| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | April 2, 2002 |
| PATENT TITLE |
Naturally occurring compounds and their derivatives as cyclooxygenase 2 and/or 5-lipoxygenase inhibitors |
| PATENT ABSTRACT | This invention discloses methods for treating inflammation by inhibiting the production of pro-inflammatory metabolites via the cyclooxygenase and/or lipoxygenase pathways, comprising administering 4-cumylphenol or salts or solvates thereof |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | December 11, 1998 |
| PATENT REFERENCES CITED |
Hahn, Gary S., "CT-746 (Cosmoderm-7) A New Compound Class which Suppresses Neurogenic Inflammation and Sensory Irritation," Cosmoderm Technologies (Jan. 12, 1998). Hahn, Gary S., "Strontium is a Potent and Selective Inhibitor of Sensory Irritation," Cosmoderm Technologies (1997). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method of treating an inflammatory disease responsive to treatment with a non-steroidal anti-inflammatory agent, comprising: administration to a patient in need of such treatment of a therapeutically effective amount of 4-cumylphenol or its salts or solvates thereof and a pharmaceutically acceptable carrier. 2. The method of claim 1 in which the anti-inflammatory agent selectively inhibits cyclooxygenase-II. 3. The method of claim 2 in which the anti-inflammatory agent selectively inhibits cyclooxygenase-II in preference to cyclooxygenase-I. 4. The method of claim 3 in which the degree of inhibition is dependent on the concentration of the 4-cumylphenol or its salt or solvate thereof. 5. The method of claim 1 in which the therapeutically effective amount comprises a daily dose of 0.01 to 100 mg/kg of patient body weight. 6. The method of claim 5 in which the therapeutically effective amount comprises a daily dose of 1 to 20 mg/kg of patient body weight. 7. The method of claim 1 in which the therapeutically effective amount comprises a 0.075 to 30% w/w of a topical or cream. 8. A method of treating cyclooxygenase mediated diseases advantageously treated by an active agent that selectively inhibits cyclooxygenase-II in preference to cyclooxygenase-I, comprising: administering to a patient in need of such treatment a therapeutically effective amount of 4-cumylphenol or its salts or solvates thereof with or without a pharmaceutically acceptable carrier. 9. The method of claim 8 in which the degree of inhibition is dependent on the concentration of the 4-cumylphenol or its salt or solvate thereof. 10. The method of claim 8 in which the therapeutically effective amount comprises a daily dose of 0.01 to 100 mg/kg of patient body weight. 11. The method of claim 10 in which the therapeutically effective amount comprises a daily dose of 1 to 20 mg/kg of patient body weight. 12. The method of claim 8 in which the therapeutically effective amount comprises a 0.075 to 30% w/w of a topical or cream. 13. A method of treating inflammation in a patient for which non-steidal anti-inflammatory drugs may be contra-indicated, comprising: administration to a patient in need of such treatment of a therapeutically effective amount of 4-cumylphenol or its salts or solvates thereof and a pharmaceutically acceptable carrier. 14. The method of claim 13 in which the anti-inflammatory agent selectively inhibits cyclooxygenase-II. 15. The method of claim 13 in which the anti-inflammatory agent selectively inhibits cyclooxygenase-II in preference to cyclooxygenase-I. 16. The method of claim 15 in which the degree of inhibition is dependent on the concentration of the 4-cumylphenol or its salt or solvate thereof. 17. The method of claim 13 in which the therapeutically effective amount comprises a daily dose of 0.01 to 100 mg/kg of patient body weight. 18. The method of claim 17 in which the therapeutically effective amount comprises a daily dose of 1 to 20 mg/kg of patient body weight. 19. The method of claim 13 in which the therapeutically effective amount comprises a 0.075 to 30% w/w of a topical or cream. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
TECHNICAL FIELD This invention relates to anti-inflammatory pharmaceutical agents and, in particular, to novel compounds isolated from a natural source for the treatment of human and animal inflammatory disorders mediated by cyclooxygenase-2 (COX II) and/or 5-lipoxygenase (5-LO). BACKGROUND OF THE INVENTION The process of inflammation entails a complex series of cellular and biochemical mechanisms orchestrated in such a manner so as to protect an organism from injury and pathogens. An inflammatory response is characterized by vasodialation, pain, swelling (edema), fever, the release of fluid transudate, and the infiltration of inflammatory cell types into inflamed tissues. Inflammation can be elicited by assorted types of insults and pathological states including acute injury (i.e., lacerations, abrasions), allergic reactions such as asthma, allergic rhinitis, and, allergic skin diseases, and immunological diseases such as rheumatoid arthritis, and some neurodegenerative disorders such as Alzheimer's disease. Prostaglandins (derived from eicosanoic essential fatty acids) are produced during an inflammatory response by inflammation-related biochemical pathways and are responsible for mediating the clinical manifestations characteristic of inflammation. In addition to mediating inflammation, there is some evidence that prostaglandins are involved in mediating the proliferative capacity of some cancerous cell types (Planchon, P., Veber, N., Magnien, V., Prevost, G., Starzec, A. B., and Israel, L., (1995), Life Sciences, v57, p1233). The major source for the production of inflammation-related prostaglandins is arachidonic acid. In addition, metabolites of linoleic or eicosapentaenoic acid and other related fatty acids present in dietary constituents, or found in other sources, are potential mediators of inflammation. The prostaglandins, thromboxanes, hydroxyeicosatetraenoic acids and other metabolites derived from linoeic, eicosapentaenoic, and other fatty acids can also, in principle, participate in pro-inflammatory processes (Sinclair, H. M. (1980) "Drugs Affecting Lipid Metabolism" (Elsevien/North-Holland, Amsterdam)). Arachidonic acid (AA) can be metabolized by one of two cyclooxygenases (COX I or COX II) producing inflammatory metabolites such as prostaglandin E.sub.2 (PGE.sub.2), PGI.sub.2, PGF.sub.2 -alpha, and thromboxane (TBX). The increased production of pro-inflammatory metabolites such as PGE.sub.2 in inflamed tissues is due to the specific upregulation of COX II (Maier, J. A. M., Hla, T., Macaig, T. J., (1990), J. Biol. Chem., v265, p10805). The increased expression of COX II during an inflammatory response is believed to be induced (in part) by exposure to bacterial endotoxins and/or the release of pro-inflammatory cytokines (Isakson, P. C., (1995), Med. Chem. Res., v5, p344; Raz, A., Wyche, A., and Needleman, P., (1989), P.N.A.S., v86, p1657; O'Sullivan, M. G., Chilton, F. H., Huggins, E. M., McCall. E., (1992), J. Biol. Chem., v267, p14547), although other materials may increase expression of COX II as well. In contrast, COX I is constituitively expressed in most tissues and has been proposed to be involved in the maintenance of physiological functions such as platelet aggregation, cytoprotection in the stomach, and in part, the regulation of normal kidney function (Prasit, P., Black, C. C., Chan, A. W., Ford-Hutchinson, J. Y., Gauthier, R., Gordon, D., Guay, S., Kargman, C. K., Lau, C. S., Li, J., Mancini, N., Quimet, P., Roy, P., Tagari, P., Vickers, E., Wong, R. N., Young, and R. Zamboni., (1995), Med. Chem. Res., v5, p364; Pinto, D. J., Pitts, W. J., Copeland, R. A., Covington, M. B., Trzaskos, J., Magolda, R., (1995), Med. Chem. Res., v5, p394; Whittle, B. J. R., Higgs, G. A., Eakins, K. E., Moncada, S., and Vane, J. R., (1980), Nature, v284, p271). Cloning of the human COX II gene has permitted a comparison between the two enzymes at the molecular level and has revealed a cassette of 18 amino acids near the C terminus of COX II that are absent in COX I (DeWitt, D. L., Bhattacharyya, D., Lecomte, M., and Smith, W. L., (1995), Med. Chem. Res., v5, p325). The differential expression of COX I versus COX II combined with differences at the molecular level suggests the possibility that compounds capable of binding to and inhibiting COX II, but not COX I could be developed. In addition to the production of pro-inflammatory eicosanoid metabolites via the cyclooxygenase pathways, AA also serves as the source for the production of another class of inflammation-related metaboliotes produced by a family of related enzymes called lipoxygenases (5-, 12- or 15-LO). In particular, 5-LO catalyzes the first step of a biochemical cascade that culminates in the biosynthesis of a class of molecules termed leukotrienes (LT) such as LTA.sub.4, -B.sub.4, -C.sub.4, and -D.sub.4 (Sirois, P., Pharmacology of the Leukotrienes, Advances in Lipid Research, R. Paoletti, D. Kritchevesky, editors, Academic Press, 21: 79, 1985). Leukotrienes have been implicated as important mediators of inflammatory responses, such as anaphylaxis, suggesting that potent inhibitors of 5-LO would provide an approach to limit the deleterious effects of all the products of this pathway. Elevated 15-LO activity has been associated with conditions such as asthma and hypereosinophilia. Selective inhibition of 5-, 12-, or 15- LO may provide an agent with a definite therapeutic advantage. Non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin are among the most frequently used drugs currently available. Originally, the medicinal utility of classical NSAIDS was suspected to be due to their ability to inhibit the activities of COX I (Mitchell, J. A., Akarasereenont, P., Thiemermann, C., Flower, R., Vane, J. R., P.N.A.S., (1993), v90, p11693; Meade, E. A., Smith, W. L., DeWitt, D. L., (1993), J. Biol. Chem., v268, p6610). Today, it is recognized that NSAIDS also have anti-inflammatory activity due to inhibition of COX II as well. Other biochemical activities associated with NSAIDS include inhibition of inflammatory mediators other than those mentioned above (i. e. histamine, serotonin, kinins), inhibition of oxidative phosphorylation, displacement of anti-inflammatory peptides from serum albumin, or displacement of peptides that hyperpolarize neuronal membranes in inflamed tissue (Foye, W. O. (1989) "Principles of Medicinal Chemistry" (Lea and Febiger/London)). However, inhibition of the constituitively expressed COX I by chronic use of NSAIDS leads to major side effects including the development of gastric ulceration and nephrotoxicity (DeWitt, D. L., Bhattacharyya, D., Lecomte, M., and Smith, W. L., (1995), Med. Chem. Res., v5, p325). Therefore, development of an agent that selectively inhibits COX II would be useful to avoid the toxicities associated with COX I inhibition. The structure-activity relationship of potential inhibitors can be manipulated to produce such a desired selective effect. Modifications of some NSAIDS have also been made to increase therapeutic activity and decrease toxicity. For example, NSAIDS prodrugs such as sulindac have reduced toxicity, have improved half life, and have better solubility characteristics than the parent-type compound indomethacin. Prodrug inhibitors of mediators of inflammation may possess significantly improved pharmacological and pharmaceutical properties. The key roles played by the AA metabolites produced by COX II and 5-, 12-, 15-LO in mediating inflammatory responses has prompted extensive research to identify compounds capable of specifically inhibiting the enzymatic activities of COX II, 5-, 12-, 15-LO, or more than one simultaneously (i.e., dual inhibitors). Compounds capable of inhibiting COX II (but not COX I) and/or 5-LO would be of great use as anti-inflammatory agents without the ensuing deleterious side effects common to most non-steroidal anti-inflammatory drugs. Alternatively, compounds inhibiting release of arachidonic acid or other fatty acids or compounds antagonizing proinflammatory cytokines would be of potential therapeutic use. Such inhibitory compounds would have great clinical utility in the treatment of such conditions as pain, fever, asthma, allergic rhinitis, rheumatoid arthritis, osteoarthritis, gout, adult respiratory disease syndrome, inflammatory bowel disease, endotoxic shock, ischemia-induced myocardial injury, atherosclerosis, and brain damage caused by stroke. Such inhibitors could also be used topically for the treatment of acne, sunburn, psoriasis, eczema, and related conditions. SUMMARY OF THE INVENTION This invention relates to a composition and method for treating inflammation by inhibiting the production of pro-inflammatory metabolites via the cyclooxygenase and/or lipoxygenase pathways. More specifically, this invention relates to the treatment of inflammation and inflammation related disorders through the use of compounds (and derivatives thereof) identified from a natural source. Numerous compounds with anti-inflammatory activity have been chemically synthesized (T. Y. Shen, J. Med. Chem., 24 1, 1981) but very few anti-inflammatory agents have been isolated from various natural product sources. Although an agent such as indomethacin can trace its route of development from observations concerning abnormal human indole metabolism, the vast number of salicylic, anilino, anthranilic acid, benzothiozines, and gold compounds find their origins from synthetic medicinal chemistry. In contrast, fewer anti-inflammation agents have been discovered from natural product searches. The source, from which compounds of the invention were identified, is a natural peat bog located in south-central Washington state containing compounds derived from plant, animal, marine, and microbial sources. In addition, the peat bog environment is conducive to microbial processing of compounds originating from plant and animal sources producing a highly variable and heterogeneous mixture of potentially biologically active molecules. Additional objects and advantages of this invention will be apparent from the following detailed description of preferred embodiments thereof which proceeds with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a structural formula showing rigid analogs of arylbutyric acid esters. FIG. 2 is a structural formula showing aralkyl or heteroaralkyl phenols. FIG. 2A is a partial structural formula showing a trisubstituted carbon that may be utilized in up to three of the groups K, L, M, N, or X in the structural formula of FIG. 2. FIG. 3A is a structural formula showing anilinamide phenolic ether compounds. FIGS. 3B-3Q are structural formulas showing additional examples of anilinamide phenolic ether compounds. FIG. 3R is a structural formula showing a preferred example of an anilinamide phenolic ether compound. FIG. 4 is a reaction diagram showing the synthesis of dehydroabietic acid methyl ester (DAAME). FIG. 5 is an NMR trace of synthesized DAAME. FIG. 6 diagrammatically depicts the initial chemical fractionation sequence of peat material. FIG. 7 is a chromatograph of fraction X-8-1-5-5 showing the DAAME 16.98 minute peak. FIG. 8 is a mass spectrum of the 16.98 minute peak fraction shown in the chromatograph of FIG. 7. FIG. 9 is a mass spectrum of DAAME, taken from the NIST Library of mass spectra, that matches the mass spectrum of FIG. 8. FIG. 10 graphically presents the results of an assay showing the inhibition of human keritinocyte PGE.sub.2 production by DAAME. FIG. 11 graphically presents the results of an assay showing the inhibition of human keratinocyte LTB.sub.4 production by DAAME. FIG. 12 graphically presents the results of an assay showing the lack of toxicity in cultures of human keratinocytes treated with DAAME. FIG. 13 is a chromatograph of fraction X-8-1-5-5 showing the peaks identified as aralkylphenols and heteroalkylphenols. FIG. 14 is a chromatograph of fraction X-8-5-1-6-2 showing the peaks identified as aralkylphenols and heteroalkylphenols. FIG. 15 is a mass spectrum from the NIST Library showing 2,4-Bis(dimethylbenzyl)-6-tert-butyphenol. FIG. 16 is a mass spectrum, taken from the NIST Library, showing 4-dimethylbenzyl-2-tert-butyphenol. FIG. 17 is a mass spectrum, taken from the NIST Library, showing 2-dimethylbenzylphenol. FIG. 18 is a mass spectrum, taken from the NIST Library, showing 2,4-Bis(dimethylbeiizyl) phenol. FIG. 19 is a NMR trace of fraction W-1-6 showing 4-cumylphenol. FIG. 20 is a mass spectrum, taken from the NIST Library, showing 4-cumylphenol. FIG. 21 graphically presents the results of an assay showing the inhibition of human keratinocyte PGE.sub.2 production by 4-cumylphenol. FIG. 22 graphically presents the results of an assay showing the lack of toxicity in cultures of human keratinocytes treated with 4-cumylphenol. FIG. 23A is a chromatograph of fraction X-6-2-3 showing the 19.825 minute peak of 3-methoxy aniline (3-M-A). FIG. 23B is a mass spectrum showing 3-M-A. FIG. 23C is a mass spectrum of 3-M-A, taken from the NIST Library, that matches the mass spectrum of FIG. 23B. FIG. 24 graphically presents the results of an assay showing the inhibition of human keratinocyte PGE.sub.2 production by 3-M-A. FIG. 25 graphically presents the results of an assay showing the lack of toxicity in cultures of human keratinocytes treated with 3-M-A. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Section I) Section I describes rigid analogs of aryl butyric acid esters represented by formula I presented in FIG. 1 and the pharmaceutically acceptable salts thereof, wherein A and B constitute part of a 5- or 6- member ring system from aromatic or partially unsaturated or unsaturated heterocyclic and carbocyclic rings wherein A and/or B is optionally substituted with hydrido, acyl, halo, lower acyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, amino, lower alkoxy, amino carbonyl, lower alkoxycarbonyl, alkyl amino, aryl amino, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, alkylthio, alkyl sulfinyl and aryl, lower aralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower N-arylaminosulfonyl, lower arylsulfonyl, lower N-alkyl-N-arylaminosulfonyl; wherein aryl is selected from phenyl, biphenyl, and naphthyl, and 5- and 6-membered heteroaryl, wherein aryl is optionally substituted with one or two substituents selected from halo, hydroxyl, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, lower haloalkyl, lower alkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl, lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, lower carbonylalkoxy; wherein the carboxylic group is optionally substituted with a substituent selected from hydrido, alkyl, halo, and alkoxy. A preferred class of compounds includes compounds of formula I wherein the A, B ring system is a radical selected from thienyl, oxazolyl, furyl, pyrolyl, thiazolyl, imidazolyl, isthiazolyl, isoxazoly, pyrazolyl, cyclopentyl, phenyl, and pyridyl; wherein X and Z are selected from hydrido, acyl, halo, lower acyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, amino, lower alkoxy, amino carbonyl, lower alkoxycarbonyl, alkyl amino, aryl amino, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, alkylthio, alkyl sulfinyl and aryl, lower aralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower N-arylaminosulfonyl, lower arylsulfonyl, lower N-alkyl-N-arylaminosulfonyl; wherein Ar is selected from phenyl, biphenyl, and naphthyl, and 5- and 6-membered heteroaryl, wherein Ar is optionally substituted with one or two substituents selected from halo, hydroxyl, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, lower haloalkyl, lower alkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl, lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, and lower carbonylalkoxy; wherein P, Q, and Y are selected from hydrido, acyl, halo, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, amino, lower alkoxy, amino carbonyl, lower alkoxycarbonyl, alkyl amino, aryl amino, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, alkylthio, alkyl sulfinyl and aryl, lower aralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower N-arylaminosulfonyl, lower arylsulfonyl, lower N-alkyl-N-arylaminosulfonyl; wherein Ar is selected from phenyl, biphenyl, and naphthyl, and 5- and 6-membered heteroaryl, wherein A.r is optionally substituted with one or two substituents selected from halo, hydroxyl, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, lower haloalkyl, lower alkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl, lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, and lower carbonylalkoxy; wherein R is selected from hydrido, acyl, halo, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, amino, lower alkoxy, amino carbonyl, lower alkoxycarbonyl, alkyl amino, aryl amino, lower carboxyalkyl, lower cyanoalkyl, lower hydroxyalkyl, alkylthio, alkyl sulfinyl and aryl, lower aralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower N-arylaminosulfonyl, lower arylsulfonyl, lower N-alkyl-N-arylaminosulfonyl; wherein Ar is selected from phenyl, biphenyl, and naphthyl, and 5- and 6-membered heteroaryl, wherein Ar is optionally substituted with one or two substituents selected from halo, hydroxyl, amino, nitro, cyano, carbamoyl, lower alkyl, lower alkenyloxy, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, lower haloalkyl, lower alkoxycarbonyl, lower N-alkylcarbamoyl, lower N,N-dialkylcarbamoyl, lower alkanoylamino, lower cyanoalkoxy, lower carbamoylalkoxy, lower carbonylalkoxy; wherein E is selected from lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower hydroalkyloxy, lower hydroalkyoxyalkyl, lower oximinoalkoxy, lower oximinoalkyloxyalkyl, lower carbonylalkyloxy, lower (alkyl)oximinoalkoxy, lower (alkyl)oximinoalkoxyalkyl, lower carbonylalkyloxyalkyl, lower hydroxyalkylthio, lower hydroxyalkylthioalkyl, lower (alkyl)oximinoalkylthio, lower (alkyl)oximinoalkylthio, lower carbonylalkylthio, lower carbonylalkylthioalkyl, lower alkylthio, lower alkylcarbonyl, lower cycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, lower cycloalkyl, lower aralkyl, lower heterocycloalkyl, lower aklynylthio, lower alkenyloxy, lower alkynyloxy, lower alkenoxyalkyl, lower alkynyloxyalkyl, phenylcarbonyl, lower aralkylcarbonyl, lower alkylaminocarbonylalkyl, lower N-alkylaminocarbonyl, N-phenylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower heterocycloaminocarbonyl, and lower alkylcarbonylalkyl. The term "hydrido" denotes a single hydrogen atom (H). When used, either alone or in conjunction within other terms such as "haloalkyl", "sulfonyl", etc., the term "alkyl" embraces linear or branched radicals having one to about twenty carbon atoms. Examples of such radicals include methyl, ethyl n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, and the like. The term "alkenyl" embraces linear or branched radicals, having at least one carbon to carbon double bond, of two to about twenty carbon atoms. The term "lower alkynyl" embraces radicals having two to about twenty carbon atoms. The terms "alkenyl" embrace radicals having cis and trans orientations, or alternatively, "E" and "Z" orientations. Preferred cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "cycloalkenyl" includes partially unsaturated carbocyclic radicals having three to twelve carbon atoms. The term "halo" means halogens such as fluorine, chlorine, bromine, or iodine. The term "haloalkyl" means one or more alkyl carbon atoms is substituted with a halogen atom. "Lower haloalkyl" means radicals having one to ten carbon atoms. The term "hydroxyalkyl" means linear or branched alkyl radicals substituted with one or more hydroxyl radicals. The term "alkoxy" and "alkyloxy" embraces linear or branched oxygen-containing radicals having alkyl moieties of between one and twenty carbon atoms. The term "hydroxyalkyl" includes linear or branched alkyl radicals having one to about twenty carbon atoms any one of which may be substituted with a hydroxyl group. The term cyanoalkyl includes linear or branched alkyl radicals having one to about twenty carbon atoms any one of which could be substituted with one or more cyano groups. The term alkoxyalkyl includes alkyl groups having one or more alkoxy radicals attached to the alkyl group. The alkoxy radical may be further substituted with one or more halo atoms. Preferred haloalkoxy groups may one to twenty carbons. The term alkenyloxy includes radicals having alkenyl moieties of two to twenty carbon atoms attached to an oxygen atom. Alkenyloxy radicals having two to twenty carbon atoms attached to an oxygen atom may be substituted with one or more alkenyl groups. The term "aryl" includes, but is not limited to, a carboxylic aromatic ring system having one, two, or three rings attached together in a pendent arrangement or as a fused system. The term "aryl" includes phenyl, naphthyl, tetrahydronaphthyl, indone, biphenyl, and aryl moieties described above with substituents. The term "heterocyclo" includes saturated, partially unsaturated, and unsaturated heteroatoms containing 3 to 6 membered cyclic systems where heteroatoms are selected from oxygen, nitrogen, sulfur, and phosphorous. The term "heteroaryl" includes unsaturated heterocyclo radicals containing three to six membered heteromonocyclic groups where the heteroatoms are selected from oxygen, nitrogen, sulfur, and phosphorous. The term also includes radicals where heterocyclo groups are fused with aryl groups. The term "alkylthio" includes radicals containing linear or branched alkyl groups of one to about twenty carbon atoms attached to a divalent sulfur atom. The term "alkylthioalkyl" includes an alkylthio group attached to a alkyl radical of about one to twenty carbon atoms through a divalent sulfur atom. The term "oximinoalkoxy" includes alkoxy radicals having one to about twenty carbon atoms, any one of which may be substituted with an oximino radical. The term "alkenylthio" includes groups containing a linear or branched alkenyl radical of two to about twenty carbon atoms attached to a divalent sulfur atom. The term "alkynylthio" includes radicals containing a linear or branched alkynyl radical from two to about twenty carbon atoms attached to a divalent sulfur atom with an alkynyl moiety attached to on or more of the carbon atoms. The term "alkylsulfinyl" includes a radical containing a linear or branched alkyl group of one to about twenty carbon atoms, attached to a sulfinyl group. The term "sulfonyl" includes a --SO.sub.2 -- group attached to an alkyl of one to about twenty carbon atoms. The term "sulfamyl", "aminosulfonyl", and "sulfonamidyl" include the --SO.sub.2 NH.sub.2 radical attached to various alkyl or aryl functionalities. The term "aroyl" includes aryl radicals with a carbonyl group. The term "aminoalkyl" includes alkyl radicals from one to about twenty carbon atoms that are substituted with amino groups. The term "arylamino" includes amino groups substituted with one or more aryl radicals. The term "alkylamino" includes amino groups substituted with one or more alkyl groups with one to about twenty carbon atoms. When the above radicals are incorporated into the parent molecule, the present invention includes all possible stereochemical arrangements of the substituents. In addition, the optional agent includes racemic or stereochemically pure compounds. Section II) Section II describes "aralkyl" or "heteroaralkyl" phenols of the formula presented in FIG. 2 or pharmaceutically acceptable salts or solvates thereof wherein: (A) of the K, L, M, N and X; one, two, or three groups are optionally assigned as the trisubstituted carbon as in the partial structure shown in FIG. 2A; (1) wherein R.sub.1 is selected from; (i) "aryl" selected from phenyl, biphenyl, and naphthyl optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, --C(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (ii) "heteroaryl" (means heterocyclic aromatic) i.e. cyclic groups having at least one oxygen, sulfur, or nitrogen heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, said rings preferably containing from 2 to 14 carbon atoms, e.g, 2-, 3-, and 4-pyridyl, 2- and 3-furyl, 2- and 3-thienyl, 2-, 4-, and 5-thiazolyl, 2-, 4-, and 5-imidazolyl, 2-, 4-, and 5-pyrimidinyl, 2-pyrazinyl, 3- and 4-pyridazinyl, 3-, 5-, and 6-[1,2,4-triazinyl], 3- and 5-[1,2,4-thia-dizolyl], 2-, 3-, 4-, 5-, 6-, and 7-benzofuranyl, 2-, 3-, 4-, 5-, 6-, and 7-indolyl, 3-, 4-, and 5-pyrazolyl, 2-, 4-, and 5-oxazolyl etc., optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, --OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (2) wherein R.sub.2 and R.sub.3 are the same or different and are selected from; (i) branched or unbranched alkyl of one to eight carbon atoms; (ii) cycloalkyl ring (means saturated carbocyclic ring) having from 3 to 8 atoms; (iii) cycloalkenyl ring (cycloalkenyl means carbocyclic ring having from 3 to 8 carbon atoms and at least one carbon to carbon double bond in the ring); (iv) heterocyclic ring containing 2 to 6 carbon atoms, which may optionally contain at least one carbon to carbon double bond and which contains at least one heteroatom selected from nitrogen, oxygen, or sulfur; representative heterocycles include, but are not limited to: pyrrolidine, piperidine, piperazine, heptamethyleneimine, hexamethyleneimine, homopiperazine, perhydroindole, azetidine, 4-piperidinopiperidine, 1-azacycloheptane, perhydroisoquioline, decahydroquinoline, 1-phenylpiperazine, 4-phenylpiperidine, 1-(fluorophenyl)piperazine, 1,3,5-hexa-hydrotriazine, morpholine, phenylmorpholine, thiomorphline, tetrahydrothiophene, thiazolidine, .omega.-thiocaprolactam, 1,4-thioxane, 1,3-dithiane, 1,4,7-trithiacyclononane, 1,3,5-trithiane, tetrahydrofuran, tetramethyleneoxide, tetrahydropyran, 1,3,5-trioxane, oxepane, and the like, optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (v) substituted alkyl wherein the alkyl chain is from one to three carbon atoms and the substituent is selected from "aryl" selected from phenyl, biphenyl and naphthyl optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, --OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (vi) substituted alkyl wherein the alkyl chain is from one to three carbon atoms and the substituent is selected from "heteroaryl" (means heterocyclic aromatic) i.e. cyclic groups having at least one oxygen, sulfur, or nitrogen heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, said rings preferably containing from 2 to 14 carbon atoms, e.g, 2-, 3-, and 4-pyridyl, 2- and 3-furyl, 2- and 3-thienyl, 2-, 4and 5-thiazolyl, 2-, 4-, and 5-imidazolyl, 2-, 4-, and 5-pyrimidinyl, 2-pyrazinyl, 3- and 4-pyridazinyl, 3-, 5-, and 6-[1,2,4-triazinyl], 3- and 5-[1,2,4-thia-dizolyl], 2-, 3-, 4-, 5-, 6-, and 7-benzofuranyl, 2-, 3-, 4-, 5-, 6-, and 7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, and 5-oxazolyl etc., optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15 and --S(O).sub.2 NR.sub.16 R.sub.17 ; (3) R.sub.1 and R.sub.2 are methylene, methine, or quarternary carbons of: (i) cycloalkyl ring (means saturated carbocyclic ring) having from 3 to 8 atoms; (ii) cycloalkenyl ring (cycloalkenyl means carbocyclic ring having from 3 to 8 carbon atoms and at least one carbon to carbon double bond in the ring); (iii) heterocyclic ring containing 2 to 6 carbon atoms, which may optionally contain at least one carbon-carbon double bond and which contains at least one heteroatom selected from nitrogen, oxygen, or sulfur; representative heterocycles include, but are not limited to: pyrrolidine, piperidine, piperazine, heptamethyleneimine, hexamethyleneimine, homopiperazine, perhydroindole, azetidine, 4-piperidinopiperidine, 1-azacycloheptane, perhydroisoquioline, decahydroquinoline, 1-phenylpiperazine, 4-phenylpiperidine, 1-(fluorophenyl)piperazine, 1,3,5-hexa-hydrotriazine, morpholine, phenylmorpholine, thiomorphline, tetrahydrothiophene, thiazolidine, .omega.-thiocaprolactam, 1,4-thioxane, 1,3-dithiane, 1,4,7-trithiacyclononane, 1,3,5-trithiane, tetrahydrofuran, tetramethyleneoxide, tetrahydropyran, 1,3,5-trioxane, oxepane and the like, optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (B) of the K, L, M, N, and X not assigned as above are selected: (1) wherein K, L, M, N, and X are the same or different and are selected from; (i) H, Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (ii) "aryl" selected from phenyl, biphenyl, and naphthyl optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, --OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (iii) "heteroaryl" (means heterocyclic aromatic) i.e. cyclic groups having at least one O, S, N heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, said rings preferably containing from 2 to 14 carbon atoms, e.g., 2-, 3- and 4-pyridyl, 2- and 3-furyl, 2- and 3-thienyl, 2-, 4-, and 5-thiazolyl, 2-, 4-, and 5-imidazolyl 2-, 4- and 5-pyrimidinyl, 2-pyrazinyl, 3- and 4-pyridazinyl, 3-, 5-, and 6-[1,2,4-triazinyl], 3- and 5-[1,2,4-thiadizolyl], 2-, 3-, 4-, 5-, 6-, and 7-benzofuranyl, 2-, 3-, 4-, 5-, 6-, and 7- indolyl, 3-, 4-, and 5-pyrazolyl, 2-, 4-, and 5-oxazolyl etc., optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, -OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (C) Certain compounds of this invention may exist in isomeric forms. The invention contemplates all such isomers both in pure form and admixture, including racemic mixtures. (D) Certain compounds of the invention with carboxylic acid functional group or phenolic hydroxyl group may form pharmaceutically acceptable metal and amine salts. Examples of such metal salts are the sodium, potassium, calcium, aluminum, gold, and silver salts. Examples of such amine salts are formed with pharmaceutically acceptable amines such as ammonia, hydroxyalk ylamines, N-methylgiucamine, and the like. All such salts and free carboxylic acids and phenolic compounds are contemplated in this invention. (E) Certain compounds of the invention e.g., those with a basic primary, secondary, or tertiary amine functional group, also form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and other suitable mineral and carboxylic acids. Amine salts and free base forms of amines are contemplated in this invention. (F) Certain compounds of this invention may exist in unsolvated as well as solvated forms, including hydrated forms. This invention contemplates both unsolvated forms and solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like. (G) One most preferred compound of this invention is represented by the formula presented in FIG. 3; (H) "aralkyl" means alkyl group, in which one of the hydrogen atoms is substituted with an "aryl" selected from phenyl, biphenyl, and naphthyl optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, --OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (I) "Heteroaralkyl" means alkyl group in which one of the hydrogen atoms is substituted with a "heteroaryl" (means heterocyclic aromatic) i.e. cyclic groups having at least one O, S, N heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, said rings preferably containing from 2 to 14 carbon atoms, e.g, 2-, 3- and 4-pyridyl, 2- and 3-furyl, 2- and 3-thienyl, 2-, 4-, and 5-thiazolyl, 2-, 4-, and 5-imidazolyl, 2-, 4- and 5-pyrimidinyl, 2-pyrazinyl, 3- and 4-pyridazinyl, 3-, 5- and 6-[1,2,4-triazinyl], 3- and 5-[1,2,4-thiadizolyl], 2-, 3-, 4-, 5-, 6-, and 7-benzofuranyl, 2-, 3-, 4-, 5-, 6-, and 7-indolyl, 3-, 4-, and 5-pyrazolyl, 2-, 4-, and 5-oxazolyl etc., optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.4, --R.sub.5, --OC(O)R.sub.6, -OC(O)NR.sub.7 R.sub.8, --C(O)R.sub.9, --CN, --NR.sub.10 R.sub.11, --SR.sub.12, --S(O)R.sub.13, --S(O).sub.2 R.sub.14, --C(O)OR.sub.15, and --S(O).sub.2 NR.sub.16 R.sub.17 ; (J) C) R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, and R.sub.17 are the same or different and are branched or unbranched alkyl groups from one to eight carbon atoms or hydrogen radicals. The compounds presented in sections I and II above can be useful for, but not limited to, the treatment of inflammation related disorders, such as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of a fever. For example, such compounds can be useful to treat various forms of arthritis, asthma, bronchitis, cancer, menstrual cramps, tendinitis, bursitis, psoriasis, eczema, burns, and dermatitis. In addition, such compounds can also be useful to treat inflammation in diseases such as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, sarciodosis, mayasthenia gravis, gingivitis, polymyositis, nephrotic syndrome, hypersensitivity, and swelling occurring after injury, and the like. These compounds can also be useful to treat neurodegenerative diseases associated with inflammation such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. As a dual COX II/5-lipoxygenase inhibitor, the compounds detailed in section I (rigid analogs of aryl butyric acid esters) can be useful for the treatment of endotoxic shock syndrome, allergic rhinitis, respiratory distress syndrome, atherosclerosis, and central nervous system damage caused by stroke. Section III) Section III describes anilinamide phenolic ether compounds represented by the formula in FIG. 3A and by the example structural formulas presented in FIGS. 3B-3Q or pharmaceutically acceptable salts or solvates thereof (1) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are optionally selected from; (i) "aryl" selected from phenyl, biphenyl and naphthyl optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.8, --R.sub.9, --OC(O)R.sub.10, --OC(O)NR.sub.11 R.sub.12, --C(O)R.sub.13, --CN, -NR.sub.14 R.sub.15, --SR.sub.16, -S(O)R.sub.17, --S(O).sub.2 R.sub.18, --C(O)OR.sub.19, and --S(O).sub.2 NR.sub.20 R.sub.21 ; (ii) "heteroaryl" (means heterocyclic aromatic) i.e. cyclic groups having at least one oxygen, sulfur, or nitrogen heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, said rings preferably containing from 2 to 14 carbon atoms, e.g, 2-, 3- and 4-pyridyl, 2- and 3-furyl, 2- and 3-thienyl, 2-, 4-, and 5-thiazolyl, 2-, 4-, and 5-imidazolyl, 2-, 4-, and 5-pyrimidinyl, 2-pyrazinyl, 3- and 4-pyridazinyl, 3-, 5- and 6-[1,2,4-triazinyl], 3- and 5-[1,2,4-thia-dizolyl], 2-, 3-, 4-, 5-, 6-, and 7-benzofuranyl, 2-, 3-, 4-, 5-, 6-, and 7-indolyl, 3-, 4-, and 5-pyrazolyl, 2-, 4-, and 5-oxazolyl etc., optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.8, --R.sub.9, --OC(O)R.sub.10, OC(O)NR.sub.11 R.sub.12, --C(O)R.sub.13, --CN, --NR.sub.14 R.sub.15, --SR.sub.16, --S(O)R.sub.17, --S(O).sub.2 R.sub.18, --C(O)OR.sub.19, and --S(O).sub.2 NR.sub.20 R.sub.21 ; (iii) branched or unbranched alkyl chain of one to five carbon atoms; (iv) substituted alkyl wherein the alkyl chain is from one to three carbon atoms and the substituent is selected from "aryl" selected from phenyl, biphenyl, and naphthyl optionally having one or two ring hydrogens substituted with substituents selected from Cl, Br, I, --OR.sub.8, --R.sub.9, --OC(O)R.sub.10, --OC(O)NR.sub.11 R.sub.12, --C(O)R.sub.13, --CN, --NR.sub.14 R.sub.15, --SR.sub.16, --S(O)R.sub.17, --S(O).sub.2 R.sub.18, --C(O)OR,.sub.19, and --S(O).sub.2 NR.sub.20 R.sub.21 ; (v) substituted alkyl wherein the alkyl chain is from one to three carbon atoms and the substituent is selected from "heteroaryl" (means heterocyclic aromatic) i.e. cyclic groups having at least one oxygen, sulfur, or nitrogen heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, said rings preferably containing from 2 to 14 carbon atoms, e.g, 2-, 3- and 4-pyridyl, 2- and 3-furyl, 2- and 3-thienyl, 2-, 4-, and 5-thiazolyl, 2-, 4-, and 5-imidazolyl, 2-, 4-, and 5-pyrimidinyl, 2-pyrazinyl, 3- and 4-pyridazinyl, 3-, 5-, and 6-[1,2,4-triazinyl], 3- and 5-[1,2,4-thia-dizolyl], 2-, 3-, 4-, 5-, 6-, and 7-benzofuranyl, 2-, 3-, 4-, 5-, 6-, and 7-indolyl, 3-, 4-, and 5-pyrazolyl, 2-, 4-, and 5-oxazolyl etc., optionally having on --OC(O)R.sub.10, --OC(O)NR.sub.11 R.sub.12, --C(O)R.sub.13, --CN, --NR.sub.14 R.sub.15, --SR.sub.16, --S(O)R.sub.17, --S(O).sub.2 R.sub.18, --C(O)OR.sub.19, and --S(O).sub.2 NR.sub.20 R.sub.21 ; (2) The substituents R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 may also be optionally selected as hydrogen; (3) The substituents R.sub.4 and R.sub.5 may be optionally be substituted as Cl, Br, I, --OR.sub.8, --R.sub.9, --OC(O)R.sub.10, --OC(O)NR.sub.11 R.sub.12, --C(O)R.sub.13, --CN, --NR.sub.14 R.sub.15, --SR.sub.16, --S(O)R.sub.17, --S(O).sub.2 R.sub.18, --C(O)OR.sub.19, and --S(O).sub.2 NR.sub.20 R.sub.21 ; (4) The ring substituents A, B, C, and D are optionally selected from CH.sub.2, O, S, NH; (5) R.sub.8, R.sub.9, R.sub.6, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are the same or different and are branched or unbranched alkyl groups from one to eight carbon atoms. (6) The most preferred formula is shown in FIG. 3R. (C) Certain compounds of this invention may exist in isomeric forms. The invention contemplates all such isomers both in pure form and admixture, including racemic mixtures. (D) Certain compounds of the invention with carboxylic acid functional group or phenolic hydroxyl group may form pharmaceutically acceptable metal and amine salts. Examples of such metal salts are the sodium, potassium, calcium, aluminum, gold, and silver salts. Examples of such amine salts are formed with pharmaceutically acceptable amines such as ammonia, hydroxyalkylamines, N-methylglucamine, and the like. All such salts and free carboxylic acids and phenolic compounds are contemplated in this invention. (E) Certain compounds of the invention e.g., those with a basic primary, secondary or tertiary amine functional group, also form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and other suitable mineral and carboxylic acids. Amine salts and free base forms of amines are contemplated in this invention. (F) Certain compounds of this invention may exist in unsolvated as well as solvated forms, including hydrated forms. This invention contemplates both unsolvated forms and solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like. |
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