloro-7-methyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, ethyl ester;  
                 
    (2S)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid.    

      In a further preferred 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 V:  
                 
 
 wherein R 16  is methyl or ethyl; 
          R 17  is chloro or fluoro;     R 1  is hydrogen or fluoro     R 19  is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;     R 20  is hydrogen or fluoro; and        

      R 21  is chloro, fluoro, trifluoromethyl or methyl, provided that R 17 , R 18 , R 19  and R 20  are not all fluoro when R 16  is ethyl and R 19  is H.  
      A particularly preferred phenylacetic acid derivative cyclooxygenase-2 selective inhibitor that is described in WO 99/11605 is a compound that has the designation of COX189 (CAS RN 346670-74-4), and that has the structure shown in Formula V, 
          wherein R 16  is ethyl;     R 17  and R 19  are chloro;     R 19  and R 20  are hydrogen; and     and R 21  is methyl.        

      Other preferred cyclooxygenase-2 selective inhibitors that can be used in the present invention have the general structure shown in formula VI, where the J group is a carbocycle or a heterocycle. Particularly preferred embodiments have the structure:  
                 
 
 where: 
      X is O; J is 1-phenyl; R 21  is 2-NHSO 2 CH 3 ; R 22  is 4-NO 2 ; and there is no R 23  group, (nimesulide), and     X is O; J is 1-oxo-inden-5-yl; R 2 , is 2-F; R 22  is 4-F; and R 23  is 6-NHSO 2 CH 3 , (flosulide); and     X is O; J is cyclohexyl; R 21  is 2-NHSO 2 CH 3 ; R 22  is 5-NO 2 ; and there is no R 23  group, (NS-398); and     X is S; J is 1-oxo-inden-5-yl; R 21  is 2-F; R 22  is 4-F; and R 23  is 6-N − SO 2 CH 3 .Na + , (L-745337); and     X is S; J is thiophen-2-yl; R 21  is 4-F; there is no R 22  group; and R 23  is 5-NHSO 2 CH 3 , (RWJ-63556); and     X is O; J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)furan-(5H)-3-yl; R 2 , is 3-F; R 22  is 4-F; and R 23  is 4-(p-SO 2 CH 3 )C 6 H 4 , (L-784512).    

      Further information on the applications of N-(2-cyclohexyloxynitrophenyl)methane sulfonamide (NS-398, CAS RN 123653-11-2), having a structure as shown in formula B-26, have been described by, for example, Yoshimi, N. et al., in  Japanese J. Cancer Res.,  90(4): 406-412 (1999); Falgueyret, J.-P. et al., in  Science Spectra , available at: http://www.gbhap.com/Science_Spectra/20-1-article.htm  
                 
 
 (Jun. 6, 2001); and Iwata, K. et al., in  Jpn. J. Pharmacol.,  75(2): 191-194 (1997). 
 
      An evaluation of the antiinflammatory activity of the cyclooxygenase-2 selective inhibitor, RWJ 63556, in a canine model of inflammation, was described by Kirchner et al., in  J Pharmacol Exp Ther  282, 1094-1101 (1997).  
      Other compounds useful as the cyclooxygenase-2 selective inhibitor in the present invention include diarylmethylidenefuran derivatives such as those described in U.S. Pat. No. 6,180,651. Such diarylmethylidenefuran derivatives have the general formula shown below in formula VII:  
                 
 
 wherein: 
      the rings T and M independently are: 
        a phenyl radical,     a naphthyl radical,     a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or     a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms;    
        at least one of the substituents Q 1 , Q 2 , L 1  or L 2  is: 
        an —S(O) n —R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms or a lower haloalkyl radical having 1 to 6 carbon atoms, or     an —SO 2 NH 2  group;     and is located in the para position,    
        the others independently being: 
        a hydrogen atom,     a halogen atom,     a lower alkyl radical having 1 to 6 carbon atoms,     a trifluoromethyl radical, or     a lower O-alkyl radical having 1 to 6 carbon atoms, or    
        Q 1  and Q 2  or L 1  and L 2  are a methylenedioxy group; and     R 24 , R 25 , R 26  and R 27  independently are: 
        a hydrogen atom,     a halogen atom,     a lower alkyl radical having 1 to 6 carbon atoms,     a lower haloalkyl radical having 1 to 6 carbon atoms, or     an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or,    
        R 24 , R 25  or R 26 , R 27  are an oxygen atom, or     R 24 , R 25  or R 26 , R 27 , together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms;     or an isomer or prodrug thereof.    

      Particular materials that are included in this family of compounds, and which can serve as the cyclooxygenase-2 selective inhibitor in the present invention, include N-(2-cyclohexyloxynitrophenyl)methane sulfonamide, and (E)-4-[(4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene) methyl] benzenesulfonamide.  
      Preferred cyclooxygenase-2 selective inhibitors that are useful in the present invention include the following individual compounds; darbufelone (Pfizer), CS-502 (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516 (Servier), SD 8381 (Pharmacia, described in U.S. Pat. No. 6,034,256), BMS-347070 (Bristol Myers Squibb, described in U.S. Pat. No. 6,180,651), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1367 (Chiroscience), L-748731 (Merck), CT3 (Atlantic Pharmaceutical), CGP-28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), 6-dioxo-9H-purin-8-yl-cinnamic acid (Glaxo Wellcome), and S-2474 (Shionogi).  
      In another preferred embodiment of the invention, the compound BMS-347070 having the formula:  
                 
 
      Information about S-33516, mentioned above, can be found in  Current Drugs Headline News , at http://www.current-drugs.com/NEWS/Inflaml.htm, Oct. 4, 2001, where it was reported that S-33516 is a tetrahydroisoinde derivative which has IC 50  values of 0.1 and 0.001 mM against cyclooxygenase-1 and cyclooxygenase-2, respectively. In human whole blood, S-33516 was reported to have an ED 50 =0.39 mg/kg.  
      The CAS reference numbers for nonlimiting examples of COX-2 inhibitors are identified in Table 3 below.  
               TABLE NO. 3                          COX-2 Inhibitors                             Compound Number   CAS Reference Number                       C1   180200-68-4           C2   202409-33-4           C3   212126-32-4           C4   169590-42-5           C5   162011-90-7           C6   181695-72-7           C7   198470-84-7           C8   170569-86-5           C9   187845-71-2           C10   179382-91-3           C11   51803-78-2           C12   189954-13-0           C13   158205-05-1           C14   197239-99-9           C15   197240-09-8           C16   226703-01-1           C17   93014-16-5           C18   197239-97-7           C19   162054-19-5           C20   170569-87-6           C21   279221-13-5           C22   170572-13-1           C23   123653-11-2           C24   80937-31-1           C25   279221-14-6           C26   279221-15-7           C27   187846-16-8           C28   189954-16-3           C29   181485-41-6           C30   187845-80-3           C31   158959-32-1           C32   170570-29-3           C33   177660-77-4           C34   177660-95-6           C35   181695-81-8           C36   197240-14-5           C37   181696-33-3           C38   178816-94-9           C39   178816-61-0           C40   279221-17-9           C41   187845-71-2           C42   123663-49-0           C43   197905-01-4           C44   197904-84-0           C45   169590-41-4           C46   202409-33-4           C47   88149-94-4           C48   266320-83-6           C49   215122-43-3           C50   215122-44-4           C51   215122-74-0           C52   215123-80-1           C53   215122-70-6           C54   264878-87-7           C55   279221-12-4           C56   215123-48-1           C57   215123-03-8           C58   215123-60-7           C59   279221-18-0           C60   215123-61-8           C61   215123-52-7           C62   279221-19-1           C63   215123-64-1           C64   215123-70-9           C65   215123-79-8           C66   215123-91-4           C67   215123-77-6                      
 
      More preferably, the COX-2 inhibitors that may be used in the present invention include, but are not limited to celecoxib, valdecoxib, parecoxib, rofecoxib, NS-398, deracoxib, Merck MK-663 and ABT-963.  
      Various classes of cyclooxygenase-2 inhibitors can be prepared as follows. Pyrazoles can be prepared by methods described in WO 95/15316. Pyrazoles can further be prepared by methods described in WO 95/15315. Pyrazoles can also be prepared by methods described in WO 96/03385. Thiophene analogs can be prepared by methods described in WO 95/00501. Preparation of thiophene analogs is also described in WO 94/15932. Oxazoles can be prepared by the methods described in WO 95/00501. Preparation of oxazoles is also described in WO 94/27980. Isoxazoles can be prepared by the methods described in WO 96/25405. Imidazoles can be prepared by the methods described in WO 96/03388. Preparation of imidazoles is also described in WO 96/03387. Cyclopentene cyclooxygenase-2 inhibitors can be prepared by the methods described in U.S. Pat. No. 5,344,991. Preparation of cyclopentene COX-2 inhibitors is also described in WO 95/00501. Terphenyl compounds can be prepared by the methods described in WO 96/16934. Thiazole compounds can be prepared by the methods described in WO 96/03,392. Pyridine compounds can be prepared by the methods described in WO 96/03392. Preparation of pyridine compounds is also described in WO 96/24,585. Benzopyranopyrazolyl compounds can be prepared by the methods described in WO 96/09304. Benzopyran compounds can be prepared by the methods described in WO 98/47890. Preparation of benzopyran compounds is also described in WO 00/23433. Benzopyran compounds can further be prepared by the methods described in U.S. Pat. No. 6,077,850. Preparation of benzopyran compounds is further described in U.S. Pat. No. 6,034,256. Arylpyridazinones can be prepared by the methods described in WO 00/24719.  
      The celecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 5,466,823.  
      The valdecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 5,633,272.  
      The parecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 5,932,598.  
      The rofecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 5,474,995.  
      The deracoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 5,521,207.  
      The compound MK-663 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in WO 98/03484.  
      The compound NS-398 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 4,885,367.  
      The compound ABT-963 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in WO 00/24719.  
      The estrogen sex steroid is preferably selected from, but is not limited to, the group consisting of ethinyl estradiol, 17β-estradiol and mestranol.  
      Still more preferably the estrogen sex steroid is ethinyl estradiol.  
      The progestin sex steroid is preferably selected from, but is not limited to, the group consisting of levonorgestrel, norethindrone acetate, norgestimate, ethynodiol acetate, desogestrel, norgestrel, gestodene, 3-ketodesogestrel, Org 30659, dienogest, trimegestone and norethindrone.  
      More preferably the progestin sex steroid is selected from the group consisting of levonorgestrel, norethindrone acetate, norgestimate, ethynodiol acetate, desogestrel, norgestrel and norethindrone.  
      Even more preferably, the progestin sex steroid is selected from the group consisting of levonorgestrel, norethindrone acetate and norgestimate.  
      The structures and CAS registry numbers of preferred estrogen and progestin sex steroids are listed in Table No. 4 below.  
               TABLE NO. 4                          Sex Steroid Structures                             CAS               Registry       Name   Number   Structure                               Ethinyl estradiol   57-63-6                                     17β-Estradiol   50-28-2                                     Mestranol   72-33-3                                     Levonorgestrel   797-63-7                                     Norethindrone acetate   51-98-9                                     Norgestimate   35189-28-7                                     Ethynodiol diacetate   297-76-7                                     Desogestrel   54024-22-5                                     Norgestrel   6533-00-2                                     Norethindrone   68-22-4                                     3-Ketodesogestrel   54048-10-1                                     Gestodene   60282-87-3                                     Org 30659   110072-15-6                                     Trimegestone   74513-62-5                                     Dienogest   65928-58-7                                        
 
      The following references listed in Table No. 5 below, hereby individually incorporated by reference, describe various sex steroids suitable for use in the present invention described herein, and processes for their manufacture.  
               TABLE NO. 5                          Sex Steroid References                             Sex Steroid   Reference                       Ethinyl estradiol   U.S. Pat. No. 3,759,961           17β-Estradiol   U.S. Pat. No. 3,274,182           Mestranol   U.S. Pat. No. 3,759,961           Levonorgestrel   U.S. Pat. No. 3,759,961           Norethindrone acetate   U.S. Pat. No. 3,408,371           Norgestimate   U.S. Pat. No. 4,027,019           Ethynodiol diacetate   U.S. Pat. No. 3,383,384           Desogestrel   U.S. Pat. No. 3,927,046           Norgestrel   U.S. Pat. No. 3,892,779           Norethindrone   U.S. Pat. No. 3,383,384           3-Ketodesogestrel   U.S. Pat. No. 4,371,529           Gestodene   U.S. Pat. No. 4,081,537           Org 30659   U.S. Pat. No. 5,236,913           Trimegestone   U.S. Pat. No. 4,273,771           Dienogest   U.S. Pat. No. 4,167,517                      
 
      The compounds useful in the present invention can have no asymmetric carbon atoms, or, alternatively, the useful compounds can have one or more asymmetric carbon atoms. When the useful compounds have one or more asymmetric carbon atoms, they therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.  
      Isomers may include geometric isomers, for example cis-isomers or trans-isomers across a double bond. All such isomers are contemplated among the compounds useful in the present invention.  
      The compounds useful in the present invention also include tautomers.  
      The compounds useful in the present invention also include their salts, solvates and prodrugs.  
      Dosages, Formulations and Routes of Administration  
      For the prophylaxis or treatment of the conditions referred to above, the compounds useful in the combinations and methods of the present invention can be used as the compound per se. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.  
      Suitable pharmaceutically-acceptable base addition salts of compounds of the present invention include metallic ion salts and organic ion salts. More preferred metallic ion salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metal ions. Such salts can be made from the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.  
      The compounds useful in the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well-known techniques of pharmacy, consisting essentially of admixing the components.  
      Optionally, the combination of the present invention can comprise a composition comprising a cyclooxygenase-2 inhibiting compound and a sex steroid compound. In such a composition, the cyclooxygenase-2 inhibiting compound and the sex steroid can be present in a single dosage form, for example a pill, a capsule, or a liquid that contains both of the compounds.  
      These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.  
      The amount of compound which is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition of the recipient.  
     Dosages  
      Dosage levels of COX-2 inhibitors on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 1.0 mg to about 1,000 mg and even more preferred levels of about 5 mg to about 500 mg. The amount of active ingredient will vary depending upon the host treated and the particular mode of administration.  
      It is understood, however, that a specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated and form of administration.  
      Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro initially can provide useful guidance on the proper doses for patient administration. Studies in animal models also generally may be used for guidance regarding effective dosages for treatment of cancers in accordance with the present invention. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route administered, the condition of the particular patient, etc. Generally speaking, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Thus, where a compound is found to demonstrate in vitro activity at, e.g., 10 μM, one will desire to administer an amount of the drug that is effective to provide about a 10 μM concentration in vivo. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.  
      An estrogen sex steroid at a daily dosage equivalent in estrogenic activity to about 5-75 ug ethinyl estradiol is useful in the treatment of the above conditions, with preferred levels of about 10 ug to about 50 ug and even more preferred levels of about 15 ug to about 35 ug. Actual dosage levels for other estrogen sex steroids may vary relative to the levels listed for ethinyl estradiol. A progestin sex steroid at a daily dosage equivalent in progestinic activity to about 10-600 ug levonorgestrel is useful in the treatment of the above conditions, with preferred levels of about 25 ug to about 400 ug and even more preferred levels of about 50 ug to about 200 ug. Actual dosage levels for other progestin sex steroids may vary relative to the levels listed for levonorgestrel.  
      The compounds of the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation-spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Formulation of drugs is discussed in, for example, Hoover, John E.,  Remington&#39;s Pharmaceutical Sciences , Mack Publishing Co., Easton, Pa. 1975. Another discussion of drug formulations can be found in Liberman, H. A. and Lachman, L., Eds.,  Pharmaceutical Dosage Forms , Marcel Decker, New York, N.Y., 1980.  
      Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, a contemplated inhibitor compound can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.  
      Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.  
      The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer&#39;s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.  
      For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. A contemplated therapeutic compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.  
      Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.  
      Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.  
      The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.  
     Treatment Regimen  
      The dosage regimen to prevent, give relief from, or ameliorate a disease condition having dysmenorrhea as an element of the disease or to protect against or treat a further dysmenorrhea related disorder with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.  
      In order to create a reproducible time of menses, specific combinations of daily administration of orally active sex steroids will be used to pharmacologically regulate the onset of menses within a small (24-48 hour) window of time. These steroids will include an estrogenic component and a progestagenic component with the effects of the latter predominating. The use of such a regimen should also result in less growth of the endometrial lining resulting in a reduced blood loss at the time of menses.  
      The use of daily orally active sex steroids to regulate endometrial growth will upon their discontinuation result in menses within 48-72 hours. The addition of a cyclooxygenase-2 inhibitor, such as celecoxib, starting 24 hours following discontinuation of the sex steroids will synchronize events such that the cyclooxygenase-2 inhibitor will be reproducibly administered at the time of initiation of increased prostaglandin synthesis triggered by the withdrawal of the steroid hormones. The cyclooxgenase-2 inhibitor can be administered until the end of menses with a variety of regimens. For example, the cyclooxygenase-2 inhibitor can be administered daily (od), twice a day (bid) or three times a day (tid). Thus the invention refers to the sequential administration of daily orally active sex steroids followed by a selective COX-2 inhibitor. This would be administered in a regular schedule (every 28 days) with the sex steroids being administered for 21 days followed by 2-7 days of a cyclooxygenase-2 inhibitor. More preferably, the sex steroids would be administered for 21 days followed by 4-7 days of a cyclooxygenase-2 inhibitor.  
      Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored to determine the effectiveness of the combination therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal effective amounts of each type of therapeutic compound are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of the therapeutic compounds which together exhibit satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the dysmenorrhea related condition.  
      A potential advantage of the combination therapy disclosed herein may be reduced dosage amount of any individual therapeutic compound, or all therapeutic compounds, effective in treating dysmenorrhea related conditions. The dosage lowering will provide advantages including reduction of side effects of the individual therapeutic compounds when compared to the monotherapy.  
      One of the several embodiments of the present invention provides a combination therapy comprising the use of a first amount of a COX-2 inhibitor and a second amount of sex steroids useful in the prophylaxis or treatment of dysmenorrhea, wherein said first and second amounts together comprise an dysmenorrhea-effective amount of said compounds. For example one of the many embodiments of the present invention is a combination therapy regimen comprising therapeutic dosages of a pyrazole COX-2 inhibitor, ethinyl estradiol and levonorgestrel.  
      The following non-limiting examples serve to illustrate various aspects of the present invention.  
     EXAMPLES  
      Table 6 illustrates examples of some combinations of the present invention wherein the combination comprises a first amount of a COX-2 inhibitor source, a second amount of a estrogen sex steroid and a third amount of a progestin sex steroid wherein the amounts together comprise an dysmenorrhea-effective amount of the compounds.  
               TABLE NO. 6                          Combination Examples                             Example   COX-2               Number   Inhibitor   Estrogen Sex Steroid   Progestin Sex Steroid                                     1   C1   Ethinyl estradiol   Levonorgestrel       2   C2   Ethinyl estradiol   Levonorgestrel       3   C3   Ethinyl estradiol   Levonorgestrel       4   C4   Ethinyl estradiol   Levonorgestrel       5   C5   Ethinyl estradiol   Levonorgestrel       6   C6   Ethinyl estradiol   Levonorgestrel       7   C7   Ethinyl estradiol   Levonorgestrel       8   C8   Ethinyl estradiol   Levonorgestrel       9   C9   Ethinyl estradiol   Levonorgestrel       10   C10   Ethinyl estradiol   Levonorgestrel       11   C11   Ethinyl estradiol   Levonorgestrel       12   C12   Ethinyl estradiol   Levonorgestrel       13   C13   Ethinyl estradiol   Levonorgestrel       14   C14   Ethinyl estradiol   Levonorgestrel       15   C15   Ethinyl estradiol   Levonorgestrel       16   C16   Ethinyl estradiol   Levonorgestrel       17   C17   Ethinyl estradiol   Levonorgestrel       18   C18   Ethinyl estradiol   Levonorgestrel       19   C19   Ethinyl estradiol   Levonorgestrel       20   C20   Ethinyl estradiol   Levonorgestrel       21   C21   Ethinyl estradiol   Levonorgestrel       22   C22   Ethinyl estradiol   Levonorgestrel       23   C23   Ethinyl estradiol   Levonorgestrel       24   C24   Ethinyl estradiol   Levonorgestrel       25   C25   Ethinyl estradiol   Levonorgestrel       26   C26   Ethinyl estradiol   Levonorgestrel       27   C27   Ethinyl estradiol   Levonorgestrel       28   C28   Ethinyl estradiol   Levonorgestrel       29   C29   Ethinyl estradiol   Levonorgestrel       30   C30   Ethinyl estradiol   Levonorgestrel       31   C31   Ethinyl estradiol   Levonorgestrel       32   C32   Ethinyl estradiol   Levonorgestrel       33   C33   Ethinyl estradiol   Levonorgestrel       34   C34   Ethinyl estradiol   Levonorgestrel       35   C35   Ethinyl estradiol   Levonorgestrel       36   C36   Ethinyl estradiol   Levonorgestrel       37   C37   Ethinyl estradiol   Levonorgestrel       38   C38   Ethinyl estradiol   Levonorgestrel       39   C39   Ethinyl estradiol   Levonorgestrel       40   C40   Ethinyl estradiol   Levonorgestrel       41   C41   Ethinyl estradiol   Levonorgestrel       42   C42   Ethinyl estradiol   Levonorgestrel       43   C43   Ethinyl estradiol   Levonorgestrel       44   C44   Ethinyl estradiol   Levonorgestrel       45   C45   Ethinyl estradiol   Levonorgestrel       46   C46   Ethinyl estradiol   Levonorgestrel       47   C47   Ethinyl estradiol   Levonorgestrel       48   C48   Ethinyl estradiol   Levonorgestrel       49   C49   Ethinyl estradiol   Levonorgestrel       50   C50   Ethinyl estradiol   Levonorgestrel       51   C51   Ethinyl estradiol   Levonorgestrel       52   C52   Ethinyl estradiol   Levonorgestrel       53   C53   Ethinyl estradiol   Levonorgestrel       54   C54   Ethinyl estradiol   Levonorgestrel       55   C55   Ethinyl estradiol   Levonorgestrel       56   C56   Ethinyl estradiol   Levonorgestrel       57   C57   Ethinyl estradiol   Levonorgestrel       58   C58   Ethinyl estradiol   Levonorgestrel       59   C59   Ethinyl estradiol   Levonorgestrel       60   C60   Ethinyl estradiol   Levonorgestrel       61   C61   Ethinyl estradiol   Levonorgestrel       62   C62   Ethinyl estradiol   Levonorgestrel       63   C63   Ethinyl estradiol   Levonorgestrel       64   C64   Ethinyl estradiol   Levonorgestrel       65   C65   Ethinyl estradiol   Levonorgestrel       66   C66   Ethinyl estradiol   Levonorgestrel       67   C67   Ethinyl estradiol   Levonorgestrel       68   C1   Ethinyl estradiol   Norethindrone acetate       69   C2   Ethinyl estradiol   Norethindrone acetate       70   C3   Ethinyl estradiol   Norethindrone acetate       71   C4   Ethinyl estradiol   Norethindrone acetate       72   C5   Ethinyl estradiol   Norethindrone acetate       73   C6   Ethinyl estradiol   Norethindrone acetate       74   C7   Ethinyl estradiol   Norethindrone acetate       75   C8   Ethinyl estradiol   Norethindrone acetate       76   C9   Ethinyl estradiol   Norethindrone acetate       77   C10   Ethinyl estradiol   Norethindrone acetate       78   C11   Ethinyl estradiol   Norethindrone acetate       79   C12   Ethinyl estradiol   Norethindrone acetate       80   C13   Ethinyl estradiol   Norethindrone acetate       81   C14   Ethinyl estradiol   Norethindrone acetate       82   C15   Ethinyl estradiol   Norethindrone acetate       83   C16   Ethinyl estradiol   Norethindrone acetate       84   C17   Ethinyl estradiol   Norethindrone acetate       85   C18   Ethinyl estradiol   Norethindrone acetate       86   C19   Ethinyl estradiol   Norethindrone acetate       87   C20   Ethinyl estradiol   Norethindrone acetate       88   C21   Ethinyl estradiol   Norethindrone acetate       89   C22   Ethinyl estradiol   Norethindrone acetate       90   C23   Ethinyl estradiol   Norethindrone acetate       91   C24   Ethinyl estradiol   Norethindrone acetate       92   C25   Ethinyl estradiol   Norethindrone acetate       93   C26   Ethinyl estradiol   Norethindrone acetate       94   C27   Ethinyl estradiol   Norethindrone acetate       95   C28   Ethinyl estradiol   Norethindrone acetate       96   C29   Ethinyl estradiol   Norethindrone acetate       97   C30   Ethinyl estradiol   Norethindrone acetate       98   C31   Ethinyl estradiol   Norethindrone acetate       99   C32   Ethinyl estradiol   Norethindrone acetate       100   C33   Ethinyl estradiol   Norethindrone acetate       101   C34   Ethinyl estradiol   Norethindrone acetate       102   C35   Ethinyl estradiol   Norethindrone acetate       103   C36   Ethinyl estradiol   Norethindrone acetate       104   C37   Ethinyl estradiol   Norethindrone acetate       105   C38   Ethinyl estradiol   Norethindrone acetate       106   C39   Ethinyl estradiol   Norethindrone acetate       107   C40   Ethinyl estradiol   Norethindrone acetate       108   C41   Ethinyl estradiol   Norethindrone acetate       109   C42   Ethinyl estradiol   Norethindrone acetate       110   C43   Ethinyl estradiol   Norethindrone acetate       111   C44   Ethinyl estradiol   Norethindrone acetate       112   C45   Ethinyl estradiol   Norethindrone acetate       113   C46   Ethinyl estradiol   Norethindrone acetate       114   C47   Ethinyl estradiol   Norethindrone acetate       115   C48   Ethinyl estradiol   Norethindrone acetate       116   C49   Ethinyl estradiol   Norethindrone acetate       117   C50   Ethinyl estradiol   Norethindrone acetate       118   C51   Ethinyl estradiol   Norethindrone acetate       119   C52   Ethinyl estradiol   Norethindrone acetate       120   C53   Ethinyl estradiol   Norethindrone acetate       121   C54   Ethinyl estradiol   Norethindrone acetate       122   C55   Ethinyl estradiol   Norethindrone acetate       123   C56   Ethinyl estradiol   Norethindrone acetate       124   C57   Ethinyl estradiol   Norethindrone acetate       125   C58   Ethinyl estradiol   Norethindrone acetate       126   C59   Ethinyl estradiol   Norethindrone acetate       127   C60   Ethinyl estradiol   Norethindrone acetate       128   C61   Ethinyl estradiol   Norethindrone acetate       129   C62   Ethinyl estradiol   Norethindrone acetate       130   C63   Ethinyl estradiol   Norethindrone acetate       131   C64   Ethinyl estradiol   Norethindrone acetate       132   C65   Ethinyl estradiol   Norethindrone acetate       133   C66   Ethinyl estradiol   Norethindrone acetate       134   C67   Ethinyl estradiol   Norethindrone acetate       135   C1   Ethinyl estradiol   Norgestimate       136   C2   Ethinyl estradiol   Norgestimate       137   C3   Ethinyl estradiol   Norgestimate       138   C4   Ethinyl estradiol   Norgestimate       139   C5   Ethinyl estradiol   Norgestimate       140   C6   Ethinyl estradiol   Norgestimate       141   C7   Ethinyl estradiol   Norgestimate       142   C8   Ethinyl estradiol   Norgestimate       143   C9   Ethinyl estradiol   Norgestimate       144   C10   Ethinyl estradiol   Norgestimate       145   C11   Ethinyl estradiol   Norgestimate       146   C12   Ethinyl estradiol   Norgestimate       147   C13   Ethinyl estradiol   Norgestimate       148   C14   Ethinyl estradiol   Norgestimate       149   C15   Ethinyl estradiol   Norgestimate       150   C16   Ethinyl estradiol   Norgestimate       151   C17   Ethinyl estradiol   Norgestimate       152   C18   Ethinyl estradiol   Norgestimate       153   C19   Ethinyl estradiol   Norgestimate       154   C20   Ethinyl estradiol   Norgestimate       155   C21   Ethinyl estradiol   Norgestimate       156   C22   Ethinyl estradiol   Norgestimate       157   C23   Ethinyl estradiol   Norgestimate       158   C24   Ethinyl estradiol   Norgestimate       159   C25   Ethinyl estradiol   Norgestimate       160   C26   Ethinyl estradiol   Norgestimate       161   C27   Ethinyl estradiol   Norgestimate       162   C28   Ethinyl estradiol   Norgestimate       163   C29   Ethinyl estradiol   Norgestimate       164   C30   Ethinyl estradiol   Norgestimate       165   C31   Ethinyl estradiol   Norgestimate       166   C32   Ethinyl estradiol   Norgestimate       167   C33   Ethinyl estradiol   Norgestimate       168   C34   Ethinyl estradiol   Norgestimate       169   C35   Ethinyl estradiol   Norgestimate       170   C36   Ethinyl estradiol   Norgestimate       171   C37   Ethinyl estradiol   Norgestimate       172   C38   Ethinyl estradiol   Norgestimate       173   C39   Ethinyl estradiol   Norgestimate       174   C40   Ethinyl estradiol   Norgestimate       175   C41   Ethinyl estradiol   Norgestimate       176   C42   Ethinyl estradiol   Norgestimate       177   C43   Ethinyl estradiol   Norgestimate       178   C44   Ethinyl estradiol   Norgestimate       179   C45   Ethinyl estradiol   Norgestimate       180   C46   Ethinyl estradiol   Norgestimate       181   C47   Ethinyl estradiol   Norgestimate       182   C48   Ethinyl estradiol   Norgestimate       183   C49   Ethinyl estradiol   Norgestimate       184   C50   Ethinyl estradiol   Norgestimate       185   C51   Ethinyl estradiol   Norgestimate       186   C52   Ethinyl estradiol   Norgestimate       187   C53   Ethinyl estradiol   Norgestimate       188   C54   Ethinyl estradiol   Norgestimate       189   C55   Ethinyl estradiol   Norgestimate       190   C56   Ethinyl estradiol   Norgestimate       191   C57   Ethinyl estradiol   Norgestimate       192   C58   Ethinyl estradiol   Norgestimate       193   C59   Ethinyl estradiol   Norgestimate       194   C60   Ethinyl estradiol   Norgestimate       195   C61   Ethinyl estradiol   Norgestimate       196   C62   Ethinyl estradiol   Norgestimate       197   C63   Ethinyl estradiol   Norgestimate       198   C64   Ethinyl estradiol   Norgestimate       199   C65   Ethinyl estradiol   Norgestimate       200   C66   Ethinyl estradiol   Norgestimate       201   C67   Ethinyl estradiol   Norgestimate       202   C1   Ethinyl estradiol   Ethynodiol diacetate       203   C2   Ethinyl estradiol   Ethynodiol diacetate       204   C3   Ethinyl estradiol   Ethynodiol diacetate       205   C4   Ethinyl estradiol   Ethynodiol diacetate       206   C5   Ethinyl estradiol   Ethynodiol diacetate       207   C6   Ethinyl estradiol   Ethynodiol diacetate       208   C7   Ethinyl estradiol   Ethynodiol diacetate       209   C8   Ethinyl estradiol   Ethynodiol diacetate       210   C9   Ethinyl estradiol   Ethynodiol diacetate       211   C10   Ethinyl estradiol   Ethynodiol diacetate       212   C11   Ethinyl estradiol   Ethynodiol diacetate       213   C12   Ethinyl estradiol   Ethynodiol diacetate       214   C13   Ethinyl estradiol   Ethynodiol diacetate       215   C14   Ethinyl estradiol   Ethynodiol diacetate       216   C15   Ethinyl estradiol   Ethynodiol diacetate       217   C16   Ethinyl estradiol   Ethynodiol diacetate       218   C17   Ethinyl estradiol   Ethynodiol diacetate       219   C18   Ethinyl estradiol   Ethynodiol diacetate       220   C19   Ethinyl estradiol   Ethynodiol diacetate       221   C20   Ethinyl estradiol   Ethynodiol diacetate       222   C21   Ethinyl estradiol   Ethynodiol diacetate       223   C22   Ethinyl estradiol   Ethynodiol diacetate       224   C23   Ethinyl estradiol   Ethynodiol diacetate       225   C24   Ethinyl estradiol   Ethynodiol diacetate       226   C25   Ethinyl estradiol   Ethynodiol diacetate       227   C26   Ethinyl estradiol   Ethynodiol diacetate       228   C27   Ethinyl estradiol   Ethynodiol diacetate       229   C28   Ethinyl estradiol   Ethynodiol diacetate       230   C29   Ethinyl estradiol   Ethynodiol diacetate       231   C30   Ethinyl estradiol   Ethynodiol diacetate       232   C31   Ethinyl estradiol   Ethynodiol diacetate       233   C32   Ethinyl estradiol   Ethynodiol diacetate       234   C33   Ethinyl estradiol   Ethynodiol diacetate       235   C34   Ethinyl estradiol   Ethynodiol diacetate       236   C35   Ethinyl estradiol   Ethynodiol diacetate       237   C36   Ethinyl estradiol   Ethynodiol diacetate       238   C37   Ethinyl estradiol   Ethynodiol diacetate       239   C38   Ethinyl estradiol   Ethynodiol diacetate       240   C39   Ethinyl estradiol   Ethynodiol diacetate       241   C40   Ethinyl estradiol   Ethynodiol diacetate       242   C41   Ethinyl estradiol   Ethynodiol diacetate       243   C42   Ethinyl estradiol   Ethynodiol diacetate       244   C43   Ethinyl estradiol   Ethynodiol diacetate       245   C44   Ethinyl estradiol   Ethynodiol diacetate       246   C45   Ethinyl estradiol   Ethynodiol diacetate       247   C46   Ethinyl estradiol   Ethynodiol diacetate       248   C47   Ethinyl estradiol   Ethynodiol diacetate       249   C48   Ethinyl estradiol   Ethynodiol diacetate       250   C49   Ethinyl estradiol   Ethynodiol diacetate       251   C50   Ethinyl estradiol   Ethynodiol diacetate       252   C51   Ethinyl estradiol   Ethynodiol diacetate       253   C52   Ethinyl estradiol   Ethynodiol diacetate       254   C53   Ethinyl estradiol   Ethynodiol diacetate       255   C54   Ethinyl estradiol   Ethynodiol diacetate       256   C55   Ethinyl estradiol   Ethynodiol diacetate       257   C56   Ethinyl estradiol   Ethynodiol diacetate       258   C57   Ethinyl estradiol   Ethynodiol diacetate       259   C58   Ethinyl estradiol   Ethynodiol diacetate       260   C59   Ethinyl estradiol   Ethynodiol diacetate       261   C60   Ethinyl estradiol   Ethynodiol diacetate       262   C61   Ethinyl estradiol   Ethynodiol diacetate       263   C62   Ethinyl estradiol   Ethynodiol diacetate       264   C63   Ethinyl estradiol   Ethynodiol diacetate       265   C64   Ethinyl estradiol   Ethynodiol diacetate       266   C65   Ethinyl estradiol   Ethynodiol diacetate       267   C66   Ethinyl estradiol   Ethynodiol diacetate       268   C67   Ethinyl estradiol   Ethynodiol diacetate       269   C1   Ethinyl estradiol   Desogestrel       270   C2   Ethinyl estradiol   Desogestrel       271   C3   Ethinyl estradiol   Desogestrel       272   C4   Ethinyl estradiol   Desogestrel       273   C5   Ethinyl estradiol   Desogestrel       274   C6   Ethinyl estradiol   Desogestrel       275   C7   Ethinyl estradiol   Desogestrel       276   C8   Ethinyl estradiol   Desogestrel       277   C9   Ethinyl estradiol   Desogestrel       278   C10   Ethinyl estradiol   Desogestrel       279   C11   Ethinyl estradiol   Desogestrel       280   C12   Ethinyl estradiol   Desogestrel       281   C13   Ethinyl estradiol   Desogestrel       282   C14   Ethinyl estradiol   Desogestrel       283   C15   Ethinyl estradiol   Desogestrel       284   C16   Ethinyl estradiol   Desogestrel       285   C17   Ethinyl estradiol   Desogestrel       286   C18   Ethinyl estradiol   Desogestrel       287   C19   Ethinyl estradiol   Desogestrel       288   C20   Ethinyl estradiol   Desogestrel       289   C21   Ethinyl estradiol   Desogestrel       290   C22   Ethinyl estradiol   Desogestrel       291   C23   Ethinyl estradiol   Desogestrel       292   C24   Ethinyl estradiol   Desogestrel       293   C25   Ethinyl estradiol   Desogestrel       294   C26   Ethinyl estradiol   Desogestrel       295   C27   Ethinyl estradiol   Desogestrel       296   C28   Ethinyl estradiol   Desogestrel       297   C29   Ethinyl estradiol   Desogestrel       298   C30   Ethinyl estradiol   Desogestrel       299   C31   Ethinyl estradiol   Desogestrel       300   C32   Ethinyl estradiol   Desogestrel       301   C33   Ethinyl estradiol   Desogestrel       302   C34   Ethinyl estradiol   Desogestrel       303   C35   Ethinyl estradiol   Desogestrel       304   C36   Ethinyl estradiol   Desogestrel       305   C37   Ethinyl estradiol   Desogestrel       306   C38   Ethinyl estradiol   Desogestrel       307   C39   Ethinyl estradiol   Desogestrel       308   C40   Ethinyl estradiol   Desogestrel       309   C41   Ethinyl estradiol   Desogestrel       310   C42   Ethinyl estradiol   Desogestrel       311   C43   Ethinyl estradiol   Desogestrel       312   C44   Ethinyl estradiol   Desogestrel       313   C45   Ethinyl estradiol   Desogestrel       314   C46   Ethinyl estradiol   Desogestrel       315   C47   Ethinyl estradiol   Desogestrel       316   C48   Ethinyl estradiol   Desogestrel       317   C49   Ethinyl estradiol   Desogestrel       318   C50   Ethinyl estradiol   Desogestrel       319   C51   Ethinyl estradiol   Desogestrel       320   C52   Ethinyl estradiol   Desogestrel       321   C53   Ethinyl estradiol   Desogestrel       322   C54   Ethinyl estradiol   Desogestrel       323   C55   Ethinyl estradiol   Desogestrel       324   C56   Ethinyl estradiol   Desogestrel       325   C57   Ethinyl estradiol   Desogestrel       326   C58   Ethinyl estradiol   Desogestrel       327   C59   Ethinyl estradiol   Desogestrel       328   C60   Ethinyl estradiol   Desogestrel       329   C61   Ethinyl estradiol   Desogestrel       330   C62   Ethinyl estradiol   Desogestrel       331   C63   Ethinyl estradiol   Desogestrel       332   C64   Ethinyl estradiol   Desogestrel       333   C65   Ethinyl estradiol   Desogestrel       334   C66   Ethinyl estradiol   Desogestrel       335   C67   Ethinyl estradiol   Desogestrel       336   C1   Ethinyl estradiol   Norgestrel       337   C2   Ethinyl estradiol   Norgestrel       338   C3   Ethinyl estradiol   Norgestrel       339   C4   Ethinyl estradiol   Norgestrel       340   C5   Ethinyl estradiol   Norgestrel       341   C6   Ethinyl estradiol   Norgestrel       342   C7   Ethinyl estradiol   Norgestrel       343   C8   Ethinyl estradiol   Norgestrel       344   C9   Ethinyl estradiol   Norgestrel       345   C10   Ethinyl estradiol   Norgestrel       346   C11   Ethinyl estradiol   Norgestrel       347   C12   Ethinyl estradiol   Norgestrel       348   C13   Ethinyl estradiol   Norgestrel       349   C14   Ethinyl estradiol   Norgestrel       350   C15   Ethinyl estradiol   Norgestrel       351   C16   Ethinyl estradiol   Norgestrel       352   C17   Ethinyl estradiol   Norgestrel       353   C18   Ethinyl estradiol   Norgestrel       354   C19   Ethinyl estradiol   Norgestrel       355   C20   Ethinyl estradiol   Norgestrel       356   C21   Ethinyl estradiol   Norgestrel       357   C22   Ethinyl estradiol   Norgestrel       358   C23   Ethinyl estradiol   Norgestrel       359   C24   Ethinyl estradiol   Norgestrel       360   C25   Ethinyl estradiol   Norgestrel       361   C26   Ethinyl estradiol   Norgestrel       362   C27   Ethinyl estradiol   Norgestrel       363   C28   Ethinyl estradiol   Norgestrel       364   C29   Ethinyl estradiol   Norgestrel       365   C30   Ethinyl estradiol   Norgestrel       366   C31   Ethinyl estradiol   Norgestrel       367   C32   Ethinyl estradiol   Norgestrel       368   C33   Ethinyl estradiol   Norgestrel       369   C34   Ethinyl estradiol   Norgestrel       370   C35   Ethinyl estradiol   Norgestrel       371   C36   Ethinyl estradiol   Norgestrel       372   C37   Ethinyl estradiol   Norgestrel       373   C38   Ethinyl estradiol   Norgestrel       374   C39   Ethinyl estradiol   Norgestrel       375   C40   Ethinyl estradiol   Norgestrel       376   C41   Ethinyl estradiol   Norgestrel       377   C42   Ethinyl estradiol   Norgestrel       378   C43   Ethinyl estradiol   Norgestrel       379   C44   Ethinyl estradiol   Norgestrel       380   C45   Ethinyl estradiol   Norgestrel       381   C46   Ethinyl estradiol   Norgestrel       382   C47   Ethinyl estradiol   Norgestrel       383   C48   Ethinyl estradiol   Norgestrel       384   C49   Ethinyl estradiol   Norgestrel       385   C50   Ethinyl estradiol   Norgestrel       386   C51   Ethinyl estradiol   Norgestrel       387   C52   Ethinyl estradiol   Norgestrel       388   C53   Ethinyl estradiol   Norgestrel       389   C54   Ethinyl estradiol   Norgestrel       390   C55   Ethinyl estradiol   Norgestrel       391   C56   Ethinyl estradiol   Norgestrel       392   C57   Ethinyl estradiol   Norgestrel       393   C58   Ethinyl estradiol   Norgestrel       394   C59   Ethinyl estradiol   Norgestrel       395   C60   Ethinyl estradiol   Norgestrel       396   C61   Ethinyl estradiol   Norgestrel       397   C62   Ethinyl estradiol   Norgestrel       398   C63   Ethinyl estradiol   Norgestrel       399   C64   Ethinyl estradiol   Norgestrel       400   C65   Ethinyl estradiol   Norgestrel       401   C66   Ethinyl estradiol   Norgestrel       402   C67   Ethinyl estradiol   Norgestrel       403   C1   Ethinyl estradiol   Norethindrone       404   C2   Ethinyl estradiol   Norethindrone       405   C3   Ethinyl estradiol   Norethindrone       406   C4   Ethinyl estradiol   Norethindrone       407   C5   Ethinyl estradiol   Norethindrone       408   C6   Ethinyl estradiol   Norethindrone       409   C7   Ethinyl estradiol   Norethindrone       410   C8   Ethinyl estradiol   Norethindrone       411   C9   Ethinyl estradiol   Norethindrone       412   C10   Ethinyl estradiol   Norethindrone       413   C11   Ethinyl estradiol   Norethindrone       414   C12   Ethinyl estradiol   Norethindrone       415   C13   Ethinyl estradiol   Norethindrone       416   C14   Ethinyl estradiol   Norethindrone       417   C15   Ethinyl estradiol   Norethindrone       418   C16   Ethinyl estradiol   Norethindrone       419   C17   Ethinyl estradiol   Norethindrone       420   C18   Ethinyl estradiol   Norethindrone       421   C19   Ethinyl estradiol   Norethindrone       422   C20   Ethinyl estradiol   Norethindrone       423   C21   Ethinyl estradiol   Norethindrone       424   C22   Ethinyl estradiol   Norethindrone       425   C23   Ethinyl estradiol   Norethindrone       426   C24   Ethinyl estradiol   Norethindrone       427   C25   Ethinyl estradiol   Norethindrone       428   C26   Ethinyl estradiol   Norethindrone       429   C27   Ethinyl estradiol   Norethindrone       430   C28   Ethinyl estradiol   Norethindrone       431   C29   Ethinyl estradiol   Norethindrone       432   C30   Ethinyl estradiol   Norethindrone       433   C31   Ethinyl estradiol   Norethindrone       434   C32   Ethinyl estradiol   Norethindrone       435   C33   Ethinyl estradiol   Norethindrone       436   C34   Ethinyl estradiol   Norethindrone       437   C35   Ethinyl estradiol   Norethindrone       438   C36   Ethinyl estradiol   Norethindrone       439   C37   Ethinyl estradiol   Norethindrone       440   C38   Ethinyl estradiol   Norethindrone       441   C39   Ethinyl estradiol   Norethindrone       442   C40   Ethinyl estradiol   Norethindrone       443   C41   Ethinyl estradiol   Norethindrone       444   C42   Ethinyl estradiol   Norethindrone       445   C43   Ethinyl estradiol   Norethindrone       446   C44   Ethinyl estradiol   Norethindrone       447   C45   Ethinyl estradiol   Norethindrone       448   C46   Ethinyl estradiol   Norethindrone       449   C47   Ethinyl estradiol   Norethindrone       450   C48   Ethinyl estradiol   Norethindrone       451   C49   Ethinyl estradiol   Norethindrone       452   C50   Ethinyl estradiol   Norethindrone       453   C51   Ethinyl estradiol   Norethindrone       454   C52   Ethinyl estradiol   Norethindrone       455   C53   Ethinyl estradiol   Norethindrone       456   C54   Ethinyl estradiol   Norethindrone       457   C55   Ethinyl estradiol   Norethindrone       458   C56   Ethinyl estradiol   Norethindrone       459   C57   Ethinyl estradiol   Norethindrone       460   C58   Ethinyl estradiol   Norethindrone       461   C59   Ethinyl estradiol   Norethindrone       462   C60   Ethinyl estradiol   Norethindrone       463   C61   Ethinyl estradiol   Norethindrone       464   C62   Ethinyl estradiol   Norethindrone       465   C63   Ethinyl estradiol   Norethindrone       466   C64   Ethinyl estradiol   Norethindrone       467   C65   Ethinyl estradiol   Norethindrone       468   C66   Ethinyl estradiol   Norethindrone       469   C67   Ethinyl estradiol   Norethindrone       470   C1   Ethinyl estradiol   3-Ketodesogestrel       471   C2   Ethinyl estradiol   3-Ketodesogestrel       472   C3   Ethinyl estradiol   3-Ketodesogestrel       473   C4   Ethinyl estradiol   3-Ketodesogestrel       474   C5   Ethinyl estradiol   3-Ketodesogestrel       475   C6   Ethinyl estradiol   3-Ketodesogestrel       476   C7   Ethinyl estradiol   3-Ketodesogestrel       477   C8   Ethinyl estradiol   3-Ketodesogestrel       478   C9   Ethinyl estradiol   3-Ketodesogestrel       479   C10   Ethinyl estradiol   3-Ketodesogestrel       480   C11   Ethinyl estradiol   3-Ketodesogestrel       481   C12   Ethinyl estradiol   3-Ketodesogestrel       482   C13   Ethinyl estradiol   3-Ketodesogestrel       483   C14   Ethinyl estradiol   3-Ketodesogestrel       484   C15   Ethinyl estradiol   3-Ketodesogestrel       485   C16   Ethinyl estradiol   3-Ketodesogestrel       486   C17   Ethinyl estradiol   3-Ketodesogestrel       487   C18   Ethinyl estradiol   3-Ketodesogestrel       488   C19   Ethinyl estradiol   3-Ketodesogestrel       489   C20   Ethinyl estradiol   3-Ketodesogestrel       490   C21   Ethinyl estradiol   3-Ketodesogestrel       491   C22   Ethinyl estradiol   3-Ketodesogestrel       492   C23   Ethinyl estradiol   3-Ketodesogestrel       493   C24   Ethinyl estradiol   3-Ketodesogestrel       494   C25   Ethinyl estradiol   3-Ketodesogestrel       495   C26   Ethinyl estradiol   3-Ketodesogestrel       496   C27   Ethinyl estradiol   3-Ketodesogestrel       497   C28   Ethinyl estradiol   3-Ketodesogestrel       498   C29   Ethinyl estradiol   3-Ketodesogestrel       499   C30   Ethinyl estradiol   3-Ketodesogestrel       500   C31   Ethinyl estradiol   3-Ketodesogestrel       501   C32   Ethinyl estradiol   3-Ketodesogestrel       502   C33   Ethinyl estradiol   3-Ketodesogestrel       503   C34   Ethinyl estradiol   3-Ketodesogestrel       504   C35   Ethinyl estradiol   3-Ketodesogestrel       505   C36   Ethinyl estradiol   3-Ketodesogestrel       506   C37   Ethinyl estradiol   3-Ketodesogestrel       507   C38   Ethinyl estradiol   3-Ketodesogestrel       508   C39   Ethinyl estradiol   3-Ketodesogestrel       509   C40   Ethinyl estradiol   3-Ketodesogestrel       510   C41   Ethinyl estradiol   3-Ketodesogestrel       511   C42   Ethinyl estradiol   3-Ketodesogestrel       512   C43   Ethinyl estradiol   3-Ketodesogestrel       513   C44   Ethinyl estradiol   3-Ketodesogestrel       514   C45   Ethinyl estradiol   3-Ketodesogestrel       515   C46   Ethinyl estradiol   3-Ketodesogestrel       516   C47   Ethinyl estradiol   3-Ketodesogestrel       517   C48   Ethinyl estradiol   3-Ketodesogestrel       518   C49   Ethinyl estradiol   3-Ketodesogestrel       519   C50   Ethinyl estradiol   3-Ketodesogestrel       520   C51   Ethinyl estradiol   3-Ketodesogestrel       521   C52   Ethinyl estradiol   3-Ketodesogestrel       522   C53   Ethinyl estradiol   3-Ketodesogestrel       523   C54   Ethinyl estradiol   3-Ketodesogestrel       524   C55   Ethinyl estradiol   3-Ketodesogestrel       525   C56   Ethinyl estradiol   3-Ketodesogestrel       526   C57   Ethinyl estradiol   3-Ketodesogestrel       527   C58   Ethinyl estradiol   3-Ketodesogestrel       528   C59   Ethinyl estradiol   3-Ketodesogestrel       529   C60   Ethinyl estradiol   3-Ketodesogestrel       530   C61   Ethinyl estradiol   3-Ketodesogestrel       531   C62   Ethinyl estradiol   3-Ketodesogestrel       532   C63   Ethinyl estradiol   3-Ketodesogestrel       533   C64   Ethinyl estradiol   3-Ketodesogestrel       534   C65   Ethinyl estradiol   3-Ketodesogestrel       535   C66   Ethinyl estradiol   3-Ketodesogestrel       536   C67   Ethinyl estradiol   3-Ketodesogestrel       537   C1   Ethinyl estradiol   Gestodene       538   C2   Ethinyl estradiol   Gestodene       539   C3   Ethinyl estradiol   Gestodene       540   C4   Ethinyl estradiol   Gestodene       541   C5   Ethinyl estradiol   Gestodene       542   C6   Ethinyl estradiol   Gestodene       543   C7   Ethinyl estradiol   Gestodene       544   C8   Ethinyl estradiol   Gestodene       545   C9   Ethinyl estradiol   Gestodene       546   C10   Ethinyl estradiol   Gestodene       547   C11   Ethinyl estradiol   Gestodene       548   C12   Ethinyl estradiol   Gestodene       549   C13   Ethinyl estradiol   Gestodene       550   C14   Ethinyl estradiol   Gestodene       551   C15   Ethinyl estradiol   Gestodene       552   C16   Ethinyl estradiol   Gestodene       553   C17   Ethinyl estradiol   Gestodene       554   C18   Ethinyl estradiol   Gestodene       555   C19   Ethinyl estradiol   Gestodene       556   C20   Ethinyl estradiol   Gestodene       557   C21   Ethinyl estradiol   Gestodene       558   C22   Ethinyl estradiol   Gestodene       559   C23   Ethinyl estradiol   Gestodene       560   C24   Ethinyl estradiol   Gestodene       561   C25   Ethinyl estradiol   Gestodene       562   C26   Ethinyl estradiol   Gestodene       563   C27   Ethinyl estradiol   Gestodene       564   C28   Ethinyl estradiol   Gestodene       565   C29   Ethinyl estradiol   Gestodene       566   C30   Ethinyl estradiol   Gestodene       567   C31   Ethinyl estradiol   Gestodene       568   C32   Ethinyl estradiol   Gestodene       569   C33   Ethinyl estradiol   Gestodene       570   C34   Ethinyl estradiol   Gestodene       571   C35   Ethinyl estradiol   Gestodene       572   C36   Ethinyl estradiol   Gestodene       573   C37   Ethinyl estradiol   Gestodene       574   C38   Ethinyl estradiol   Gestodene       575   C39   Ethinyl estradiol   Gestodene       576   C40   Ethinyl estradiol   Gestodene       577   C41   Ethinyl estradiol   Gestodene       578   C42   Ethinyl estradiol   Gestodene       579   C43   Ethinyl estradiol   Gestodene       580   C44   Ethinyl estradiol   Gestodene       581   C45   Ethinyl estradiol   Gestodene       582   C46   Ethinyl estradiol   Gestodene       583   C47   Ethinyl estradiol   Gestodene       584   C48   Ethinyl estradiol   Gestodene       585   C49   Ethinyl estradiol   Gestodene       586   C50   Ethinyl estradiol   Gestodene       587   C51   Ethinyl estradiol   Gestodene       588   C52   Ethinyl estradiol   Gestodene       589   C53   Ethinyl estradiol   Gestodene       590   C54   Ethinyl estradiol   Gestodene       591   C55   Ethinyl estradiol   Gestodene       592   C56   Ethinyl estradiol   Gestodene       593   C57   Ethinyl estradiol   Gestodene       594   C58   Ethinyl estradiol   Gestodene       595   C59   Ethinyl estradiol   Gestodene       596   C60   Ethinyl estradiol   Gestodene       597   C61   Ethinyl estradiol   Gestodene       598   C62   Ethinyl estradiol   Gestodene       599   C63   Ethinyl estradiol   Gestodene       600   C64   Ethinyl estradiol   Gestodene       601   C65   Ethinyl estradiol   Gestodene       602   C66   Ethinyl estradiol   Gestodene       603   C67   Ethinyl estradiol   Gestodene       604   C1   Ethinyl estradiol   Org 30659       605   C2   Ethinyl estradiol   Org 30659       606   C3   Ethinyl estradiol   Org 30659       607   C4   Ethinyl estradiol   Org 30659       608   C5   Ethinyl estradiol   Org 30659       609   C6   Ethinyl estradiol   Org 30659       610   C7   Ethinyl estradiol   Org 30659       611   C8   Ethinyl estradiol   Org 30659       612   C9   Ethinyl estradiol   Org 30659       613   C10   Ethinyl estradiol   Org 30659       614   C11   Ethinyl estradiol   Org 30659       615   C12   Ethinyl estradiol   Org 30659       616   C13   Ethinyl estradiol   Org 30659       617   C14   Ethinyl estradiol   Org 30659       618   C15   Ethinyl estradiol   Org 30659       619   C16   Ethinyl estradiol   Org 30659       620   C17   Ethinyl estradiol   Org 30659       621   C18   Ethinyl estradiol   Org 30659       622   C19   Ethinyl estradiol   Org 30659       623   C20   Ethinyl estradiol   Org 30659       624   C21   Ethinyl estradiol   Org 30659       625   C22   Ethinyl estradiol   Org 30659       626   C23   Ethinyl estradiol   Org 30659       627   C24   Ethinyl estradiol   Org 30659       628   C25   Ethinyl estradiol   Org 30659       629   C26   Ethinyl estradiol   Org 30659       630   C27   Ethinyl estradiol   Org 30659       631   C28   Ethinyl estradiol   Org 30659       632   C29   Ethinyl estradiol   Org 30659       633   C30   Ethinyl estradiol   Org 30659       634   C31   Ethinyl estradiol   Org 30659       635   C32   Ethinyl estradiol   Org 30659       636   C33   Ethinyl estradiol   Org 30659       637   C34   Ethinyl estradiol   Org 30659       638   C35   Ethinyl estradiol   Org 30659       639   C36   Ethinyl estradiol   Org 30659       640   C37   Ethinyl estradiol   Org 30659       641   C38   Ethinyl estradiol   Org 30659       642   C39   Ethinyl estradiol   Org 30659       643   C40   Ethinyl estradiol   Org 30659       644   C41   Ethinyl estradiol   Org 30659       645   C42   Ethinyl estradiol   Org 30659       646   C43   Ethinyl estradiol   Org 30659       647   C44   Ethinyl estradiol   Org 30659       648   C45   Ethinyl estradiol   Org 30659       649   C46   Ethinyl estradiol   Org 30659       650   C47   Ethinyl estradiol   Org 30659       651   C48   Ethinyl estradiol   Org 30659       652   C49   Ethinyl estradiol   Org 30659       653   C50   Ethinyl estradiol   Org 30659       654   C51   Ethinyl estradiol   Org 30659       655   C52   Ethinyl estradiol   Org 30659       656   C53   Ethinyl estradiol   Org 30659       657   C54   Ethinyl estradiol   Org 30659       658   C55   Ethinyl estradiol   Org 30659       659   C56   Ethinyl estradiol   Org 30659       660   C57   Ethinyl estradiol   Org 30659       661   C58   Ethinyl estradiol   Org 30659       662   C59   Ethinyl estradiol   Org 30659       663   C60   Ethinyl estradiol   Org 30659       664   C61   Ethinyl estradiol   Org 30659       665   C62   Ethinyl estradiol   Org 30659       666   C63   Ethinyl estradiol   Org 30659       667   C64   Ethinyl estradiol   Org 30659       668   C65   Ethinyl estradiol   Org 30659       669   C66   Ethinyl estradiol   Org 30659       670   C67   Ethinyl estradiol   Org 30659       671   C1   Ethinyl estradiol   Trimagestone       672   C2   Ethinyl estradiol   Trimegestone       673   C3   Ethinyl estradiol   Trimegestone       674   C4   Ethinyl estradiol   Trimegestone       675   C5   Ethinyl estradiol   Trimegestone       676   C6   Ethinyl estradiol   Trimegestone       677   C7   Ethinyl estradiol   Trimegestone       678   C8   Ethinyl estradiol   Trimegestone       679   C9   Ethinyl estradiol   Trimegestone       680   C10   Ethinyl estradiol   Trimegestone       681   C11   Ethinyl estradiol   Trimegestone       682   C12   Ethinyl estradiol   Trimegestone       683   C13   Ethinyl estradiol   Trimegestone       684   C14   Ethinyl estradiol   Trimegestone       685   C15   Ethinyl estradiol   Trimegestone       686   C16   Ethinyl estradiol   Trimegestone       687   C17   Ethinyl estradiol   Trimegestone       688   C18   Ethinyl estradiol   Trimegestone       689   C19   Ethinyl estradiol   Trimegestone       690   C20   Ethinyl estradiol   Trimegestone       691   C21   Ethinyl estradiol   Trimegestone       692   C22   Ethinyl estradiol   Trimegestone       693   C23   Ethinyl estradiol   Trimegestone       694   C24   Ethinyl estradiol   Trimegestone       695   C25   Ethinyl estradiol   Trimegestone       696   C26   Ethinyl estradiol   Trimegestone       697   C27   Ethinyl estradiol   Trimegestone       698   C28   Ethinyl estradiol   Trimegestone       699   C29   Ethinyl estradiol   Trimegestone       700   C30   Ethinyl estradiol   Trimegestone       701   C31   Ethinyl estradiol   Trimegestone       702   C32   Ethinyl estradiol   Trimegestone       703   C33   Ethinyl estradiol   Trimegestone       704   C34   Ethinyl estradiol   Trimegestone       705   C35   Ethinyl estradiol   Trimegestone       706   C36   Ethinyl estradiol   Trimegestone       707   C37   Ethinyl estradiol   Trimegestone       708   C38   Ethinyl estradiol   Trimegestone       709   C39   Ethinyl estradiol   Trimegestone       710   C40   Ethinyl estradiol   Trimegestone       711   C41   Ethinyl estradiol   Trimegestone       712   C42   Ethinyl estradiol   Trimegestone       713   C43   Ethinyl estradiol   Trimegestone       714   C44   Ethinyl estradiol   Trimegestone       715   C45   Ethinyl estradiol   Trimegestone       716   C46   Ethinyl estradiol   Trimegestone       717   C47   Ethinyl estradiol   Trimegestone       718   C48   Ethinyl estradiol   Trimegestone       719   C49   Ethinyl estradiol   Trimegestone       720   C50   Ethinyl estradiol   Trimegestone       721   C51   Ethinyl estradiol   Trimegestone       722   C52   Ethinyl estradiol   Trimegestone       723   C53   Ethinyl estradiol   Trimegestone       724   C54   Ethinyl estradiol   Trimegestone       725   C55   Ethinyl estradiol   Trimegestone       726   C56   Ethinyl estradiol   Trimegestone       727   C57   Ethinyl estradiol   Trimegestone       728   C58   Ethinyl estradiol   Trimegestone       729   C59   Ethinyl estradiol   Trimegestone       730   C60   Ethinyl estradiol   Trimegestone       731   C61   Ethinyl estradiol   Trimegestone       732   C62   Ethinyl estradiol   Trimegestone       733   C63   Ethinyl estradiol   Trimegestone       734   C64   Ethinyl estradiol   Trimegestone       735   C65   Ethinyl estradiol   Trimegestone       736   C66   Ethinyl estradiol   Trimegestone       737   C67   Ethinyl estradiol   Trimegestone       738   C1   Ethinyl estradiol   Dienogest       739   C2   Ethinyl estradiol   Dienogest       740   C3   Ethinyl estradiol   Dienogest       741   C4   Ethinyl estradiol   Dienogest       742   C5   Ethinyl estradiol   Dienogest       743   C6   Ethinyl estradiol   Dienogest       744   C7   Ethinyl estradiol   Dienogest       745   C8   Ethinyl estradiol   Dienogest       746   C9   Ethinyl estradiol   Dienogest       747   C10   Ethinyl estradiol   Dienogest       748   C11   Ethinyl estradiol   Dienogest       749   C12   Ethinyl estradiol   Dienogest       750   C13   Ethinyl estradiol   Dienogest       751   C14   Ethinyl estradiol   Dienogest       752   C15   Ethinyl estradiol   Dienogest       753   C16   Ethinyl estradiol   Dienogest       754   C17   Ethinyl estradiol   Dienogest       755   C18   Ethinyl estradiol   Dienogest       756   C19   Ethinyl estradiol   Dienogest       757   C20   Ethinyl estradiol   Dienogest       758   C21   Ethinyl estradiol   Dienogest       759   C22   Ethinyl estradiol   Dienogest       760   C23   Ethinyl estradiol   Dienogest       761   C24   Ethinyl estradiol   Dienogest       762   C25   Ethinyl estradiol   Dienogest       763   C26   Ethinyl estradiol   Dienogest       764   C27   Ethinyl estradiol   Dienogest       765   C28   Ethinyl estradiol   Dienogest       766   C29   Ethinyl estradiol   Dienogest       767   C30   Ethinyl estradiol   Dienogest       768   C31   Ethinyl estradiol   Dienogest       769   C32   Ethinyl estradiol   Dienogest       770   C33   Ethinyl estradiol   Dienogest       771   C34   Ethinyl estradiol   Dienogest       772   C35   Ethinyl estradiol   Dienogest       773   C36   Ethinyl estradiol   Dienogest       774   C37   Ethinyl estradiol   Dienogest       775   C38   Ethinyl estradiol   Dienogest       776   C39   Ethinyl estradiol   Dienogest       777   C40   Ethinyl estradiol   Dienogest       778   C41   Ethinyl estradiol   Dienogest       779   C42   Ethinyl estradiol   Dienogest       780   C43   Ethinyl estradiol   Dienogest       781   C44   Ethinyl estradiol   Dienogest       782   C45   Ethinyl estradiol   Dienogest       783   C46   Ethinyl estradiol   Dienogest       784   C47   Ethinyl estradiol   Dienogest       785   C48   Ethinyl estradiol   Dienogest       786   C49   Ethinyl estradiol   Dienogest       787   C50   Ethinyl estradiol   Dienogest       788   C51   Ethinyl estradiol   Dienogest       789   C52   Ethinyl estradiol   Dienogest       790   C53   Ethinyl estradiol   Dienogest       791   C54   Ethinyl estradiol   Dienogest       792   C55   Ethinyl estradiol   Dienogest       793   C56   Ethinyl estradiol   Dienogest       794   C57   Ethinyl estradiol   Dienogest       795   C58   Ethinyl estradiol   Dienogest       796   C59   Ethinyl estradiol   Dienogest       797   C60   Ethinyl estradiol   Dienogest       798   C61   Ethinyl estradiol   Dienogest       799   C62   Ethinyl estradiol   Dienogest       800   C63   Ethinyl estradiol   Dienogest       801   C64   Ethinyl estradiol   Dienogest       802   C65   Ethinyl estradiol   Dienogest       803   C66   Ethinyl estradiol   Dienogest       804   C67   Ethinyl estradiol   Dienogest                  
 
     Biological Assays  
      The utility of the combinations of the present invention can be shown by the following assays. These assays are performed in vitro and in animal models essentially using procedures recognized to show the utility of the present invention.  
      Rat Carrageenan Foot Pad Edema Test  
      The carrageenan foot edema test is performed with materials, reagents and procedures essentially as described by Winter, et al., (Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley rats are selected in each group so that the average body weight is as close as possible. Rats are fasted with free access to water for over sixteen hours prior to the test. The rats are dosed orally (1 mL) with compounds suspended in vehicle containing 0.5% methylcellulose and 0.025% surfactant, or with vehicle alone. One hour later a subplantar injection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% saline is administered and the volume of the injected foot is measured with a displacement plethysmometer connected to a pressure transducer with a digital indicator. Three hours after the injection of the carrageenan, the volume of the foot is again measured. The average foot swelling in a group of drug-treated animals is compared with that of a group of placebo-treated animals and the percentage inhibition of edema is determined (Otterness and Bliven, Laboratory Models for Testing NSAIDS, in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)). The % inhibition shows the % decrease from control paw volume determined in this procedure.  
      Rat Carrageenan-Induced Analgesia Test  
      The analgesia test using rat carrageenan is performed with materials, reagents and procedures essentially as described by Hargreaves, et al., (Pain, 32, 77 (1988)). Male Sprague-Dawley rats are treated as previously described for the Carrageenan Foot Pad Edema test. Three hours after the injection of the carrageenan, the rats are placed in a special plexiglass container with a transparent floor having a high intensity lamp as a radiant heat source, positionable under the floor. After an initial twenty minute period, thermal stimulation is begun on either the injected foot or on the contralateral uninjected foot. A photoelectric cell turns off the lamp and timer when light is interrupted by paw withdrawal. The time until the rat withdraws its foot is then measured. The withdrawal latency in seconds is determined for the control and drug-treated groups, and percent inhibition of the hyperalgesic foot withdrawal determined.  
      Evaluation of COX-1 and COX-2 Activity In Vitro  
      The compounds of this invention exhibit inhibition in vitro of COX-2. The COX-2 inhibition activity of the compounds of this invention illustrated in the Examples is determined by the following methods.  
      a. Preparation of Recombinant COX Baculoviruses  
      A 2.0 kb fragment containing the coding region of either human or murine COX-1 or human or murine COX-2 is cloned into a BamH1 site of the baculovirus transfer vector pVL1393 (Invitrogen) to generate the baculovirus transfer vectors for COX-1 and COX-2 in a manner similar to the method of D. R. O&#39;Reilly et al (Baculovirus Expression Vectors: A Laboratory Manual (1992)). Recombinant baculoviruses are isolated by transfecting 4 μg of baculovirus transfer vector DNA into SF9 insect cells (2×10 eB) along with 200 ng of linearized baculovirus plasmid DNA by the calcium phosphate method. See M. D. Summers and G. E. Smith, A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agric. Exp. Station Bull. 1555 (1987). Recombinant viruses are purified by three rounds of plaque purification and high titer (10E7-10E8 pfu/ml) stocks of virus are prepared. For large scale production, SF9 insect cells are infected in 10 liter fermentors (0.5×10 6 /ml) with the recombinant baculovirus stock such that the multiplicity of infection is 0.1. After 72 hours the cells are centrifuged and the cell pellet homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). The homogenate is centrifuged at 10,000×G for 30 minutes, and the resultant supernatant is stored at −80° C. before being assayed for COX activity.  
      b. Assay for COX-1 and COX-2 Activity  
      COX activity is assayed as PGE2 formed/μg protein/time using an ELISA to detect the prostaglandin released. CHAPS-solubilized insect cell membranes containing the appropriate COX enzyme are incubated in a potassium phosphate buffer (50 mM, pH 8.0) containing epinephrine, phenol, and heme with the addition of arachidonic acid (10 μM). Compounds are pre-incubated with the enzyme for 10-20 minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme is stopped after ten minutes at 37° C./room temperature by transferring 40 μl of reaction mix into 160 μl ELISA buffer and 25 μM indomethacin. The PGE2 formed is measured by standard ELISA technology (Cayman Chemical).  
      The examples herein can be performed by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.  
      The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.