WO2006040676A1 - Nitrosated benzopyran compounds as novel cyclooxygenase-2 selective inhibitors - Google Patents

Abstract

This invention specifically relates to novel cyclooxygenase 2 (COX-2) selective inhibitor compounds that donate, transfer or release nitric oxide, stimulate endogenous synthesis of nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase. Compounds of particular interest and their analogs defined by formula (I) wherein Z, X, R1, R2, R3, and R4 are as described in the specification. This invention also relates to pharmaceutical compositions and methods for treating COX-2 mediated disorders, such as inflammation and inflammation related disorders.

Description

NITROSATED BENZOPYRAN COMPOUNDS AS NOVEL CYCLOOXYGENASE-2 SELECTIVE INHIBITORS Cross Reference to Related Applications

This application claims priority from U.S. Provisional Application Serial Number 60/618036, filed October 12, 2004, the disclosure of each of which is incorporated herein by reference in its_entirety.

Field

[0001] This invention is in the field of anti-inflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating cyclooxygenase-2 mediated disorders, such as inflammation and inflammation-related disorders.

Background

[0002] 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 antiinflammatory drug discovery. However, common non-steroidal antiinflammatory 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 NSAEDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSADOs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.

[0003] 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 discovery of an inducible enzyme associated with inflammation (named "cyclooxygenase-2" or "COX-2") provides a viable target of inhibition which effectively reduces inflammation and produces fewer and less drastic side effects. [0004] Nitric oxide (NO) is a major paracrine signaling molecule in the nervous, immune, and circulatory systems. NO is produced by endothelial cells and is involved in the regulation of vascular tone, platelet aggregation, neurotransmission and immune activation. Nitric oxide is an important mediator of relaxation of vascular smooth muscle. Nitric oxide is synthesized by the oxidative deamination of a guanidino nitrogen of L-arginine by at least three different isoforms of a flavin-containing enzyme, nitric oxide synthase (NOS). Nitric oxide elevates levels of cGMP (1,4,5-cyclic guanosine monophosphate) within vascular smooth muscle to produce relaxation and to reduce blood vessel tone. Nitric oxide binds to heme and thus activates soluble guanylate cyclase resulting in an increase in cellular cGMP. cGMP activates a cGMP-dependent kinase (PKG), which mediates the vasorelaxant effects of NO by phosphorylating several proteins that regulate intracellular Ca ⁺ levels, effectively reducing cytoplasmic calcium concentration, resulting in vasorelaxation. See Soff, G.A., et al, J. dim. Invest. 700:2580-7 (1997).

[0005] The role that NO plays in the inflammatory response is less well understood. While it is evident that NO production frequently accompanies inflammatory states, it is unclear whether NO promotes, inhibits, or has no effect on the inflammatory process. One mechanism by which NO may influence the progression of the inflammatory process is through its interaction with the NF-κB family of transcription factors. NF-κB regulates the expression of many inducible inflammatory genes, including pro-inflammatory cytokines and endothelial cell adhesion molecules (ECAMs). See Ghosh, S., et al, Annu. Rev. Immunol. 16:225-60 (1998).

[0006] Given the fact that NO plays a role in such a variety of important bioregulatory processes, great effort has been expended to develop compounds capable of releasing NO. Some of these compounds are capable of releasing NO spontaneously, for example, by hydrolysis in aqueous media, whereas others are capable of releasing NO only upon being metabolized. See Lefer et al., Drugs Future 19:665-612 (1994). [0007] It has long been recognized that nitrovasodilators, such as nitro-prusside and nitroglycerin, inhibit vascular smooth muscle contractility to produce relaxation or to reduce vascular tone. These agents have been used since the late 1980s as vasodilators. However, only recently has the mechanism of action of these compounds been realized. Nitrovasodilators are now classified as nitric oxide donors because they are metabolized to, or spontaneously release, nitric oxide. [0008] There is little known about the effects of NO on COX-2 inhibitor-mediated anti¬ inflammatory actions. Various nitrosated and nitrosylated COX-2 inhibitors have been described:

[0009] US patent No. 6,593,347 to Bandarage et al., describes nitrosated and nitrosylated COX-2 inhibitors.

_[0010]_ LJS_patent_No. 6,649,629 to Bandarage et al., describes nitrosated and nitrosylated COX-2 inhibitors.

[0011] WO 2004/010945 to Garvey et al., describes nitrosated and nitrosylated COX-2 inhibitors.

[0012] US patent NO. 6,706,724 to Khanapure et al., describes COX-2 inhibitors in combination with a compound that donates nitric oxide.

[0013] While it is widely recognized that COX-2 selective inhibitors are useful in the treatment of inflammation, the effect of a combination of a COX-2 inhibitor and an NO- donating agent on inflammation and inflammation-related disorders is not known. [0014] Although novel therapeutics, such as COX-2 selective inhibitors, have been useful as anti-inflammatory agents, there still exists a need for more effective therapies for the prevention and treatment of pain, inflammation, and inflammation-related disorders.

BRIEF DESCRIPTION

[0015] Briefly, therefore, the present invention is directed to novel compounds that are COX-2 selective inhibitors that donate nitric oxide. These compounds can be nitrosated or nitrosylated. The present compounds can be both nitrosated and nitrosylated. These compounds are analgesics, have anti-inflammatory properties and have a potential for facilitating wound healing.

[0016] Among its many embodiments the present invention provides a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of O and NH; Z is selected from the group consisting of O, S and NH; n is an integer from 1 to 5; R¹, R , R , and R⁴ are each independently selected from the group consisting of H, alkanoyl, alkenyl, alkenylalkynyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxyalkynyl, alkoxyaryl, alkoxyarylalkenyl, alkoxyarylalkyl, alkoxyarylalkynyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylaminoarylalkyl, alkoxyheteroaryl, alkyl, alkylamino, alkylaminoalkyl, alkylaminoalkynyl, alkyl aminoaryl alkyl, alkylaryl, alkylarylalkoxy, alkylarylalkyl, alkylarylalkynyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaminoalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheteroarylalkynyl, alkylheterocyclo, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkynyl, amino, aminoalkyl, aminoalkynyl, aminoarylalkynyl, aminoaryl, aminocarbonylalkenyl, aminocarbonylalkyl, aminosulfonylaryl, aminosulfonylarylalkynyl, aryloxyalkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryl alkyl amino, arylcarbonyl, arylalkylthio, arylalkynyl, arylaminoalkyl, arylheteroarylalkyl, arylthio, arylthioalkyll, aryloxy, aryloxyalkyl, alkanoylalkyl, alkanoylheteroarylalkyl, carboxy, carboxyalkoxy, carboxyalkyl, carboxyarylalkyl, cyano, cyanoalkyl, cyanoalkynyl, cycloalkoxy, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cycloalkylalkylamino, cycloalkylalkynyl, dialkylamino, diheteroarylalkylaminoalkyl, halo, haloalkoxy, haloalkyl, haloalkylarylalkynyl, haloalkylhydroxyalkyl, haloarylalkyl, haloarylalkynyl, haloarylcarbonylaminoalkyl, haloheteroarylalkyl, haloheteroarylcarbonylalkyl, heteroaryl, heteroaryl alkenyl ,heteroarylalkoxy, heteroarylalkyl, heteroarylalkynyl, heteroarylalkylaminoalkyl, heteroaryloxy, heteroaryl carbonyl, heteroarylhydroxyalkyl, heterocyclo, heterocycloalkoxy, heterocycloalkyl, heterocyclyloxy, heteroarylcarbonylaminoalkyl, hydroxy, hydroxyalkynyl, hydroxyalkyl, hydroxyaryl, hydroxyarylalkynyl, carboxyalkynyl, hydroxycycloalkylalkynyl, nitro, and thio; wherein: each alkyl, aryl, heteroaryl, and heterocyclo, wherever they occur, is optionally and independently substituted with one or more substituents independently selected from the group_^consisting.oLalkenyl_^alkoxy_^alkoxycarbonyl_^alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, alkanoyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, dialkylamino, halo, haloalkoxy, haloalkyl, haloaryl, hydroxy, hydroxyalkyl, oxo and nitro; wherein R¹ and R² together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; R and R together with the atoms to which they are attached optionally form a cycloalkyl ring, a heterocyclo ring or a heteroaryl ring; R³ and R⁴ together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; wherein the cycloalkyl ring and the heteroaryl ring wherever they occur are optionally and independently substituted with one or more substitutents selected from the group consisting of alkyl, aryl, haloaryl, arylalkyl and heterocyclo; and R⁶ is selected from the group consisting of hydrogen, hydroxy, -ONO₂, halogen, nitroxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms, wherein each of hydroxy, nitroxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms are independently and optionally substituted with a radical selected from the group consisting of hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amino, nitro, cyano, carboxyl and haloalkyl; or R⁶ is a group of the formula OCO-R⁷ wherein R⁷ is selected from the group consisting of carboxyalkyl, alkyl, alkenyl, alkynyl, and alkoxy. [0017] The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of at least one COX-2 selective inhibitor that donates nitric oxide and a pharmaceutically acceptable excipient.

[0018] The invention also provides methods for treatment or prevention of a COX-2 mediated disorder in a subject in need of such treatment or prevention, wherein the method comprises administering to the subject an amount of a novel compound that donates nitric oxide, and wherein the amount of the compound is effective for the treatment or prevention of the COX-2 mediated disorder.

[Oθi9] The following 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.

[0020] 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.

DETAILED DESCRIPTION

[0021] This detailed description of embodiments is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the embodiments described in this specification, and may be variously modified.

Compounds of This Invention

[0022] As noted above, the compounds of this invention generally have a structure corresponding to Formula I:

[0023] In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein: X is selected from the group consisting of O and NH; Z is selected from the group consisting of O, S and NH; n is an integer from 1 to 5; R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, alkanoyl, alkenyl, alkenylalkynyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxyalkynyl, alkoxyaryl, alkoxyarylalkenyl, alkoxyarylalkyl, alkoxyarylalkynyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylaminoarylalkyl, alkoxyheteroaryl, alkyl, alkylamino, alkylaminoalkyl, alkylaminoalkynyl, alkylaminoarylalkyl, alkylaryl, alkylarylalkoxy, alkylarylalkyl, alkylarylalkynyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaminoalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheteroarylalkynyl, alkylheterocyclo, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkynyl, amino, aminoalkyl, aminoalkynyl, aminoarylalkynyl, aminoaryl, aminocarbonylalkenyl, aminocarbonylalkyl, aminosulfonylaryl, aminosulfonylarylalkynyl, aryloxyalkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylamino, arylcarbonyl, arylalkylthio, arylalkynyl, arylaminoalkyl, arylheteroarylalkyl, arylthio, arylthioalkyll, aryloxy, aryloxyalkyl, alkanoylalkyl, alkanoylheteroarylalkyl, carboxy, carboxyalkoxy, carboxyalkyl, carboxyarylalkyl, cyano, cyanoalkyl, cyanoalkynyl, cycloalkoxy, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cycloalkylalkylamino, cycloalkylalkynyl, dialkylamino, diheteroarylalkylaminoalkyl, halo, haloalkoxy, haloalkyl, haloalkylarylalkynyl, haloalkylhydroxyalkyl, haloarylalkyl, haloarylalkynyl, haloarylcarbonylaminoalkyl, haloheteroarylalkyl, haloheteroarylcarbonylalkyl, heteroaryl, heteroarylalkenyl ,heteroaryl alkoxy, heteroarylalkyl, heteroarylalkynyl, heteroarylalkylaminoalkyl, heteroaryloxy, heteroarylcarbonyl, heteroarylhydroxyalkyl, heterocyclo, heterocycloalkoxy, heterocycloalkyl, heterocyclyloxy, heteroarylcarbonylaminoalkyl, hydroxy, hydroxyalkynyl, hydroxyalkyl, hydroxyaryl, hydroxyarylalkynyl, carboxyalkynyl, hydroxycycloalkylalkynyl, nitro, and thio; wherein: each alkyl, aryl, heteroaryl, and heterocyclo, wherever they occur, is optionally and independently substituted with one or more substituents independently selected-from-the group-consisting of-alkenyl,-alkoxy,_alkox-ycarbonyl,_ alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, alkanoyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, dialkylamino, halo, haloalkoxy, haloalkyl, haloaryl, hydroxy, hydroxyalkyl, oxo and nitro; wherein R¹ and R² together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; R² and R³ together with the atoms to which they are attached optionally form a cycloalkyl ring, a heterocyclo ring or a heteroaryl ring; R³ and R⁴ together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; wherein the cycloalkyl ring and the heteroaryl ring wherever they occur are optionally and independently substituted with one or more substitutents selected from the group consisting of alkyl, aryl, haloaryl, arylalkyl and heterocyclo; and R⁶ is selected from the group consisting of hydrogen, hydroxy, -ONO₂, halogen, nitroxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms, wherein each of hydroxy, nitroxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms are independently and optionally substituted with a radical selected from the group consisting of hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amino, nitro, cyano, carboxyl and haloalkyl; or R⁶ is a group of the formula OCO-R⁷ wherein R is selected from the group consisting of carboxyalkyl, alkyl, alkenyl, alkynyl, and alkoxy.

[0024] In another embodiment, R¹, R², R³, and R⁴ are independently selected from the group consisting of alkoxyaryl, alkoxyarylalkenyl, alkoxyarylalkyl, alkoxyarylalkynyl, alkoxycarbonylaminoarylalkyl, alkylaminoarylalkyl, alkylaryl, alkylarylalkoxy, alkylarylalkyl, alkylarylalkynyl, aminoarylalkynyl, aminoaryl, aminocarbonylalkenyl, aminosulfonylaryl, aminosulfonylarylalkynyl, aryloxyalkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylamino, arylcarbonyl, arylalkylthio, arylalkynyl, arylaminoalkyl, arylheteroarylalkyl, arylthio, arylthioalkyll, aryloxy, aryloxyalkyl, carboxyarylalkyl, haloalkylarylalkynyl, haloarylalkyl, haloarylalkynyl, haloarylcarbonylaminoalkyl, hydroxyaryl and hydroxyarylalkynyl, wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkyl thio, alkynyl, amino, aminoalkyl, aminocarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, alkanoyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, dialkylamino, halo, haloalkoxy, haloalkyl, haloaryl, hydroxy, hydroxyalkyl, and nitro; wherein R¹, R², R³, and R⁴ are independently heteroaryloxy, wherein heteroaryloxy is optionally and independently substituted with one to three substituents selected from the group consisting of alkyl, alkylthio, halo and haloalkyl; wherein R¹, R², R³, and R⁴ are independently selected from the group consisting of alkoxyheteroaryl, alkylheteroaryl, alkylheteroarylalkyl, alkylheteroarylalkynyl, arylheteroarylalkyl, alkanoylheteroarylalkyl, diheteroarylalkylaminoalkyl, haloheteroaryl alkyl, haloheteroarylcarbonylalkyl, heteroaryl, heteroarylalkenyl ,heteroarylalkoxy, heteroarylalkyl, heteroarylalkynyl, heteroaryl alkylaminoalkyl, heteroarylcarbonyl, heteroarylhydroxyalkyl and heteroarylcarbonylaminoalkyl, wherein each heteroaryl is optionally and independently substituted with one to three substituents selected from the group consisting of carboxy, haloalkyl, and halo; and wherein R¹, R², R³, and R⁴ are independently aelected from the group consisting of alkylheterocyclo, heterocyclo, heterocycloalkoxy and heterocycloalkyl, wherein each heterocyclo is optionally and independently substituted with one to three substituents selected from the group consisting of alkyl, alkoxy and oxo. [0025] hi yet another embodiment, Z is O. [0026] In yet another embodiment, R⁶ is ONO₂. [0027] In yet another embodiment, n is 4. [0028] In yet another embodiment X is O. [0029] hi yet another embodiment R⁶ is ONO₂, n is 4, and X is O. [0030] In one embodiment Z is O and R¹, R², R³, and R⁴ are defined above. [0031] In one embodiment, R¹' R², R³, and R⁴ are each independently selected from the group consisting of H, (Ci-Cio)-alkanoyl, (C₂-C₁₀)-alkenyl, (C₂-Ci₀)-alkenyl-(C₂-Ci₀)- alkynyl, (C₂-C io)-alkenyloxy, (CrCio)-alkoxy, (C₁-Ci₀)-alkoxy-(Ci-Cio)-alkoxy, (C₁-Ci₀)- alkoxy-(Ci-Cio)-alkyl, (C_rCio)-alkoxy-(C₂-Ci₀)-alkynyl, (C₁-C₁₀)-alkoxyaryl, (C₁-C₁₀)- .dkQxyar4d4C2d^io)ralkejiyJ,XQ^C4o)-alkoxyaryl-(Ci^C₁o)-alkyl,.(.Ci--Cio)-alkoxyaryl-(C₂- C]₀)-alkynyl, (C₁-C₁₀)-alkoxycarbonyl-(C₁-Ci₀)-alkyl, (Ci-C₁o)-alkoxycarbonylamino-(Ci- Ci_O)-alkyl, (C₁-Cio)-alkoxycarbonylaminoaryl-(C₁-Ci₀)-alkyl, (Ci-Ci₀)-alkoxyheteroaryl, (Ci- Cio)-alkyl, (Ci-Cio)-alkylamino, (Ci-Cio)-alkylamino-(Ci-C₁₀)-alkyl, (Ci-Ci₀)-alkylamino- (C₂-C₁₀)-alkynyl, (C₁-Ci₀)-alkylaminoaryl(Ci-Ci₀)-alkyl, (C₁-C₁₀)-alkylaryl, (C₁-C₁₀)- alkylaryl-(C,-C,o)-alkoxy, (Ci-Cio)-alkylaryl-(C₁-C_lo)-alkyl, (CrCi_O)-alkylaryl-(C₂-Cio)- alkynyl, (d-Cio)-alkylcarbonyl, (Ci-Cio)-alkylcarbonyl-(Ci-Ci₀)-alkyl, (C₁-C₁₀)- alkylcarbonylamino-(Ci-Cio)-alkyl, (d-Cio)-alkylheteroaryl, (Ci-Ci₀)-alkylheteroaryl-(d- C₎₀)-alkyl, (Ci-Ci₀)-alkylheteroaryl-(C₂-Ci₀)-alkynyl, (d-d^-alkylheterocyclo, (Ci-Ci₀)- alkylthio, (C₁-Ci₀)-alkylthio-(C₁-Ci₀)-alkyl, (d-C₁₀)-alkylsulfinyl, (Crd^-alkylsulfonyl, (Ci-do)-alkylsulfonyl-(Ci-do)-alkyl, (C₂-Ci₀)-alkynyl, amino, amino-(C₁-C₁₀)-alkyl, amino- (C₂-Ci₀)-alkynyl, aminoaryl-(C₂-C₁₀)-alkynyl, aminoaryl, aminocarbonyl-(C₂-Ci₀)-alkenyl, aminocarbonyl-(Ci-Cio)-alkyl, aminosulfonylaryl, aminosulfonylaryl-(C₂-Ci₀)-alkynyl, aryl- (Ci-Cio)-alkoxy-(C₂-Cio)-alkynyl, aryl, aryl-(C₂-C₁₀)-alkenyl, aryl-^rCi^-alkoxy, aryl-(d- Cio)-alkyl, aryl-(Ci-C]o)-alkylamino, arylcarbonyl, aryl-(C₁-C₁o)-alkylthio, aryl-(C₂-C₁₀)- alkynyl, arylamino-(Ci-Cjo)-alkyl, arylheteroaryl-(C₁-C]₀)-alkyl, arylthio, arylthio-(Ci-C₁₀)- alky, aryloxy, aryloxy-(d-Cio)-alkyl, (Ci-Cio)-alkanoyl-(C₁-C₁₀)-alkyl, (Ci-Ci₀)- alkanoylheteroaryl-(Ci-Ci₀)-alkyl, carboxy, carboxy-(Ci-Ci₀)-alkoxy, carboxy-(Ci-Cio)- alkyl, carboxyaryl-(Ci-Ci₀)-alkyl, cyano, cyano-(Ci-Ci₀)-alkyl, cyano-(C₂-Ci₀)-alkynyl, cyclo-(Ci-Cio)-alkoxy, cyclo-(C_rCio)-alkyl, cyclo-(Ci-Ci₀)-alkyl-(Ci-Ci₀)-alkoxy, cyclo-(Ci- Cio)-alkyl-(Ci-Cio)-alkyl, cyclo-(Ci-Ci₀)-alkyl-(Ci-Ci₀)-alkylamino, cyclo-(Ci-Ci₀)-alkyl- (C2-Cio)-alkynyl, di-(Ci-Cio)-alkylamino, diheteroaryl-(Ci-Ci₀)-alkylamino-(Ci-Ci₀)-alkyl, halo, halo-(Ci-Ci₀)-alkoxy, halo-(Ci-Ci₀)-alkyl, halo-(Ci-Ci₀)-alkylaryl-(C₂-Cio)-alkynyl, halo-(Ci-Ci₀)-alkylhydroxy-(Ci-Ci₀)-alkyl, haloaryl-(C_rCio)-alkyl, haloaryl-(C₂-Ci₀)- alkynyl, haloarylcarbonylamino-(Ci-C]₀)-alkyl, haloheteroaryl-(C]-Ci₀)-alkyl, haloheteroarylcarbonyl-(Ci-Cio)-alkyl, heteroaryl, heteroaryl-(C₂-do)-alkenyl ,heteroaryl- (Ci-Cio)-alkoxy, heteroaryl-(Ci-C₁₀)-alkyl, heteroaryl-(C₂-C₁₀)-alkynyl, heteroaryHd-Cio)- alkylamino-(C]-C₁o)-alkyl, heteroaryloxy, heteroarylcarbonyl, heteroarylhydroxy-CCi-Qo)- alkyl, heterocyclo, heterocyclo-(Ci-C_!o)-alkoxy, heterocyclo-(C₁-Cio)-alkyl, heterocyclyloxy, heteroarylcarbonylamino-(C₁-Cio)-alkyl, hydroxy, hydroxyl-(C₂-Cio)- _alkynyl,_Lyilrjixyl-(C4rC₄o)^alkyl,.hy_droxyaryl,.hy_dtoxyarylz(C₂^Cio)^alkynyl, carboxy-(C₂- Cio)-alkynyl, hydroxycyclo-(Ci-Cio)-alkyl-(C₂-C₁₀)-alkynyl, nitro, and thio; wherein: each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of (C₂-C₁o)-alkenyl, (C)-Cio)-alkoxy, (C₁- Cio)-alkoxycarbonyl, (Ci-C)₀)-alkoxycarbonyl-(C₂-Cio)-alkenyl, (C₁-Cio)-alkoxycarbonyl- (Ci-Cio)-alkyl, (Ci-C_]0)-alkyl, (Ci-Cio)-alkylamino, (Ci-Cjo)-alkylcarbonyl, (Ci-C₁₀)- alkylcarbonylamino, (Ci-Cio)-alkylsulfonylamino, (C₁-C₁o)-alkylthio, (C₂-C_!o)-alkynyl, amino, amino-(C₁-C₁o)-alkyl, aminocarbonyl, aryl, aryl-(C₁-C₁o)-alkoxy, aryl-(Ci-Cio)-alkyl, aryloxy, (Ci-CuO-alkanoyl, carboxy, carboxy-(C₂-C_!o)-alkenyl, carboxy-(Ci-Cio)-alkyl, cyano, cyano-(C₁-C₁o)-alkyl, cyclo-CCrQoJ-alkyl, di-(Ci-Cio)-alkylamino, halo, halo-(Cj- Cio)-alkoxy, halo-(C₁-C₁o)-alkyl, haloaryl, hydroxy, hydroxyl-(C₁-C₁o)-alkyl, and nitro; each heteroaryloxy is optionally and independently substituted with one to three substituents selected from the group consisting of alkyl, alkylthio, halo and haloalkyl; each heteroaryl is optionally and independently substituted with one to three substituents selected from the group consisting of carboxy, haloalkyl, and halo; and each heterocyclo is optionally and independently substituted with one to three substituents selected from the group consisting of alkyl, alkoxy and oxo; and wherein R¹ and R² together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; R² and R³ together with the atoms to which they are attached optionally form a cycloalkyl ring, a heterocyclo ring or a heteroaryl ring; R³ and R⁴ together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; wherein the cycloalkyl ring and the heteroaryl ring wherever they occur are optionally and independently substituted with one or more substitutents selected from the group consisting of alkyl, aryl, haloaryl, arylalkyl and heterocyclo. [0032] In another embodiment, R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, (C2-Ci_O)-alkenyl, (C₂-Cio)-alkenyl-(C₂-C_lo)-alkynyl, (C₂-Ci₀)- alkejnyloxy, (Ci-Cio)-alkoxy, (Ci-Cio)-alkoxy-(C₂-Cio)-alkynyl, (d-Cio)-alkoxyheteroaryl, (Ci-Cio)-alkyl, (Ci-C_]0)-alkylamino, (Ci-Ci_O)-alkylaryl(Ci-Ci_O)-alkyl, (d-do)-alkylaryl-(C₂- Cio)'-alkynyl, (C]-Ci₀)-alkylcarbonyl, (Ci-Cio)-alkylheteroaryl, (Ci-Cio)-alkylheteroaryl-(Ci- i^₁₀)ralkyJ,XCi^Cio)-alkyJheterojiryHC₂rCjo)-alkynyl,XCirCio)-alkylsulf^ (Ci-C₁₀)-alkylthio, (C₂-Ci₀)-alkynyl, aminoaryl-(C₂-C₁₀)-alkynyl, aryl, aryl-(C₂-Cjo)-alkynyl, aryl-(C₁-C₁o)-alkyl, arylcarbonyl, aryloxy, (Ci-Cio)-alkanoylheteroaryl-(C₁-C₁o)-alkyl, cyano- (Ci-Cio)-alkyl, cyano-(C₂-Ci₀)-alkynyl, cyclo-(Ci-Cio)-alkoxy, cyclo-(C i -Ci₀)- alkyl(d -Ci₀)- alkoxy, cyclo-(C₁-C_]0)-alkyl-(Ci-C₁₀)-alkyl, cyclo-(C₁-Ci₀)-alkyl-(C₁-Cio)-alkylamino, di(Ci- C_!o)-alkylamino, halo, halo-(C₁-C₁o)-alkoxy, halo-(C₁-Cio)-alkylaryl-(C₂-C₁o)-alkynyl, haloaryl-(Ci-C₁₀)-alkyl, haloaryl-(C₂-Cio)-alkynyl, haloarylcarbonylamino-(C₁-Cio)-alkyl, heteroaryl, heteroaryl(Ci-Cio)-alkoxy, heteroaryl-(Cj-C₁o)-alkyl, heteroaryl-(C₂-C₁o)-alkynyl, heteroaryloxy, heterocyclo, hydroxy, hydroxy-(C₂-Cio)-alkynyl, hydroxyaryl-(C₂-Cio)- alkynyl, and hydroxycyclo-(Ci-Cio)-alkyl-(C₂-Cio)-alkynyl; wherein each aryl, wherever it occurs, is independently substituted with one to five substituents selected from the group consisting of (C₂-Ci₀)-alkenyl, (Ci-do)-alkoxy, (Ci-do)-alkoxycarbonyl, (Ci-Cio)-alkyl, (C₁- Cio)-alkylamino, (Ci-Cio)-alkylthio, (C₂-Cio)-alkynyl, amino, aryl-(d-Cio)-alkyl, alkanoyl, carboxy-(Ci-Cio)-alkyl, cyano, cyano-(C₁-Cio)-alkyl, halo, halo-(Ci-do)-alkoxy, halo-(d- Cio)-alkyl, hydroxyl, hydroxy-(d-Cio)-alkyl and nitro; and wherein: each heteroaryloxy is optionally and independently substituted with one to three substituents selected from the group consisting of: (Ci-Cio)-alkyl, and halo; and each heteroaryl is optionally and independently substituted with one to three substituents selected from the group consisting of halo-(C]-Cio)-alkyl, and halo; and wherein R¹ and R² together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; R and R together with the atoms to which they are attached optionally form a cyclo-(Ci-Cio)-alkyl ring or a heteroaryl ring; R³ and R⁴ together with the atoms to which they are attached optionally form a cyclo-(Ci-Cio)-alkyl ring or a heteroaryl ring; wherein the cyclo-(Ci-do)-alkyl ring and the heteroaryl ring are optionally substituted with one or more (Ci-Cio)-alkyl groups. [0033] In another embodiment, R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, (C₂-C ₁₀)-alkenyl (Ci-C₁₀)-alkoxy, (C₁ -C ₁₀)-alkoxy- (C₂-Ci₀)- alkynyl, (Ci-Cio)-alkyl, (C_rC₁₀)-alkylamino, (C₁-Cio)-alkylaryl-(C₁-Ci_O)-alkyl, (C₁-Ci₀)- alkylthio, (C₂-Ci₀)-alkynyl, aryl, aryl-(Ci-Ci_O)-alkyl, aryl-(C2-C₁₀)-alkynyl, arylcarbonyl, cyclo-(Ci-C₁₀)-alkyl-(Ci-Cio)-alkoxy, cyclo-(Ci-Ci₀)-alkyl-(Ci-Ci₀)-alkyl, (Ci-Ci₀)-

alkylamino, halo, halo-(Ci-Ci₀)-alkoxy , haloaryl-(Ci-Cio)-alkyl, haloaryl-(C₂-Cio)-alkynyl, heteroaryl, heteroaryl-(Ci-Cio)-alkyl, heteroaryloxy, and heterocyclo; wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of: (C₂-C i_O)-alkenyl, (Ci-C]₀)-alkoxy, (Ci-Cio)-alkyl, (Ci- Cio)-alkylthio, (C₂-Ci₀)-alkynyl, amino, cyano, halo, halo-(Ci-Ci₀)-alkoxy, halo-(Ci-Cio)- alkyl, and hydroxy-(Ci-Ci₀)-alkyl; wherein heteroaryl, wherever it occurs, is optionally and independently substituted with one to three substituents selected from the group consisting of: halo-(Ci-Cio)-alkyl, and halo.

[0034] In yet another embodiment, R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, (Ci-Cio)-alkoxy, (Ci-Cio)-alkoxy-(C₂-Cio)-alkynyl, (Ci-Qo)- alkyl, (Ci-Cio)-alkylamino, (Ci-Ci_O)-alkylaryl-(Ci-Cio)-alkyl, (Ci-C₁₀)-alkylthio, (Ci-Ci₀)- alkylsulfonyl-(C₁-Ci₀)-alkyl, (C₂-Ci₀)-alkynyl, aryl, aryl-(Ci-Ci_O)-alkyl, aryl-(C₂-Cio)- alkynyl, arylcarbonyl, cyclo-(C₁-Ci₀)-alkyl-(C₁-Cio)-alkoxy, halo, halo-(C₁-C₁₀)-alkoxy, haloaryl-(CrC]o)-alkyl, haloaryl-(C₂-Ci₀)-alkynyl, heteroaryl-(d-Cio)-alkyl, and heterocyclo; and wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of (C₂-C₁₀)- alkenyl, (Ci-Cio)-alkoxy, (Ci-Cio)-alkyl, (Ci-Cio)-alkylthio, (C₂-C₁₀)-alkynyl, cyano, halo, and halo-(Ci-C]₀)-alkoxy.

[0035] In another embodiment, R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, (d-C₈)-alkoxy, (Ci-C₈)-alkoxy-(C₂-C₈)-alkynyl, (Ci-C₈)-alkyl, (Ci-C₈)-alkylamino, (C_rC₈)-alkylaryl-(Ci-C₈)-alkyl, (Ci-C₈)-alkylthio, (Ci-C₈)- alkylsulfonyl-(Ci-C₈)-alkyl, (C₂-C₈)-alkynyl, aryl, aryl-(Ci-C₈)-alkyl, aryl-(C₂-C₈)-alkynyl arylcarbonyl, cyclo-(Ci-C₈)-alkyl-(C]-C₈)-alkoxy, halo, halo-(Ci-C₈)-alkoxy, haloaryl-(Ci- C₈)-alkyl, haloaryl-(C₂-C₈)-alkynyl, heteroaryl-(Ci-C₈)-alkyl, and heterocyclo; and wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of (C₂-C₈)-alkenyl, (CrC₈)-alkoxy, (C₁-Cg)- alkyl, (Ci-Cg)-alkylthio, (C₂-C₈)-alkynyl, cyano, halo, and halo-(Ci-C₈)-alkoxy.

[0036] In yet another embodiment, R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, (d-C₆)-alkoxy, (C_!-C₆)-alkoxy-(C₂-C₆)-alkynyl, (Ci-C₆)-

alkylsulfonyl-(C_!-C₆)-alkyl, (C₂-C₆)-alkynyl, aryl, aryl-(Ci-C₆)-alkyl, aryl-(C₂-C₆)-alkynyl arylcarbonyl, cyclo-(Ci-C₆)-alkyl-(Ci-C₆)-alkoxy, halo, halo-(Ci-C₆)-alkoxy, haloaryl-(d-

C₆)-alkyl, haloaryl-(C₂-C₆)-alkynyl, heteroaryl-(Cj-C₆)-alkyl, and heterocyclo; and wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of (C₂-C₆)-alkenyl, (Ci-C₆)-alkoxy, (C₁-C₆)- alkyl, (d-C₆)-alkylthio, (C₂-C₆)-alkynyl, cyano, halo, and halo-(C_!-C₆)-alkoxy.

[0037] In one embodiment, the compound selected from the group consisting of

4-(nitrooxy)butyl (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate;

4-(nitrooxy)butyl (2S)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate;

4-(nitrooxy)butyl (2R)-7-benzyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3- carboxylate; and

4-(nitrooxy)butyl (2S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3- carboxylate, or their isomer and pharmaceutically acceptable salt thereof. [0038] In one embodiment, the compound having an S-absolute configuration at the 2- carbon of Formula 1.

[0039] In another embodiment, the compound an R-absolute configuration at the 2- carbon of Formula 1.

[0040] In yet another embodiment, the compound having a mixture of S- and R-absolute configuration at the 2-carbon of Formula 1.

[0041] In one embodiment, a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable excipient.

[0042] In one embodiment, a method for the treatment or prevention of a COX-2 mediated disorder in a subject in need of such treatment or prevention, wherein the method comprises administering to the subject an amount of a compound of Formula I wherein the amount of the compound is effective for the treatment or prevention of the COX-2 mediated disorder.

[0043] In one embodiment the COX-2 mediated disorder is an inflammatory disorder. [0044] The present invention further provides compositions comprising at least one selective COX-2 inhibitor and at least one nitric oxide donor. -[0-045]- T_he-present-inv.ention_also-pro-vides-a-kit-Comprisiong.atJeast-one COX-2 selective inhibitor and at least one nitric oxide donor.

[0046] This invention also is directed to tautomers of such compounds, as well as salts (particularly pharmaceutically-acceptable salts) of such compounds and tautomers. [0047] In one embodiment of the present invention, the COX-2 selective inhibitor is of the chromene/chroman ("chromene") structural class, which encompasses substituted benzopyrans or substituted benzopyran analogs, as well as substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes, and including, by way of non-limiting example, the chromene compounds, and the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof.

[0048] Chromenes of the present invention that can serve as COX-2 selective inhibitors include any one or more of the compounds that are described in U.S. Patent No. 6,034,256, which is herein incorporated by reference.

[0049] Chromenes of the present invention that can serve as COX-2 selective inhibitors include any one or more of the compounds that are described in U.S. patent applications 10/801,446, filed March 16, 2004, which is herein incorporated by reference. [0050] Chromenes of the present invention that can serve as COX-2 selective inhibitors include any one or more of the compounds that are described in U.S. patent applications 10/801,429, filed March 16, 2004, which is herein incorporated by reference. [0051] Another component of the present invention is a nitric oxide- or NO-donating agent. The nitric oxide- or NO-donating agent of the present invention is any compound that donates, releases, or directly or indirectly transfers a nitrogen monoxide species; and/or stimulates the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo; and/or elevates endogenous levels of nitric oxide or EDRF in vivo. NO- donating agents also include compounds that are substrates for nitric oxide synthase. [0052] Examples of NO-donating agents that are useful in the present invention are presented in Tablel.

Table 1: Nitric Oxide-Donating Agents

[0053] Also included in the family of compounds of Formula I are the stereoisomers thereof. Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof. Accordingly, some of the compounds of this invention may be present in racemic mixtures which are also included in this invention. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active base and then separation of the mixture of diastereoisomers by crystallization, followed by liberation of the optically active bases from these salts. Examples of appropriate bases are brucine, strychnine, dehydroabietylamine, quinine, cinchonidine, ephedrine, alpha-methylbenzylamine, amphetamine, deoxyphedrine, chloramphenicol intermediate, 2-amino-l-butanol, and l-(l-napthyl)ethylamine. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials. These isomers may be in the_form_of_a.free_acid, a.free_base, an ester or a salt. Additional methods for resolving optical isomers are known to those skilled in the art.

[0054] Also included in the family of compounds of Formula I are the protected acids thereof, such as the esters, hydroxyamino derivatives, amides and sulfonamides. Thus primary and secondary amines can be reacted with the l,la,2,7b-tetrahydro- cyclopropa[c]chromene-la-carboxylic acid of Formula I to form amides which can be useful as prodrugs. Preferred amines include heterocyclicamines, including optionally substituted aminothiazoles, optionally substituted amino-isoxazoles, and optionally substituted aminopyri dines; aniline derivatives; sulfonamides; aminocarboxylic acids; and the like. Additionally, 3-acylated-la,2,3,7b-tetrahydro-lH-cyclopropa[c]quinoline-la-carboxylic acid can behave as prodrugs for the la^^Jb-tetrahydro-lH-cyclopropatcJquinoline-la- carboxylic acid. The esters, hydroxyamino derivatives and sulfonamides can be prepared from the acids by methods known to one skilled in the art.

[0055] The compounds of the present invention can be administered for the prophylaxis and treatment of cyclooxygenase related (e.g. COX-I related or COX-2 related) diseases or conditions by any means, preferably oral, that produce contact of these compounds with their site of action in the body. For the prophylaxis or treatment of the conditions referred to above, the compounds 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 compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, salicyclic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic,Joluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, .beta.-hydroxybutyric, salicyclic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine and tromethamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formula I.

[0056] Alternatively, pharmaceutically acceptable salts can comprise an anionic counterion, for example where the molecule contains a cationic functional group such as an ammonium group. The anions, of course, are also required to be pharmaceutically acceptable and are also selected from the above list.

[0057] Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. Companion animals include horses, dogs, and cats.

Treating Conditions Using the Compounds of The Present Invention [0058] The compounds, methods and combinations of the present invention are useful for, but not limited to, the prevention or treatment of pain and inflammation in a subject, and for treatment of inflammation-related disorders, such as for use as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, combinations of the invention will be useful as anti-inflammatory agents to treat arthritis, including, but not limited to, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such combinations of the invention will be useful in the treatment of asthma, bronchitis, menstrual cramps, tendonitis, bursitis, connective tissue injuries or disorders, and skin related conditions such as psoriasis, eczema, burns and dermatitis.

[0.059]. In-other_embodiments, the compounds,.methods_and_comp.ositions_of the present invention encompass the prevention or treatment of several inflammation-related disorders selected from the group consisting of connective tissue and joint disorders, neoplasia disorders, cardiovascular disorders, otic disorders, ophthalmic disorders, respiratory disorders, gastrointestinal disorders, angiogenesis-related disorders, immunological disorders, allergic disorders, nutritional disorders, infectious diseases and disorders, endocrine disorders, metabolic disorders, neurological and neurodegenerative disorders, psychiatric disorders, hepatic and biliary disorders, musculoskeletal disorders, genitourinary disorders, gynecologic and obstetric disorders, injury and trauma disorders, surgical disorders, dental and oral disorders, sexual dysfunction disorders, dermatologic disorders, hematological disorders, and poisoning disorders.

[0060] As used herein, the terms "neoplasia" and "neoplasia disorder", used interchangeably, refer to new cell growth that results from a loss of responsiveness to normal growth controls, e.g. to "neoplastic" cell growth. Neoplasia is also used interchangeably herein with the term "cancer" and for purposes of the present invention; cancer is one subtype of neoplasia. As used herein, the term "neoplasia disorder" also encompasses other cellular abnormalities, such as hyperplasia, metaplasia and dysplasia. The terms neoplasia, metaplasia, dysplasia and hyperplasia can be used interchangeably herein and refer generally to cells experiencing abnormal cell growth.

[0061] Both of the terms, "neoplasia" and "neoplasia disorder", refer to a "neoplasm" or tumor, which may be benign, premalignant, metastatic, or malignant. Also encompassed by the present invention are benign, premalignant, metastatic, or malignant neoplasias. Also encompassed by the present invention are benign, premalignant, metastatic, or malignant tumors. Thus, all of benign, premalignant, metastatic, or malignant neoplasia or tumors are encompassed by the present invention and may be referred to interchangeably, as neoplasia, neoplasms or neoplasia-related disorders. Tumors are generally known in the art to be a mass of neoplasia or "neoplastic" cells. Although, it is to be understood that even one neoplastic cell is considered, for purposes of the present invention to be a neoplasm or alternatively, neoplasia.

[0062] In other embodiments, the compounds, methods and compositions of the present iny_ention^encompass^the_prey_ention.and.treatment.oLthe_connectiy.eJissue_andjoint.disorders selected from the group consisting of arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, carpal tunnel syndrome, canine hip dysplasia, systemic lupus erythematosus, osteoarthritis, tendonitis and bursitis.

[0063] In other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the neoplasia disorders selected from the group consisting of acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, familial adenomatous polyposis, familial polyps, colon polyps, polyps, adenosarcoma, adenosquamous carcinoma, adrenocortical carcinoma, AEDS- related lymphoma, anal cancer, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bile duct cancer, bladder cancer, brain stem glioma, brain tumors, breast cancer, bronchial gland carcinomas, capillary carcinoma, carcinoids, carcinoma, carcinosarcoma, cavernous, central nervous system lymphoma, cerebral astrocytoma, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, esophageal cancer, Ewing's sarcoma, extragonadal germ cell tumor, fibrolamellar, focal nodular hyperplasia, gallbladder cancer, gastrinoma, germ cell tumors, gestational trophoblastic tumor, glioblastoma, glioma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, intraocular melanoma, invasive squamous cell carcinoma, large cell carcinoma, islet cell carcinoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, lentigo maligna melanomas, leukemia-related disorders, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, malignant mesothelial tumors, malignant thymoma, medulloblastoma, medulloepithelioma, melanoma, meningeal, merkel cell carcinoma, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, -neuroepitheliaLadenocarcinoma-nodular-melanoma.-non-Hodgkinls-Lymphoma.-oat cell- carcinoma, oligodendroglial, oral cancer, oropharyngeal cancer, osteosarcoma, pancreatic polypeptide, ovarian cancer, ovarian germ cell tumor, pancreatic cancer, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, parathyroid cancer, penile cancer, pheochromocytoma, pineal and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, small intestine cancer, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, supratentorial primitive neuroectodermal tumors, thyroid cancer, undifferentiatied carcinoma, urethral cancer, uterine sarcoma, uveal melanoma, verrucous carcinoma, vaginal cancer, vipoma, vulvar cancer, Waldenstrom's macroglobulinemia, well differentiated carcinoma, and Wilm's tumor. [0064] In other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the cardiovascular disorders selected from the group consisting of myocardial ischemia, hypertension, hypotension, heart arrhythmias, pulmonary hypertension, hypokalemia, cardiac ischemia, myocardial infarction, cardiac remodeling, cardiac fibrosis, myocardial necrosis, aneurysm, arterial fibrosis, embolism, vascular plaque inflammation, vascular plaque rupture, bacterial-induced inflammation and viral induced inflammation, edema, swelling, fluid accumulation, cirrhosis of the liver, Bartter's syndrome, myocarditis arteriosclerosis, atherosclerosis, calcification (such as vascular calcification and valvar calcification), coronary artery disease, heart failure, congestive heart failure, shock, arrhythmia, left ventricular hypertrophy, angina, diabetic nephropathy, kidney failure, eye damage, cardiac damage, diabetic cardiac myopathy, renal insufficiency, renal injury, renal arteriopathy, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache.

[0065] hi other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the metabolic disorders selected from the group consisting of obesity, overweight, type I and type II diabetes, hypothyroidism, and hyperthyroidism.

[0066] In other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the respiratory disorders selected from the group consisting of asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary embolism, pneumonia, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome and emphysema.

[0067] In other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the angiogenesis-related disorders selected from the group consisting of angiofibroma, neovascular glaucoma, arteriovenous malformations, arthritis, osler-weber syndrome, atherosclerotic plaques, psoriasis, corneal graft neovascularization, pyogenic granuloma, delayed wound healing, retrolental fibroplasias, diabetic retinopathy, scleroderma, granulations, solid tumors, hemangioma, trachoma, hemophilic joints, vascular adhesions, hypertrophic scars, age-related macular degeneration, coronary artery disease, stroke, cancer, AIDS complications, ulcers and infertility.

[0068] In other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the infectious diseases and disorders selected from the group consisting of viral infections, bacterial infections, prion infections, spirochetes infections, mycobacterial infections, rickettsial infections, chlamydial infections, parasitic infections and fungal infections.

[0069] In still further embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the infectious diseases and disorders selected from the group consisting of hepatitis, HIV (AIDS), small pox, chicken pox, common cold, influenza, warts, oral herpes, genital herpes, herpes zoster, bovine spongiform encephalopathy, septicemia, streptococcus infections, staphylococcus infections, anthrax, severe acquired respiratory syndrome (SARS), malaria, African sleeping sickness, yellow fever, chlamydia, botulism, canine heartworm, rocky mountain spotted fever, lyme disease, cholera, syphilis, gonorrhea, encephalitis, pneumonia, conjunctivitis, yeast infections, rabies, dengue fever, Ebola, measles, mumps, rubella, West Nile virus, meningitis, gastroenteritis, tuberculosis, hepatitis, and scarlet fever.

[0070] ^In-other-embodiments_^the-compoundSj-methods-and-compositions-of-the-present invention encompass the prevention and treatment of the neurological and neurodegenerative disorders selected from the group consisting of headaches, migraine headaches, Alzheimer's disease, Parkinson's disease, dementia, memory loss, senility, amyotrophy, ALS, amnesia, seizures, multiple sclerosis, muscular dystrophies, epilepsy, schizophrenia, depression, anxiety, attention deficit disorder, hyperactivity, bulimia, anorexia nervosa, anxiety, autism, phobias, spongiform encephalopathies, Creutzfeldt-Jakob disease, Huntington's Chorea, ischemia, obsessive-compulsive disorder, manic depression, bipolar disorders, drug addiction, alcoholism and smoking addiction.

[0071] In other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the dermatological disorders selected from the group consisting of acne, psoriasis, eczema, burns, poison ivy, poison oak and dermatitis.

[0072] In other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the surgical disorders selected from the group consisting of pain and swelling following surgery (including treatment prio to surgery to decrease post operative pain), infection following surgery and inflammation following surgery.

[0073] In other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the gastrointestinal disorders selected from the group consisting of inflammatory bowel syndrome, Crohn's disease, gastritis, irritable bowel syndrome, diarrhea, constipation, dysentery, ulcerative colitis, gastric esophageal reflux, ulcers, and heartburn.

[0074] In other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the otic disorders selected from the group consisting of otic pain, inflammation, otorrhea, otalgia, fever, otic bleeding, Lermoyez's syndrome, Meniere's disease, vestibular neuronitis, benign paroxysmal positional vertigo, herpes zoster oticus, Ramsay Hunt's syndrome, viral neuronitis, ganglionitis, geniculate herpes, labyrinthitis, purulent labyrinthitis, viral endolymphatic labyrinthitis, perilymph fistulas, noise-induced hearing loss, presbycusis, drug-induced ototoxicity, acousticneuromas, aerotitis media, infectious myringitis, bullous myringitis, otitis media, otitis media with effusion, acute otitis media, secretory otitis media, serous otitis media, acute mastoiditis, chronic otitis media, otitis externa, otosclerosis, squamous cell carcinoma, basal cell carcinoma, nonchromaffin paragangliomas, chemodectomas, globus jugulare tumors, globus tympanicum tumors, external otitis, perichondritis, aural eczematoid dermatitis, malignant external otitis, subperichondrial hematoma, ceruminomas, impacted cerumen, sebaceous cysts, osteomas, keloids, otalgia, tinnitus, vertigo, tympanic membrane infection, typanitis, otic furuncles, otorrhea, acute mastoiditis, petrositis, conductive and sensorineural hearing loss, epidural abscess, lateral sinus thrombosis, subdural empyema, otitic hydrocephalus, Dandy's syndrome, bullous myringitis, cerumen-impacted, diffuse external otitis, foreign bodies, keratosis obturans, otic neoplasm, otomycosis, trauma, acute barotitis media, acute eustachian tube obstruction, post-otic surgery, postsurgical otalgia, cholesteatoma, conductive and sensorineural hearing loss, epidural abscess, lateral sinus thrombosis, subdural empyema and otitic hydrocephalus.

[0075] hi other embodiments, the compounds, methods and compositions of the present invention encompass the prevention and treatment of the ophthalmic disorders selected from the group consisting of conjunctivitis, age-related macular degeneration diabetic retinopathy, detached retina, glaucoma, vitelliform macular dystrophy type 2, gyrate atrophy of the choroid and retina, conjunctivitis, corneal infection, fuchs' dystrophy, iridocorneal endothelial syndrome, keratoconus, lattice dystrophy, map-dot-fϊngerprint dystrophy, ocular herpes, pterygium, myopia, hyperopia, and cataracts.

[0076] Compounds and combinations of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention or treatment of cancer, such as colorectal cancer. Combinations of the invention would be useful in treating inflammation in diseases and conditions such as herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylarthrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis_^multiple-sclerosis.-sarcoidosis_^nephrotic-syndrome^.ehcetls-syndroine_^polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. [0077] Compounds and compositions having the novel combination would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and of acute injury to the eye tissue. The compositions would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compositions would also be useful for the treatment of certain central nervous system disorders such as cortical dementias including Alzheimer's disease.

Dosage and Administration

[0078] The compound of the present invention can be administered to the subject as the neat compound alone. Alternatively the compounds of the present invention can be presented with one or more pharmaceutically acceptable excipients in the form of a pharmaceutical composition. A useful excipient can be, for example, a carrier. 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. [0079] 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.

[0080] 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-clinicaLcondition.of the recipient.

[0081] In general, a daily dose of the COX-2 inhibitors can be in the range of from about 0.01 to about 100 mg/kg body weight/day, in another embodiment from about 0.05 mg to about 50 mg/kg body weight/day, in another embodiment from about 0.01 to about 20 mg/kg body weight/day, in another embodiment from about 0.01 to about 10 mg/kg body weight/day. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.

[0082] Orally administrable unit dose formulations of the COX-2 inhibitors, such as tablets or capsules, can contain, for example, from about 0.1 to about 1000 mg of the compound, in another embodiment about 1 to about 500 mg of compound, more preferably from about 2 to about 400 mg of compound, in another embodiment from about 2 to about 200 mg of compound, in another embodiment from about 2 to about 100 mg of compound, in another embodiment from about 2 to about 50 mg of compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the ion derived from the salt.

[0083] Oral delivery of the COX-2 inhibitors of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action by manipulation of the dosage form. Thus, enteric-coated and enteric- coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester. [.0084.]. -\\^en^administered_intray.enously,_the_daily_dose_can,_for_example,-bejn_the.range of from about 0.1 mg/kg body weight to about 20 mg/kg body weight, in another embodiment from about 0.25 mg/kg body weight to about 10 mg/kg body weight, in another embodiment from about 0.4 mg/kg body weight to about 5 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 2000 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, in another embodiment from about 1 mg to about 200 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 200 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 200 mg.

[0085] The dosage level of a nitric oxide-donating agent will necessarily depend on the particular nitric oxide-donating agent that is used. However, in general, the appropriate dosage level of a nitric oxide-donating agent will generally be from about 0.0001 mg per kg to about 200 mg per kg subject body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.001 mg per kg to about 100 mg per kg per day; more preferably about 0.01 mg per kg to about 50 mg per kg per day; even more preferably about 0.1 mg per kg to about 10 mg per kg subject body weight. [0086] A combination therapy comprising a nitric oxide-donating agent that is intended for oral administration to humans may contain from about 10 micrograms to about 10 grams of active agent optionally compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. More preferably, the nitric oxide-donating agent is dosed at between about 0.1 mg and about 1 gram. Even more preferably, the nitric oxide-donating agent is dosed at between about 1 mg and about 750 mg. More preferably still, the nitric oxide-donating agent is dosed at between about 100 mg and about 500 mg. [0087] Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route ofladministration is oral.

[0088] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in such formulations in a concetration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.

[0089] Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water- in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

[0090] Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia. [0091] Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering_iiie.reiuJting-solution_sterile_andJsotQnic_with the_bLood..Injeciable_compositions according to the invention will generally contain from 0.1 to 5% w/w of a compound disclosed herein.

[0092] Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0093] Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.

[0094] Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, in another embodiment about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3(6), 318 (1986).

[0095] In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration. [0096] The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, _and_pills,_the_dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

[0097] 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 may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

[0098] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may 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 may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0099] Pharmaceutically acceptable carriers encompass all the foregoing and the like. [0100] The present invention further comprises kits that are suitable for use in performing the methods of treatment described above. In one embodiment, the kit contains a first dosage form comprising a COX-2 selective inhibitor and a second dosage form comprising a nitric oxide-donating agent, in quantities sufficient to carry out the methods of the present invention. Preferably, the first dosage form and the second dosage form together comprise a therapeutically effective amount of the compounds for the prevention or treatment of pain, inflammation, and inflammation-related disorders. Treatment Regimen

[0101] The dosage regimen to prevent, give relief from, or ameliorate a disease condition 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, sex, 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.

[0102] Initial treatment of a patient suffering from a therapeutic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the disease condition has been controlled or eliminated. Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum cholesterol levels by any of the methods well known in the art, to determine the effectiveness of therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal effective amounts of compounds of the present invention 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 compound of the present invention which exhibits satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the condition.

[0103] The administration of compounds of the present invention may be used alone or in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia. Alternatively, the compounds described herein may be used in conjunctive therapy. By way of example, the compounds may be administered alone or in conjunction with other antineoplastic agents or other growth inhibiting agents or other drugs or nutrients. [0104] There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be selected for treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous-agents._AlternatLvel_y,-.other_anti=neoplastic_agents,_such_as metallomatrix proteases (MMP), SOD mimics or alpha_vbeta₃ inhibitors may be used. [0105] A first family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antimetabolite-type antineoplastic agents. Suitable antimetabolite antineoplastic agents may be selected from the group consisting of 5- FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL- AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimeterxate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT and uricytin.

[0106] A second family of antineoplastic agents which may be used in combination with compounds of the present invention consists of alkylating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR- 2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA- 2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC- 342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F- 101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku Υ A-011, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol. [0107] .A third family of antineoplastic-agents which may be used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN- 201-11, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY- 25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C- 1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC- 102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB -41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, -SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN- 10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin. [0108] A fourth family of antineoplastic agents which may be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston AlO, antineoplaston A2, antineoplaston A3, antineoplaston^AS_^antineoplaston-ASl-l.-HenkeLAED_^aphidicolin-glycinate_^asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron- 10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT- 11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN- 9693, elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY- 186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST- 16, N- (retinoyl)amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone- Poulenc RP-56976, SmithKline SK&F- 104864, Sumitomo SM- 108, Kuraray SMANCS, SeaPharm SP- 10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide-dismutase,_Ioyama-T=506,-.Toyama-T_^680,-taxol,_Teijin_TEI-0303,-teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, topoisomerase inhibitors (including irinotecan and topotecan ), Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN- 1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534. [0109] Examples of radioprotective agents which may be used in combination with compounds of the present invention are AD-5, adchnon, amifostine analogues, detox, dimesna, 1-102, MM- 159, N-acylated-dehydroalanines, TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon.

[0110] The present compounds will also be useful in combination with radiation therapy for treatment of neoplasias including malignant tumors.

[0111] The present compounds may also be used in co-therapies, partially or completely, in addition to other antiinflammatories, such as together with steroids, NSAIDs, nitric oxide synthase inhibitors (NOS inhibitors, including iNOS inhibitors), kinase inhibitors (including IKK inhibitors and MK-2 inhibitors), p-38 inhibitors, TNF inhibitors, 5-lipoxygenase inhibitors, FLAP inhibitor, LTB₄ receptor antagonists and LTA₄ hydrolase inhibitors. Suitable LTA₄ hydrolase inhibitors include RP-64966, (S,S)-3-amino-4-(4-benzyloxyphenyl)- 2-hydroxybutyric acid benzyl ester (Scripps Res. Inst.), N-(2(R)-(cyclohexylmethyl)-3- (hydroxycarbamoyl)propionyl)-L- alanine (Searle), 7-(4-(4-ureidobenzyl)phenyl)heptanoic acid (Rhone-Poulenc Rorer), and 3-(3-(lE,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithium salt (Searle). Suitable LTB₄ receptor antagonists include, among others, ebselen, linazolast, ontazolast, Bayer Bay-x-1005, BIIL-284, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Merck compound MAFP, Terumo compound TMK-688, Tanabe compound T-0757, Lilly compounds LY-213024, LY-210073, LY223982, LY233469, and LY255283, LY-293111, 264086 and 292728, ONO compounds ONO- LB457, ONO-4057, and ONO-LB-448, Shionogi compound S-2474, calcitrol, Lilly compounds Searle compounds SC-53228, SC-41930, SC-50605 and SC-51146, Warner Lambert compound BPC 15, SmithKline Beecham compound SB-209247 and SK&F compound S KF- 104493. Preferably, the LTB₄ receptor antagonists are selected from

compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, and Terumo compound TMK-688. Suitable 5-LO inhibitors include, among others, Abbott compounds A- 76745, 78773 and ABT761, Bayer Bay-x-1005, Cytomed CMI-392, Eisai E-3040, Scotia Pharmaceutica EF-40, Fujirebio F-1322, Merckle ML-3000, Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, flobufen, linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast.

[0112] The present compounds may also be used in combination therapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non- addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin- 1 receptor antagonists and sodium channel blockers, among others. More preferred will be combinations with compounds selected from morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone, Tramadol [(+) enantiomer], DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608, E- 2078, ICI-204448, acetominophen (paracetamol), propoxyphene, nalbuphine, E-4018, filenadol, mirfentanil, amitriptyline, DuP631, Tramadol [(-) enantiomer], GP-531, acadesine, AKI-I, AKI-2, GP-1683, GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742, SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, and CP-99,994. [0113] The present compounds will also be useful in therapeutic combination with lipid- lowering drugs including HMG Co-A reductase inhibitors (including pravastatin, simvastatin, lovastatin, ZD4522, atorvastatin, cerivastatin, and fluvastatin), bile acid sequestrants (including cholestyramine and cholestepol), nicotinic acis derivatives (including niacin), fibric acid deravitives (including clofibrate, gemfibrozil, fenofibrate, ciprofibrate and bezafibrate), MTP inhibitors, ACAT inhibitors, and CETP inhibitors.

[0114] The compounds will also be useful for the control of urinary conditions and other muscarinic receptor-related conditions in therapeutic combination with an anti-muscarinic agent such as tolterodine, tiotropium, ipratropium, pirenzepine, homatropine, scopolamine, and.atropine.

[0115] The compounds will also be useful in therapeutic combination with a sex steroid for the treatment or prevention of menstrual cramps.

[0116] The compounds will also be useful alone or in combination with other therapeutic agents for the treatment or prevention of migraine headaches. Such combination therapies include caffeine, an ergot alkaloid (such as ergotamine or dihydroergotamine), a 5-HT _JB/ID receptor antagonist (such as sumatriptan), and a GABA-analog (such as gabopentin).

[0117] The compounds can be used in co-therapies, in place of other conventional antiinflammatories, in combination with one or more antihistamines, decongestants, diuretics, antitussive agents or with other agents previously known to be effective in combination with antiinflammatory agents.

Definitions

[0118] The term "prevention" includes either preventing the onset of clinically evident cardiovascular disorders altogether or preventing the onset of a preclinically evident stage of cardiovascular disorder in individuals. This includes prophylactic treatment of those at risk of developing a disease, such as a cardiovascular disorder, dementia or cancer, for example. [0119] The phrase "therapeutically-effective" is intended to qualify the amount of each agent which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.

[0120] The term "COX-2 selective" as used herein means the ability of a compound to inhibit COX-2 more than it inhibits COX-I in an in vitro assay. The present invention includes compounds which are COX-2 selective. In one embodiment, the COX-2 selective compounds have an in vitro COX-2 IC₅Q of less than about 0.5 micromolar. The COX-2 selective compounds preferably have a selectivity ratio of COX- 2 inhibition over COX-I inhibition of at least 2, preferably at least 5, more preferably at least 10, still more preferably at least 20, more preferably still at least 50 and yet more preferably at least 100. Even more preferably, the COX-2 selective compounds have a COX-I IC₅0 of greater than about 5 micromolar. Such preferred selectivity will indicate an ability to reduce the incidence of £ommon-NSAID=induced-side-effects.-

[0121] The term "COX-I selective" as used herein means the ability of a compound to inhibit COX-I more than it inhibits COX-2 in an in vitro assay. The present invention also includes compounds which are COX-I selective. Preferably, the COX-I selective compounds have an in vitro COX-I IC₅₀ of less than about 0.5 micromolar. The COX-I selective compounds preferably have a selectivity ratio of COX-I inhibition over COX-2 inhibition of at least 2, preferably at least 5, more preferably at least 10, still more preferably at least 20, more preferably still at least 50 and yet more preferably at least 100. Even more preferably, the COX-I selective compounds have a COX-2 IC₅₀ of greater than about 5 micromolar. Such preferred selectivity will have usefulness, for example, in tissues in which COX-I enzyme products produce a deleterious effect to the subject. [0122] The terms "nitric oxide donor" or "NO donor" refer to compounds that donate, release or directly or indirectly transfer a nitrogen monoxide species, or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo. "NO donor" also includes compounds that are substrates for nitric oxide synthase. [0123] The terms "benzopyran" and "chromene" are used interchangeably. [0124] The terms "hydrogen," "H" and "hydrido can be used interchangeably. [0125] "Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof. [0126] "Aryl" means a fully unsaturated mono- or multi-ring carbocyle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl. [0127] "Heterocycle" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or O. This includes, for example, the following structures:

1 2 3 1 2 3 wherein Z, Z , Z or Z is C, S, P, O, or N, with the proviso that one of Z, Z , Z or Z is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, the optional substituents are understood to be

1 2 3 attached to Z, Z , Z or Z only when each is C.

[0128] The term "heteroaryl" means a fully unsaturated heterocycle.

[0129] In either "heterocycle" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.

[0130] The term "hydroxy" means a group having the structure -OH.

[0131] The term "halogen" or "halo" means a fluoro, chloro, bromo or iodo group.

[0132] The term "haloalkyl" means alkyl substituted with one or more halogens.

[0133] The term "cycloalkyl" means a mono- or multi-ringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds, examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term "cycloalkyl" additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven- membered heterocyclic ring of the benzothiepine.

[0134] The term "oxo" means a doubly bonded oxygen. [0135] The term "cycloaklylidene" means a mono- or multi-ringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not within the ring structures.

[0136] The term "nitro" means a group having the formula -NO₂. [0137] The term "sulfo" means a sulfo group, -SO₃ H, or its salts. _[0138]_ The_termilthio"jneans.a group having the formula -SH.

[0139] The term "sulfoalkyl" means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.

[0140] The term "aminosulfonyl" means a group having the formula -SO₂NH₂. [0141] The term "alkylsilyloxy" means a group having the formula -O-Si-alkyl. [0142] The term "alkylthio" means a moiety containing an alkyl radical which is attached to an sulfer atom, such as a methylthio radical. The alkylthio moiety is bonded to the molecule of interest at the sulfer atom of the alkylthio.

[0143] The term "aryloxy" a moiety containing an aryl radical which is attached to an oxygen atom, such as a phenoxy radical. The aryloxy moiety is bonded to the molecule of interest at the oxygen atom of the aryloxy.

[0144] The term "alkenyloxy" a moiety containing an alkenyl radical which is attached to an oxygen atom, such as a 3-propenyloxy radical. The alkenyloxy moiety is bonded to the molecule of interest at the oxygen atom of the alkenyloxy.

[0145] The term "arylalkyl" means an aryl-substituted alkyl radical such as benzyl. The term "alkylarylalkyl" means an arylalkyl radical that is substituted on the aryl group with one or more alkyl groups.

[0146] The term "amino" means a group having the structure -NH₂. Optionally the amino group can be substituted for example with one, two or three groups such as alkyl, alkenyl, alkynyl, aryl, and the like.

[0147] The tern "cyano" means a group having the structure -CN. [0148] The term "heterocyclyl alkyl" means an alkyl radical that is substituted with one or more heterocycle groups.

[0149] The term "heteroarylalkyl" means an alkyl radical that is substituted with one or more heteroaryl groups. [0150] The term "alkylheteroarylalkyl" means a heteroarylalkyl radical that is substituted with one or more alkyl groups.

[0151] The term "alkoxy" means a moiety containing an alkyl radical which is attached to an oxygen atom, such as a methoxy radical. The alkoxy moiety is bonded to the molecule of interest at the oxygen atom of the alkoxy. examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy. [0152] The term "carboxy" means the carboxy group, -CO₂H, or its salts. [0153] The term "carbonyl", whether used alone or with other terms, such as "alkoxycarbonyl", means -(C=O)-.

[0154] The term "alkanoyl" means a -C(=O)H group, examples of such alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, β-hydroxybutyric, galactaric and galacturonic acids.

[0155] The term "carboxyalkyl" means an alkyl radical that is substituted with one or more carboxy groups. Preferable carboxyalkyl radicals are "lower carboxyalkyl" radicals -having one or more carboxy groups attached to an alkyl radical having one to six carbon atoms.

[0156] The term "carboxyheterocycle" means a heterocycle radical that is substituted with one or more carboxy groups.

[0157] The term "carboxyheteroaryl" means a heteroaryl radical that is substituted with one or more carboxy groups.

[0158] The term "carboalkoxyalkyl" means an alkyl radical that is substituted with one or more alkoxycarbonyl groups. Preferable carboalkoxyalkyl radicals are "lower carboalkoxyalkyl" radicals having one or more alkoxycarbonyl groups attached to an alkyl radical having one to six carbon atoms.

[0159] The term "carboxyalkylamino" means an amino radical that is mono- or di- substituted with carboxyalkyl. Preferably, the carboxyalkyl substituent is a "lower carboxyalkyl" radical wherein the carboxy group is attached to an alkyl radical having one to six carbon atoms. [0160] When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above.

[0161] The terms "cyclooxygenase-2 inhibitor", or "COX-2 inhibitor", which can be used interchangeably herein, embrace compounds which inhibit the COX-2 enzyme regardless of the degree of inhibition of the Cox-1 enzyme, and include pharmaceutically acceptable salts of-those_compounds._Thus,-for.purposes-θf-the. present-invention, a compound is considered a COX-2 inhibitor irrespective of whether the compound inhibits the COX-2 enzyme to an equal, greater, or lesser degree than the Cox-1 enzyme.

General Synthetic Procedures

[0162] The compounds of the invention can be synthesized according to the following procedures of Scheme 1, wherein the R'-R4 substituents are as defined for Formulas I_above, except where further noted. The following general route exemplifies the preparation of a 4- nitroalkyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate derivative (Z= O). This and other routes may be used to prepare additional series.

Scheme - 1

[0163] Chromene acids are coupled with a dihydroxyalkane or cycloalkane using dicyclohexylcarbodiimide and dimethylaminopyridine in dichloromethane at room temperature and then purified by silica gel chromatography to produce 2. The resulting alcohol esters are nitrosylated using a mixture of nitric acid in acetic anhydride dissolved in dichloromethane at zero degrees and then purified by reverse phase chromatography to produce nitrated ester chromenes 3.

Detailed Preparative Method

The following abbreviations are used:

EIHRMS - Electron Impact High Resonance Mass Spectrometry ESHRMS - Electrospray Ionization High Resonance Mass Spectrometry HNMR - Proton Nuclear Magnetic Resonance MHz - Megahertz Hz - Hertz J - Coupling Value m/z - mass to charge ratio q - quartet d - doublet s - singlet - ^• - m - multiplet M⁺ - Parent Ion

M+H - Parent ion plus 1 hydrogen CO₂ - Carbon Dioxide Na₂SO₄ - sodium, sulfate MgSO₄Magnesium sulfate CHCl₃ -de - Deuterated chloroform ⁰C - degrees Celsius g - gram mg - milligrams mmole - millimoles mL - milliliters μL - microliters

EXAMPLE 1

-4=(nitrooxy.)butyl-(2S)=6,8=dichloro-2-(trifluoromethyl)=2H-chromene=3--carboxylate-

Step 1. Preparation of 4-hydroxybutyl (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3- carboxylate.

[0164] The acid from US patent 6,271,253 Bl, Example 175 (300 mg, 0.958 mmole) was dissolved into dichloromethane (5 mL) and added to the round bottom flask. 1,3- dicyclohexylcarbodiimide (329 mg, 1.59 mmole) was partially dissolved in dichloromethane (5 mL) and added to the round bottom. 4-dimethylaminopyridine (19 mg) was added to the round bottom followed by the syringe addition of 1,4-butane diol ( 155 μL, 1.75 mmole). The resulting solution stirred for 4 hours at room temperature and then the cloudy solution was filtered through a 1 inch pad of silica. Washed pad with dichloromethane (2 x 25 mL) the organic layer was washed with brine (2 x 25 mL), dried organic layer over Na₂SO₄ (Ig) and filtered, removed solvent in vacuo. Subjected crude material to silica gel chromatography to produce the title compound. (85 %) ESHRMS m/z 385.0230 (M+H, C₁₅Hi₄Cl₂O₄F₃ Calc'd 385.0216).

Step 2. Preparation of 4-(nitrooxy)butyl (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene- 3-carboxylate.

[0165] The ester, step 1, was dissolved into dichloromethane (5 mL) and chilled to -5⁰C. A NaHCO₃ sat. solution (500 mL) was chilled to O⁰C in an ice-water bath. In a separate round bottom flask acetic anhydride (1 mL) was cooled with stirring to -1O⁰C using an ethylene glycol/CO₂ bath. HNO₃ (300 μL) was added to the chilled acetic anhydride dropwise while maintaining the temperature below O⁰C. Allowed temperature to rise to 8⁰C with raising and lowering of the bath. Once temperature reached 8°C I rapidly cooled to -5⁰C and dripped in the ester solution while maintaining the temperature below I⁰C, after the addition was complete the resulting solution stirred for 25 min while maintaining the temperature at O⁰C. Quenched reaction by syringe addition of NaHCO₃ Sat. (50 mL) with cooling and maintaining the temperature blow 1O⁰C. The quenched reaction was extracted with Chloroform (2 x 25 mL), the organic layer was washed with brine (2 x 25 mL), dried organic layer_o.v.eiLMgS.O₄_(l g)_and.filtered, removed solvent in vacuo. Subjected crude material to reverse phase chromatography to produce the title compound. (55%). EIHRMS m/z 428.9986 (M+, C]₅Hi₂Cl₂ F₃NO₆ Calc'd 428.9994). ¹HNMR (CHCl₃-4/400 MHZ), 7.60 (s, IH), 7.35 (d, IH, J = 2.2Hz), 7.12 (s, IH), 5.76 (q, IH, J = 6.5Hz), 4.46 - 4.49 (m, 2H), 4.26 - 4.33 (m, 2H), 1.81 - 1.87 (m, 4H).

4-(nitrooxy)butyl (2S)-6-chloro-2-(trifluoromethyI)-2H-chromene-3-carboxylate

Step 1. Preparation of 4-hydroxybutyl (2S)-6-chloro-2-(trifluorornethyl)-2H-chrornene-3- carboxylate

[0166] The acid from US patent 6,271,253 Bl, Example 66 was esterified and purified according to the same procedure as Example 1, step 1. (99%) ESHRMS m/z 351.0613 (M+H,

Ci₅H₁₅ClO₄F₃ Calc'd 351.0605).

Step 2. Preparation of 4-(nitrooxy)butyl (2S)-6-chloro-2-(trifluoromethyl)-2H-chromene-3- carboxylate

[0167] The ester from step 1 was nitrated and purified using the same method as described in Example 1, step 2. EIHRMS m/z 395.0397 (M+, Ci₅Hi₃O₆NClF₃ CaIcM

395.0383). ¹HNMR (CHCl₃-^OO MHz), 7.61 (s, IH), 7.25 (d, IH, J = 2.4 Hz), 7.20 (d, IH, J = 2.4 Hz), 7.10 (d, IH, J = 8.7 Hz), 5.65 (q, IH, J = 6.8 Hz), 4.47 - 4.49 (m, 2H), 4.24 - 4.32 (m, 2H), 1.82 - 1.86 (m, 4H).

4-(nitrooxy)butyl (2R)-7-benzyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3- carboxylate

Step 1. Preparation of 2-hydroxy-4-iodobenzaldehyde.

[0168] To a chilled solution of commercially available 2-iodophenol (30 g, 136 mmole) in ACN was added MgCl₂ (19.5 g, 204 mmole) portion-wise while maintaining the temperature below 10 ⁰C, followed by paraformaldehyde (28.6 g, 954 mmole) and TEA (76 mL, 545 mmole) producing a 15 °C exotherm. The solution was heated to 72 ⁰C for 2 h. The reaction was cooled to room temperature and poured into Saturated aqueous Ammonium Chloride (500 mL), extracted with ethyl acetate (2 X 150 mL). The combined organic phases were washed with aqueous NaHCO₃ solution (2 X 150 mL), aqueous IN HCl solution (2 X 150 mL), and brine (2 X 150 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude material was subjected to flash chromatography (Silica, 5% Ethyl acetate/ Hexane). Desired fractions were collected and combined, removed solvent in vacuo producing the ethyl ester (27 g, 79%) as a yellow solid. This salicylaldehyde was of suitable purity to use without further purification. ¹HNMR (DMSO-^₆MOO MHz) 10.95 (s, IH), 10.19 (s, IH), 7.33 (m, 3H), 4.31 (m, IH). Step 2. Preparation of ethyl 7-iodo-2-(trifluoromethyl)-2H-chromene-3- carboxylate.

[0169] To a solution of the aldehyde from Step 1 (25 g, 114 mmole) (5 g, 27 mmole) in DMF (50 mL) was added, potassium carbonate (3.79 g, 27.5mmole) and ethyl 4,4,4- trifluorocrotonate (5.08 g, 30 mmole). The mixture was heated to 65 °C for 4 h. The reaction was-cooled to room temperature, poured into H₂O (150 mL), and extracted with ethyl acetate (2 X 150 mL). The combined organic phases were washed with aqueous NaHCO₃ solution (2 X 50 mL), aqueous 3 N HCl solution (2 X 50 mL), and brine (2 X 50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo producing the ethyl ester (15 g, 52%) as an amber oil. This ester was of suitable purity to use without further purification: ESHRMS m/z 361.1040 (M-H, C₁₃H₉IF₃O₃, Calc'd 361.1046).

Step 3. Preparation of ethyl 7-benzyl-2-(trifluorornethyl)-2H-chrornene-3- carboxylate.

[0170] To a solution of β-benzyl 9-BBN (20 mL, 10 mmole) in THF (20 mL) was added the ester from Step 2 dissolved into THF (25 mL), Pd(dppf)Cl CH₂Cl₂ (0.133 g, 5 mole %), K₃PO₄(aq)(3.5 mL, 7.1 mmole). The reaction was heated to 60 °C for 4 h. The reaction was cooled to room temperature and poured into Saturated aqueous Ammonium Chloride (500 mL), extracted with ethyl acetate (2 X 150 mL). The combined organic phases were washed with aqueous NaHCO₃ solution (2 X 150 mL), aqueous IN HCl solution (2 X 150 mL), and brine (2 X 150 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude material was subjected to flash chromatography (Silica, 5% Ethyl acetate/ Hexane). Desired fractions were collected and combined, removed solvent in vacuo producing the ethyl ester (1.4 g, 76%) as a pale yellow solid. This ester was of suitable purity to use without further purification: ESLRMS m/z 363 (M+H).

Step 4. Preparation of ethyl 7-benzyl-6-chloro-2-(trifIuorornethyl)-2H-chromene-3- carboxylate. [0171] The ester from Step 3 was dissolved into acetic acid (25 mL). Chlorine gas was bubble through this solution for 15 min. The solution was allowed to stand at room temperature for 30 minutes. The reaction was cooled to room temperature, poured into H₂O (150 mL), and extracted with ethyl acetate (2 X 150 mL). The combined organic phases were washed with aqueous NaHCO₃ solution (2 X 50 mL), aqueous 3N HCl solution (2 X 50 mL), and brine (2 X 50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo producing the ethyl ester (80%) as an amber oil. This ester was of suitable purity to use without further purification: ESLRMS m/z 397 (M+H).

Step 5. Preparation of 7-benzyl-6-chloro-2-(trifluoromethyl)-2H-chrornene-3-carboxylic acid.

[0172] To the ester from Step 4 was added THF(7):EtOH(2):H₂O(l) followed by LiOH (1.5 eq) and heated to 40 ⁰C for 4 h. The reaction was cooled to room temperature, concentrated in vacuo. Acidified with HCl to pH 1, filtered solid and subjected solid to preparative reverse phase chromatography to produce the title (99%): ESHRMS m/z 367.0343 (M-H, Ci₈H_nClF₃O₃, Calc'd 367.0329). ¹HNMR (DMSO-^₆MOO MHz) 13.34 (brs, IH), 7.81 (s, IH), 7.61 (s, IH), 7.25 - 7.29 (m, 2H), 7.17 - 7.19 (m, 3H), 6.99 (s, IH), 5.89 (q, IH, J= 7.1 Hz), 4.00 (s, 2H).

Step 6. Preparation of (2R)-7-benzyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3- carboxylic acid

[0173] A racemic mixture of the compound prepared in step 5 was resolved by chiral separation using Chiralcel OJ column eluting with EtOH/heptane/TFA = 5/95/0.1 and detecting at 254nm as peak 2 with retention time 5.76 min: ESHRMS m/z 367.0343 (M-H, C_2OHnClF₃O₃, Calc'd 367.0329). ¹HNMR (DMSO-d«/400 MHz) 13.34 (brs, IH), 7.81 (s, IH), 7.61 (s, IH), 7.25 - 7.29 (m, 2H), 7.17 - 7.19 (m, 3H), 6.99 (s, IH), 5.89 (q, IH, J= 7.1 Hz), 4.00 (s, 2H). [α]²⁵ ₅₈₉ = + 2.0 in MeOH. Step 7. Preparation of 4-hydroxybutyl (2R)-7-benzyl-6-chloro-2-(trifluoromethyl)-2H- chromene-3-carboxylate

[0174] The acid from step 6 was esterified using the same method as described in

Example 1, step 1. ESHRMS m/z 441.1082 (M+H, C₂₂H₂₁ClO₄F₃ Calc'd 441.1075)

Step-8-Ereparation-of-4^fnitroox-V-)butyl-(2RV7^benzyl-6-chloro-2-(trifluoromethvπ-2H- chromene-3-carboxylate

[0175] The ester from step 7 was nitrated using the same method as described in Example

1, step 2. EIHRMS m/z 485.0851 (M+, C₂₂H₁₉O₆NClF₃ Calc'd 485.0853). ¹HNMR (CHCl₃-

4/400 MHz), 7.60 (s, IH), 7.14 - 7.28 (m, 6H), 6.73 (s, IH), 5.60 (q, IH, J = 8.7Hz), 4.47 (s,

2H), 4.27 (s, 2H), 4.05 (s, 2H), 1.81 - 1.84 (m, 4H).

4-(nitrooxy)butyl (2S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3- carboxylate

Step 1. Preparation of 4-hydroxybutyl (2S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H- chromene-3-carboxylate

[0176] The acid from US patent 6,271,253 Bl, Example 67 was esterified using the same method as described in Example 1, step 1. EIHRMS m/z 400.0766 (M+, C]₆H₁₄O₅F₆ Calc'd

400.0745).

Step 2. Preparation of 4-(nitrooxy)butyl (2S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H- chromene-3-carboxylate [0177] The ester from step 1 was nitrated using the same procedure as described in in Example 1, step 2. EIHRMS m/z 445.0583 (M+, C₁₆H₁₃O₇NF₃ CaIcM 445.0596). ¹HNMR (CHCl₃- J/400 MHz), 7.64 (s, IH), 7.14 (d, IH, J = 8.8 Hz), 7.09 (s, IH), 6.97 (d, IH, J = 8.8 Hz), 5.67 (q, IH, J = 6.7 Hz), 4.48 (s, 2H), 4.28 - 4.32 (m, 2H), 1.83 - 1.84 (m, 4H).

Biological Evaluation

[0178] Further description of the methods for biological evaluation are found in U.S. Patent No. 6,077,850, herein incorporated by reference. U.S. Patent No. 6,034,256 (herein incorporated by reference) also provides description of biological evaluation methods. Additional description of methods is provided in U.S. Patent No. 6,271,253, herein incorporated by reference.

Isolated rat aortic ring assay

[0179] The isolated rat aortic ring assay can be used to evaluate function and regulation of vascular smooth muscle. Various extrinsic and intrinsic factors affect vascular smooth muscle cells, which regulate vascular tone. The radius of the blood vessel changes as the VSMCs contract or relax. Isolated aortic rings are attached to force transducers and changes in tension are recorded as the vessel responds to different agents. It is also possible to predict from the vascular activity in this assay, the effects of these agents on vascular resistance and blood pressure in-vivo.

[0180] Two baths containing isolated rat aortic rings are established. A baseline tension is produced and stabilized at 1.4 grams followed by the addition of 3.0 mM L-NAME to each bath and both are allowed to incubate for 10 minutes. Norepinephrine (300 nM) is prepared in lmg/ml of ascorbic acid; this vasoconstrictor is added to the bath and allowed to plateau over a 20-minute period. Acetylcholine (lμM) is then added to the bath to assess the presence of endogenous NO in the bath. The vessel has previously shown a response to acetylcholine, under these conditions, with L-NAME in the bath, there should be no response. Cysteine (ImM) enhances the release of NO, and is added to the bath 10 minutes after the ACh. This is allowed to incubate in the bath for 25 minutes and the vessel response is allowed to plateau. Test compounds are prepared as stock solutions dissolved in DMSO. These are then diluted to IOOOX the concentration required in the bath. Once a concentration has been added, the response is allowed to plateau prior to adding the next concentration, usually 10 - 30 minutes. A 10-point concentration response curve was generated for each compound and GTN-was-used as the positive control-in each run.

[0181] The purpose of these experiments is to demonstrate NO donor activity in novel compounds versus inactive parent (COX-2 inhibitor) compounds. Since endothelium intact rings are used in this assay, L-NAME is added for complete inhibition of endogenous NO. The vessel has no response to Acetylcholine once L- NAME is present, ensuring that subsequent vasodilation is due to NO donor activity of the compounds. Cysteine is added to the bath because it enhances the release of NO from the compounds. Glyceryl trinitrate (GTN) is used as a positive control in this assay because its NO donor activity is also enhanced by cysteine.

Air Pouch Assay

[0100] The carrageenan-induced prostaglandin production rat air pouch assay can be performed in a prophylactic dosing regimen with materials, reagents and procedures essentially as described by Masferrer, et.al., (Proc. Natl. Acad. Sci. 91:3228-3232 (1994)). Air pouches are produced by subcutaneous injection of sterile air into the intrascapular area of the back of male Lewis rats (175-200 g). Pouches are allowed to develop for one day. Rats are fasted with free access to water for over sixteen hours prior to drug administration. Drugs or vehicle are administered by gavage one hour prior to injection of 2 ml of a 1% suspension of carrageenan (Sigma Chemical Co, St. Louis MO Cat# C3889) dissolved in saline into the pouch. At five hours post- carrageenan injection, the pouch fluid is collected by lavage with 1 ml of cold heparin- saline. The fluid is centrifuged and the supernatants are collected for analysis of PGE₂. Prostaglandin levels are quantitated by ELISA (Cayman Chemical Company, Ann Arbor, MI). Evaluation of COX-I and COX-2 activity in vitro

[0182] The compounds of this invention exhibited inhibition in vitro of COX-2. The COX-2 inhibition activity of the compounds of this invention illustrated in the examples were determined by the following methods.

a. Preparation of recombinant COX baculoviruses

[0183] Recombinant COX-I and COX-2 were prepared as described by Gierse et al. [J. Biochem., 305, 479-84 (1995)]. A 2.0 kb fragment containing the coding region of either human or murine COX-I or human or murine COX-2 was cloned into a BamHl site of the baculovirus transfer vector pVL1393 (Invitrogen) to generate the baculovirus transfer vectors for COX-I and COX-2 in a manner similar to the method of D.R. O'Reilly et al (Baculovirus Expression Vectors: A Laboratory Manual (1992)). Recombinant baculoviruses were isolated by transfecting 4 μg of baculovirus transfer vector DNA into SF9 insect cells (2x10^) 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 were purified by three rounds of plaque purification and high titer (10^-10^ pfu/mL) stocks of virus were prepared. For large scale production, SF9 insect cells were infected in 10 liter fermentors (0.5 x lO^/mL) with the recombinant baculovirus stock such that the multiplicity of infection was 0.1. After 72 hours the cells were centrifuged and the cell pellet homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1% 3-[(3- cholamidopropyl)dimethylammonio]-l-propanesulfonate (CHAPS). The homogenate was centrifuged at 10,00OxG for 30 minutes, and the resultant supernatant was stored at

-8O⁰C before being assayed for COX activity.

b. Assay for COX-I and COX-2 activity

[0184] COX activity was 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 were 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 were pre-incubated with the enzyme for about 10 minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme was 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 was measured by standard ELISA technology (Cayman Chemical). Results are shown in Table 11.

c. Modified assay for COX-I and COX-2 activity

[0185] COX activity was 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 were incubated in a potassium phosphate buffer (0.05 M Potassium phosphate, pH 7.5, 2 μM phenol, 1 μM heme, 300 μM epinephrine) with the addition of 20 μl of 100 μM arachidonic acid (10 μM). Compounds were pre-incubated with the enzyme for about 10 minutes at 25 ⁰C prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme was stopped after two 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 was measured by standard ELISA technology (Cayman Chemical). Results are shown in Table 2.

Table 2

* * * * * * * * *

[0186] The above detailed description is intended only to acquaint others skilled in the art with the invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This invention, therefore, is not limited to the above embodiments, and may be variously modified.

Claims

ClaimsWhat is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:

X is selected from the group consisting of O and NH;

Z is selected from the group consisting of O, S and NH; n is an integer from 1 to 5;

R¹, R², R , and R⁴ are each independently selected from the group consisting of H, alkanoyl, alkenyl, alkenylalkynyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxyalkynyl, alkoxyaryl, alkoxyarylalkenyl, alkoxyarylalkyl, alkoxyarylalkynyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylaminoarylalkyl, alkoxyheteroaryl, alkyl, alkylamino, alkylaminoalkyl, alkylaminoalkynyl, alkylaminoarylalkyl, alkylaryl, alkylarylalkoxy, alkylarylalkyl, alkylarylalkynyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaminoalkyl, alkylheteroaryl, alky lheteroaryl alkyl, alkylheteroaryl alkynyl, alkylheterocyclo, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkynyl, amino, aminoalkyl, aminoalkynyl, aminoarylalkynyl, aminoaryl, aminocarbonyl alkenyl, aminocarbonylalkyl, aminosulfonylaryl, aminosulfonylarylalkynyl, aryloxyalkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylamino, arylcarbonyl, arylalkylthio, arylalkynyl, arylaminoalkyl, arylheteroarylalkyl, arylthio, arylthioalkyll, aryloxy, aryloxyalkyl, alkanoylalkyl, alkanoylheteroarylalkyl, carboxy, carboxyalkoxy, carboxyalkyl, carboxyarylalkyl, cyano, cyanoalkyl, cyanoalkynyl, cycloalkoxy, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cyclpalkylalkylamino, cycloalkylalkynyl, dialkylamino, diheteroarylalkylaminoalkyl, halo, haloalkoxy, haloalkyl, haloalkylarylalkynyl, haloalkylhydroxyalkyl, haloarylalkyl, haloarylalkynyl, haloarylcarbonylaminoalkyl, haloheteroarylalkyl, haloheteroarylcarbonylalkyl, heteroaryl, heteroarylalkenyl ,heteroarylalkoxy, heteroarylalkyl, heteroarylalkynyl, heteroarylalkylaminoalkyl, heteroaryloxy, heteroarylcarbonyl, heteroarylhydroxyalkyl, heterocyclo, heterocycloalkoxy, heterocycloalkyl, heterocyclyloxy, heteroarylcarbonylaminoalkyl, hydroxy, hydroxyalkynyl, hydroxyalkyl, hydroxyaryl, hydroxyarylalkynyl, carboxyalkynyl, hydroxycycloalkylalkynyl, nitro, and thio; wherein: each alkyl, aryl, heteroaryl, and heterocyclo, wherever they occur, is optionally and independently substituted with one or more substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, alkanoyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, dialkylamino, halo, haloalkoxy, haloalkyl, haloaryl, hydroxy,. hydroxyalkyl, oxo and nitro; wherein R¹ and R² together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; R and R together with the atoms to which they are attached optionally form a cycloalkyl ring, a heterocyclo ring or a heteroaryl ring; R³ and R⁴ together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; wherein the cycloalkyl ring and the heteroaryl ring wherever they occur are optionally and independently substituted with one or more substitutents selected from the group consisting of alkyl, aryl, haloaryl, arylalkyl and heterocyclo; and

R⁶ is selected from the group consisting of hydrogen, hydroxy, -ONO₂, halogen, nitroxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms, wherein each of hydroxy, nitroxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms are independently and optionally substituted with a radical selected from the group consisting of hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amino, nitro, cyano, carboxyl and haloalkyl; or

R⁶ is a group of the formula OCO-R⁷ wherein R⁷ is selected from the group consisting of carboxyalkyl, alkyl, alkenyl, alkynyl, and alkoxy.

2. The compound of Claim 1 wherein R¹, R², R³, and R⁴ are independently selected from the group consisting of alkoxyaryl, alkoxyarylalkenyl, alkoxyarylalkyl, alkoxyarylalkynyl, alkoxycarbonylaminoarylalkyl, alkylaminoarylalkyl, alkylaryl, alkylarylalkoxy, alkyl aryl alkyl, alkylarylalkynyl, aminoarylalkynyl, aminoaryl, aminocarbonylalkenyl, aminosulfonylaryl, aminosulfonylarylalkynyl, aryloxyalkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylamino, arylcarbonyl, aryl alky lthio, arylalkynyl, arylaminoalkyl, arylheteroarylalkyl, arylthio, arylthioalkyll, aryloxy, aryloxyalkyl, carboxyarylalkyl, haloalkylarylalkynyl, haloarylalkyl, haloarylalkynyl, haloarylcarbonylaminoalkyl, hydroxyaryl and hydroxyarylalkynyl, wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, alkanoyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, dialkylamino, halo, haloalkoxy, haloalkyl, haloaryl, hydroxy, hydroxyalkyl, and nitro; wherein R¹, R², R³, and R⁴ are independently heteroaryloxy, wherein heteroaryloxy is optionally and independently substituted with one to three substituents selected from the group consisting of alkyl, alkylthio, halo and haloalkyl; wherein R¹, R , R , and R⁴ are independently selected from the group consisting of alkoxyheteroaryl, alkylheteroaryl, alkylheteroaryl alkyl, alkylheteroarylalkynyl, arylheteroarylalkyl, alkanoylheteroarylalkyl, diheteroarylalkylaminoalkyl, haloheteroarylalkyl, haloheteroarylcarbonylalkyl, heteroaryl, heteroarylalkenyl ,heteroarylalkoxy, heteroarylalkyl, heteroarylalkynyl, heteroarylalkylaminoalkyl, heteroarylcarbonyl, heteroarylhydroxyalkyl and heteroarylcarbonylaminoalkyl, wherein each heteroaryl is optionally and independently substituted with one to three substituents selected from the group consisting of carboxy, haloalkyl, and halo; and wherein R¹, R², R³, and R⁴ are independently aelected from the group consisting of alkylheterocyclo, heterocyclo, heterocycloalkoxy and heterocycloalkyl, wherein each heterocyclo is optionally and independently substituted with one to three substituents selected-froπUhe group-consisting-of-alkyl,-alkoxy- and oxo — -

3. The compound of Claim 2 wherein Z is O.

4. The compound of Claim 3 wherein R⁶ is ONO₂.

5. The compound of Claim 3 wherein n is 4.

6. The compound of Claim 3 wherein X is O.

7. The compound of Claim 3 wherein R⁶ is ONO₂, n is 4, and X is O.

8. The compound of Claim 3 wherein R¹, R , R , and R⁴ are defined as in Claim 2.

9. The compound of Claim 8 wherein R¹' R², R³, and R⁴ are each independently selected from the group consisting of H, (C₁-Cio)-alkanoyl, (C₂-Cio)-alkenyl, (C₂-C₁o)-alkenyl-(C₂- Cio)-alkynyl, (C₂-Cio)-alkenyloxy, (Ci-Cio)-alkoxy, (C₁-Ci₀)-alkoxy-(C₁-Ci₀)-alkoxy, (Ci- C₁₀)-alkoxy-(C,-C₁₀)-alkyl, (Ci-Cio)-alkoxy-(C₂-C₁₀)-alkynyl, (Ci-Cio)-alkoxyaryl, (Ci-C₁₀)- alkoxyaryl-(C₂-Cio)-alkenyl, (Ci-Cio)-alkoxyaryl-(Ci-Cio)-alkyl, (Ci-Ci₀)-alkoxyaryl-(C₂- C i o)-alkynyl, (C i -C i o)-alkoxycarbonyl-(C i -C ₁₀)-alkyl, (Ci-Ci ₀)-alkoxycarbonylamino-(C i - Cio)-alkyl, (C₁-Ci₀)-alkoxycarbonylaminoaryl-(Ci-C₁₀)-alkyl, (Ci-Cio)-alkoxyheteroaryl, (C]- Cio)-alkyl, (Ci-Cio)-alkylamino, (Ci-Ci₀)-alkylamino-(Ci-Cio)-alkyl, (Ci-Cio)-alkylamino- (C₂-Ci₀)-alkynyl, (Ci-Ci₀)-alkylaminoaryl(Ci-Ci₀)-alkyl, (Ci-Cio)-alkylaryl, (Ci-Ci₀)- alkylaryl-(C,-C,₀)-alkoxy, (C,-Cio)-alkylaryl-(C,-Cio)-alkyl, (Ci-Cio)-alkylaryl-(C₂-Cio)- alkynyl, (Ci-Cio)-alkylcarbonyl, (Ci-Ci₀)-alkylcarbonyl-(Ci-Ci₀)-alkyl, (Ci-Ci₀)- alkylcarbonylamino-CQ-Q_tO-alkyl, (Ci-C₁₀)-alkylheteroaryl, (Ci-Ci₀)-alkylheteroaryl-(C₁- Cio)-alkyl, (Ci-C₁₀)-alkylheteroaryl-(C₂-Ci₀)-alkynyl, (Ci-C₁₀)-alkylheterocyclo, (C₁-C₁₀)- alkylthio, (Ci-Cio)-alkylthio-(Ci-C₁₀)-alkyl, (Ci-Cio)-alkylsulfinyl, (C_rC₁₀)-alkylsulfonyl, (C₁-Cio)-alkylsulfonyl-(C₁-Cio)-alkyl, (C₂-C io)-alkynyl, amino, amino-(Ci-Cio)-alkyl, amino- (C₂-C₁o)-alkynyl, aminoaryl-(C₂-C₁o)-alkynyl, aminoaryl, aminocarbonyl-(C₂-C₁o)-alkenyl,

aminosulfonylaryl, aminosulfonylaryl-(C₂-C₁₀)-alkynyl, aryl- (C₁-C₁₀)-alkoxy-(C₂-Cio)-alkynyl, aryl, aryl-(C₂-Cj₀)-alkenyl, aryl-(C₁-C₁₀)-alkoxy, aryl-(Ci- C_!o)-alkyl, aryl-(Ci-C₁o)-alkylamino, arylcarbonyl, aryl-(Ci-Ci₀)-alkylthio, aryl-(C₂-Ci₀)- alkynyl, arylamino-(C₁-Ci₀)-alkyl, arylheteroaryl-(C₁-C₁o)-alkyl, arylthio, arylthio-tQ-Cio)- alky, aryloxy, aryloxy-(C₁-C₁₀)-alkyl, (C₁-C₁₀)-alkanoyl-(C₁-C₁₀)-alkyl, (C₁-C₁₀)- alkanoylheteroaryl-(Cj-C]o)-alkyl, carboxy, carboxy-(C]-Ci₀)-alkoxy, carboxy-(Ci-Cio)- alkyl, carboxyaryl-(C]-Cio)-alkyl, cyano, cyano-(CrC₁₀)-alkyl, cyano-(C₂-C₁₀)-alkynyl, cyclo-(Ci-C₁₀)-alkoxy, cyclo-(Ci-Ci₀)-alkyl, cyclo-(C₁-C₁₀)-alkyl-(Ci-C₁₀)-alkoxy, CyCIo-(C₁-

cyclo-(Ci-C,₀)-alkyl-(Ci-Cio)-alkylamino, cyclo-(Ci-Ci₀)-alkyl- (C₂-C]₀)-alkynyl, di-(C₁-Cio)-alkylamino, diheteroaryl-(Ci-C₁₀)-alkylamino-(Ci-Ci₀)-alkyl, halo, halo-(Ci-C₁₀)-alkoxy, halo-(Ci-C_]0)-alkyl, halo-(C₁-Ci₀)-alkylaτyl-(C₂-Ci₀)-alkynyl,

haloaτyl-(C₂-C₁₀)- alkynyl, haloarylcarbonylamino-(Ci-C₁₀)-alkyl, haloheteroaryl-(C₁-Ci₀)-alkyl, haloheteroarylcaτbonyl-(Ci-Cio)-alkyl, heteroaryl, heteroaryl-(C₂-Ci₀)-alkenyl ,heteroaryl- (C]-C₁₀)-alkoxy, heteroaτyl-(Ci-Ci₀)-alkyl, heteroaτyl-(C₂-C₁₀)-alkynyl,

alkylamino-(C₁-Cio)-alkyl, heteroaryloxy, heteroarylcarbonyl, HeIeTOaTyIlIyOrOXy-(C₁-Ci_O)- alkyl, heterocyclo, heterocyclo^CrQoJ-alkoxy, heterocyclo-(C]-C₁₀)-alkyl, heterocyclyloxy, heteτoarylcarbonylamino-(C₁-C₁o)-alkyl, hydroxy, hydroxyl-(C₂-C₁₀)- alkynyl, hydroxyl-(Ci-Cio)-alkyl, hydroxyaryl, hydroxyaryl-(C₂-C₁₀)-alkynyl, carboxy-(C₂- do)-alkynyl, hydroxycyclo-(Ci-Cio)-alkyl-(C₂-C₁o)-alkynyl, nitro, and thio; wherein: each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of (C₂-C_!o)-alkenyl, (Cr Cio)-alkoxy, (Ci-Cio)-alkoxycarbonyl, (Ci-Cio)-alkoxycarbonyl-(C₂-Cio)-alkenyl, (Ci- Cio)-alkoxycarbonyl-(Ci-Cio)-alkyl, (Ci-Cio)-alkyl, (C_]-Ci₀)-alkylamino, (Ci-C₁₀)- alkylcarbonyl, (Ci-CioJ-alkylcarbonylamino, (Ci-Cio)-alkylsulfonylamino, (Ci-Ci₀)- alkylthio, (C₂-Ci₀)-alkynyl, amino, amino-(Ci-Cio)-alkyl, aminocarbonyl, aryl, aryl- (Ci-Cio)-alkoxy, aryl-(Ci-C!o)-alkyl, aryloxy, (Ci-Cio)-alkanoyl, carboxy, carboxy- (C₂-Cio)-alkenyl, carboxy-(C₁-C₁₀)-alkyl, cyano, cyano-(Cj-Cio)-alkyl, cyclo-(Q- Ci_O)-alkyl, di-(C₁-C₁₀)-alkylamino, halo, halo-(Cj-Cio)-alkoxy, halo-(Ci-C₁₀)-alkyl, haloaryl, hydroxy, hydroxyl-(C₁-C₁o)-alkyl, and nitro; each.heteroaryloxyJs optionally and.independently substituted with one to three substituents selected from the group consisting of alkyl, alkylthio, halo and haloalkyl; each heteroaryl is optionally and independently substituted with one to three substituents selected from the group consisting of carboxy, haloalkyl, and halo; and each heterocyclo is optionally and independently substituted with one to three substituents selected from the group consisting of alkyl, alkoxy and oxo; and wherein R¹ and R² together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; R² and R³ together with the atoms to which they are attached optionally form a cycloalkyl ring, a heterocyclo ring or a heteroaryl ring; R³ and R⁴ together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; wherein the cycloalkyl ring and the heteroaryl ring wherever they occur are optionally and independently substituted with one or more substitutents selected from the group consisting of alkyl, aryl, haloaryl, arylalkyl and heterocyclo.

10. The compound of Claim 9 wherein R¹, R², R , and R⁴ are each independently selected from the group consisting of H, (C₂-C _!o)-alkenyl, (C₂-Cio)-alkenyl-(C₂-C₁o)-alkynyl, (C₂- C₁₀)-alkenyloxy, (C _!-C₁₀)- alkoxy, (C₁-C₁₀)-alkoxy-(C₂-do)-alkynyl, (Ci-Ci₀)- alkoxyheteroaryl, (Cj -Ci₀)- alkyl, (Ci-C₁₀)-alkylamino, (Ci-Ci₀)-alkylaryl(C₁-C₁₀)-alkyl, (Ci- Cio)-alkylaryl-(C₂-Cio)-alkynyl, (Ci-C₁₀)-alkylcarbonyl, (Ci-Cio)-alkylheteroaryl, (Ci-C₁₀)- alkylheteroaryl-(Ci-Cio)-alkyl, (C]-Cio)-alkylheteroaryl-(C₂-Ci₀)-alkynyl, (C₁-C₁₀)- alkylsulfonyl-(C]-Cio)-alkyl, (C)-Cio)-alkylthio, (C₂-Ci₀)-alkynyl, aminoaryl-(C₂-Ci₀)- alkynyl, aryl, aryl-(C₂-C]₀)-alkynyl, aryl-(C]-Ci_O)-alkyl, arylcarbonyl, aryloxy, (C₁-C₁₀)- alkanoylheteroaryl-(Ci-Ci₀)-alkyl, cyano-(C_!-Cio)-alkyl, cyano-(C₂-Ci₀)-alkynyl, cyclo-(Ci- Cio)-alkoxy, CyCIo-(C₁-CiO)-HIlCyI(C₁-C_1O)-HIkOXy, cyclo-(C₁-C₁₀)-alkyl-(C₁-C₁₀)-alkyl, cyclo- (C₁-Cio)-alkyl-(C₁-Cio)-alkylamino, di(Ci-Ci₀)-alkylamino, halo,

halo- (C₁-Cio)-alkylaryl-(C₂-Cio)-alkynyl, haloaryl-(Ci-C₁o)-alkyl, haloaryl-(C₂-C₁₀)-alkynyl, haloarylcarbonylamino-(Ci-Cio)-alkyl, heteroaryl, heteroaryl(Ci-Cio)-alkoxy, heteroaryl-(Ci- C₁₀)-alkyl, heteroaryl-(C₂-Cio)-alkynyl, heteroaryloxy, heterocyclo, hydroxy, hydroxy-(C₂- Cio)=alkynyl, hydroxyaryU(C₂-C₁o)-alkynyl, and-hydroxycyclθr(C₁-C₁o)-alkyl-(C₂-Cio)- - alkynyl; wherein each aryl, wherever it occurs, is independently substituted with one to five substituents selected from the group consisting of (C₂-Cio)-alkenyl, (C₁-C_1O)- alkoxy,

(C₁-C₁₀)-alkyl, (C₁-C₁o)-alkylamino, (C₁-Ci_O)- alkylthio, (C₂-Ci₀)-alkynyl, amino, aryl-(Ci-C_!o)-alkyl, alkanoyl, carboxy-(Ci-Cio)- alkyl, cyano, cyano-(C₁-Cio)-alkyl, halo, halo-(Ci-Cio)-alkoxy, halo-(Ci-C_!o)-alkyl, hydroxyl, hydroxy-(Ci-Cio)-alkyl and nitro; and wherein: each heteroaryloxy is optionally and independently substituted with one to three substituents selected from the group consisting of: (Ci-Cio)-alkyl, and halo; and each heteroaryl is optionally and independently substituted with one to three substituents selected from the group consisting of halo-(Cj-Cio)-alkyl, and halo; and wherein R¹ and R² together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; R and R together with the atoms to which they are attached optionally form a cyclo-(Ci-Cio)-alkyl ring or a heteroaryl ring; R³ and R⁴ together with the atoms to which they are attached optionally form a cyclo-(Ci-Cio)-alkyl ring or a heteroaryl ring; wherein the cyclo-(Ci-Cio)-alkyl ring and the heteroaryl ring are optionally substituted with one or more (Ci-C]o)-alkyl groups.

11. The compound of Claim 10 wherein R¹ , R², R³, and R⁴ are each independently selected from the group consisting of H, (C₂-C io)-alkenyl

(C₁-C₁o)-alkoxy- (C₂-Cio)-alkynyl, (Ci-C_]0)-alkyl, (C₁-Ci₀)-alkylamino, (Ci-Ci_O)-alkylaryl-(Ci-Ci_O)-alkyl, (Ci-C₁₀)-alkylthio, (C₂-Ci₀)-alkynyl, aryl, aryl-(C,-Ci_O)-alkyl, aryl-(C₂-Ci₀)-alkynyl, arylcarbonyl, cyclo-(Ci-C₎₀)-alkyl-(Ci-Cio)-alkoxy, cyclo-(Ci-C₁₀)-alkyl-(Ci-Ci₀)-alkyl, (Ci- Cio)-alkylsulfonyl-(Ci-Cio)-alkyl, cyclo-(Ci-Cio)-alkyl-(Ci-Cio)-alkylamino, di-(Ci-Cio)- alkylamino, halo, halo-(Ci-Cio)-alkoxy , haloaryl-(C]-Cio)-alkyl, haloaryl-(C₂-Cio)-alkynyl, heteroaryl, heteroaryl-(Ci-do)-alkyl, heteroaryloxy, and heterocyclo; wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of: (C₂- Cio)-alkenyl, (Ci-Cio)-alkoxy, (d-Cio)-alkyl, (d-C₁₀)-alkylthio, (C₂-Ci₀)-alkynyl,

_ amino,-cyano,-halo,-halo4Ci-Cio)=alkoxy,-halo=(Ci-_iCio)=alkyl,-and-h.ydroxy-(Ci-Cio)- alkyl; wherein heteroaryl, wherever it occurs, is optionally and independently substituted with one to three substituents selected from the group consisting of: halo- (C₁-Cio)-alkyl, and halo.

12. The compound of Claim 11 wherein R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, (Ci-Cio)-alkoxy, (Ci-Ci₀)-alkoxy-(C₂-C₁o)-alkynyl, (Ci-Cio)-alkyl, (C₁-C₁₀)-alkylamino, (C₁-C₁₀)-alkylaryl-(C₁-C₁₀)-alkyl, (Ci-Cio)-alkylthio, (C₁-Cio)-alkylsulfonyl-(Ci-Cio)-alkyl, (C₂-Ci₀)-alkynyl, aryl, aryl-(Ci-Ci_O)-alkyl, aryl-(C₂- Cio)-alkynyl, arylcarbonyl, cyclo-(C₁-Cio)-alkyl-(Ci-C₁o)-alkoxy, halo, halo-(C₁-Cio)-alkoxy, haloaryl-(Ci-Cio)-alkyl, haloaryl-(C₂-C₁₀)-alkynyl, heteroaryl-(Ci-Ci₀)-alkyl, and heterocyclo; and wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of (C₂- Ci_O)-alkenyl, (Ci-Cio)-alkoxy, (Ci-C,₀)-alkyl, (C₁-Ci₀)-alkylthio, (C₂-C₁₀)-alkynyl, cyano, halo, and halo-(CrCio)-alkoxy.

13. The compound of Claim 12 wherein R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, (Ci-C₈)-alkoxy, (Ci-C₈)-alkoxy-(C₂-C₈)-alkynyl, (Ci-C₈)-alkyl, (Ci-C₈)-alkylamino, (Ci-C₈)-alkylaryl-(C₁-C₈)-alkyl, (Ci-C₈)-alkylthio, (C,- C₈)-alkylsulfonyl-(Ci-C₈)-alkyl, (C₂-C₈)-alkynyl, aryl, aryl-(Ci-C₈)-alkyl, aryl-(C₂-C₈)- alkynyl arylcarbonyl, cyclo-(Ci-C₈)-alkyl-(C]-C₈)-alkoxy, halo, halo-(Ci-C₈)-alkoxy, haloaryl-(Ci-C₈)-alkyl, haloaryl-(C₂-C₈)-alkynyl, heteroaryl-(C]-C₈)-alkyl, and heterocyclo; and wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of (C₂- C₈)-alkenyl, (Ci-C₈)-alkoxy, (d-C₈)-alkyl, (C₁-C₈)-alkylthio, (C₂-C₈)-alkynyl, cyano, halo, and halo-(Ci-C₈)-alkoxy.

_14. The-compound-of-Claim-lS-wherein-Rl.-R-_^R^-and Rtare-each-independently selected from the group consisting of H, (d-C₆)-alkoxy, (C₁-C₆)-alkoxy-(C₂-C₆)-alkynyl, (Ci-C₆)-alkyl, (d-C₆)-alkylamino, (C_rC₆)-alkylaryl-(C₁-C₆)-alkyl, (Cj-C₆)-alkylthio, (C₁- C₆)-alkylsulfonyl-(Ci-C₆)-alkyl, (C₂-C₆)-alkynyl, aryl, aryl-(C₁-C₆)-alkyl, aryl-(C₂-C₆)- alkynyl arylcarbonyl, cyclo-(C₁-C₆)-alkyl-(Ci-C₆)-alkoxy, halo, halo-(CrC₆)-alkoxy, haloaryl-(C]-C₆)-alkyl, haloaryl-(C₂-C₆)-alkynyl, heteroaryl-(d-C₆)-alkyl, and heterocyclo; and wherein each aryl, wherever it occurs, is optionally and independently substituted with one to five substituents selected from the group consisting of (C₂- C₆)-alkenyl, (Ci-C₆)-alkoxy, (Ci-C₆)-alkyl, (d-C₆)-alkylthio, (C₂-C₆)- alkynyl, cyano, halo, and halo-(d-C₆)-alkoxy.

15. The compound of Claim 1 selected from the group consisting of

4-(nitrooxy)butyl (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3- carboxylate;

4-(nitrooxy)butyl (2S)-6-chloro-2-(trifluoromethyl)-2H-chromene-3- carboxylate;

4-(nitrooxy)butyl (2R)-7-benzyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3- carboxylate; and

4-(nitrooxy)butyl (2S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H- chromene-3-carboxylate, or their isomer and pharmaceutically acceptable salt thereof.

16. The compound of Claim 1 having an S-absolute configuration at the 2-carbon of Formula 1.

17. The compound of Claim 1 having an R-absolute configuration at the 2-carbon of Formula 1.

18. The compound of Claim 1 having a mixture of S- and R-absolute configuration at the _2-carbon_of-Eormula-l .

19. A pharmaceutical composition comprising a compound of Formula I

or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:

X is selected from the group consisting of O and NH;

Z is selected from the group consisting of O, S and NH; n is an integer from 1 to 5;

R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, alkanoyl, alkenyl, alkenylalkynyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxyalkynyl, alkoxyaryl, alkoxyarylalkenyl, alkoxyarylalkyl, alkoxyarylalkynyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylaminoarylalkyl, alkoxyheteroaryl, alkyl, alkylamino, alkylaminoalkyl, alkylaminoalkynyl, alkylaminoarylalkyl, alkylaryl, alkylarylalkoxy, alkylarylalkyl, alkylarylalkynyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaminoalkyl, alkylheteroaryl, alkylheteroaryl alkyl, alkylheteroarylalkynyl, alkylheterocyclo, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkynyl, amino, aminoalkyl, aminoalkynyl, aminoarylalkynyl, aminoaryl, aminocarbonylalkenyl, aminocarbonylalkyl, aminosulfonylaryl, aminosulfonylarylalkynyl, aryloxyalkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylamino, arylcarbonyl, arylalkylthio, arylalkynyl, arylaminoalkyl, arylheteroarylalkyl, arylthio, arylthioalkyl, aryloxy, aryloxyalkyl, alkanoylalkyl, _alkano-ylheteroarylalkyl,xarboxy,_carboxyalkoxy,_carboxyalkyl,-carbox.yarylalkyl, cyano, cyanoalkyl, cyanoalkynyl, cycloalkoxy, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cycloalkylalkylamino, cycloalkyl alkynyl, dialkylamino, diheteroarylalkylaminoalkyl, halo, haloalkoxy, haloalkyl, haloalkylarylalkynyl, haloalkylhydroxyalkyl, haloarylalkyl, haloarylalkynyl, haloarylcarbonylaminoalkyl, haloheteroarylalkyl, haloheteroarylcarbonylalkyl, heteroaryl, heteroarylalkenyl ,heteroarylalkoxy, heteroarylalkyl, heteroaryl alkynyl, heteroarylalkylaminoalkyl, heteroaryloxy, heteroarylcarbonyl, heteroarylhydroxyalkyl, heterocyclo, heterocycloalkoxy, heterocycloalkyl, heterocyclyloxy, heteroarylcarbonylaminoalkyl, hydroxy, hydroxyalkynyl, hydroxyalkyl, hydroxyaryl, hydroxyarylalkynyl, carboxyalkynyl, hydroxycycloalkylalkynyl, nitro, and thio; wherein: each aryl, heteroaryl, and heterocyclo, wherever they occur, is optionally and independently substituted with one to five substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, alkanoyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, dialkylamino, halo, haloalkoxy, haloalkyl, haloaryl, hydroxy, hydroxyalkyl, oxo and nitro; and wherein R¹ and R² together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; R² and R³ together with the atoms to which they are attached optionally form a cycloalkyl ring, a heterocyclo ring or a heteroaryl ring; R³ and R⁴ together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; wherein the cycloalkyl ring and the heteroaryl ring wherever they occur are optionally and independently substituted with one or more substitutents selected from the group consisting of alkyl, aryl, haloaryl, arylalkyl and heterocyclo; i R⁶ is selected from the group consisting of hydrogen, hydroxy, -ONO₂, halogen, nitrpxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms, wherein each of hydroxy, nitroxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms are independently and optionally substituted with a radical selected from the group consisting of hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amino, nitro, cyano, carboxyl and haloalkyl; or

R⁶ is a group of the formula OCO-R⁷ wherein R⁷ is selected from the group consisting of carboxyalkyl, alkyl, alkenyl, alkynyl, and alkoxy; and a pharmaceutically acceptable excipient.

20. A method for the treatment or prevention of a COX-2 mediated disorder in a subject in need of such treatment or prevention, wherein the method comprises administering to the subject an amount of a compound of Formula I

or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein: X is selected from the group consisting of O and NH; Z is selected from the group consisting of O, S and NH; i n is an integer from 1 to 5;

, R¹, R², R³, and R⁴ are each independently selected from the group consisting of H, alkanoyl, alkenyl, alkenylalkynyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, _alkoxyalkynyl,_alkoxyaryl,-alkox-yarylalkenyl,-alkoxyar-ylalkyl, alkoxyarylalkynyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylaminoarylalkyl, alkoxyheteroaryl, alkyl, alkylamino, alkylaminoalkyl, alkylaminoalkynyl, alkylaminoarylalkyl, alkylaryl, alkylarylalkoxy, alkylarylalkyl, alkylarylalkynyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylaminoalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheteroarylalkynyl, alkylheterocyclo, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkynyl, amino, aminoalkyl, aminoalkynyl, aminoarylalkynyl, aminoaryl, aminocarbonylalkenyl, aminocarbonylalkyl, aminosulfonylaryl, aminosulfonylarylalkynyl, aryloxyalkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylamino, arylcarbonyl, arylalkylthio, arylalkynyl, arylaminoalkyl, arylheteroarylalkyl, arylthio, arylthioalkyl, aryloxy, aryloxyalkyl, alkanoylalkyl, alkanoylheteroarylalkyl, carboxy, carboxyalkoxy, carboxyalkyl, carboxyarylalkyl, cyano, cyanoalkyl, cyanoalkynyl, cycloalkoxy, cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, cycloalkylalkylamino, cycloalkylalkynyl, dialkylamino, diheteroarylalkylaminoalkyl, halo, haloalkoxy, haloalkyl, haloalkylarylalkynyl, haloalkylhydroxyalkyl, haloarylalkyl, haloarylalkynyl, haloarylcarbonylaminoalkyl, haloheteroarylalkyl, haloheteroarylcarbonylalkyl, heteroaryl, heteroarylalkenyl ,heteroarylalkoxy, heteroarylalkyl, heteroarylalkynyl, heteroarylalkylaminoalkyl, heteroaryloxy, heteroarylcarbonyl, heteroarylhydroxy alkyl, heterocyclo, heterocycloalkoxy, heterocycloalkyl, heterocyclyloxy, heteroarylcarbonylaminoalkyl, hydroxy, hydroxyalkynyl, hydroxyalkyl, hydroxyaryl, hydroxyarylalkynyl, carboxyalkynyl, hydroxycycloalkylalkynyl, nitro, and thio; wherein: each aryl, heteroaryl, and heterocyclo, wherever they occur, is optionally and independently substituted with one to five substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, alkanoyl, carboxy, carboxyalkenyl, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, dialkylamino, halo, haloalkoxy, haloalkyl, haloaryl, hydroxy, hydroxyalkyl, oxo and nitro; wherein R¹ and R² together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; R² and R³ together with the atoms to which they are attached optionally form a cycloalkyl ring, a heterocyclo ring or a heteroaryl ring; R³ and R⁴ together with the atoms to which they are attached optionally form a cycloalkyl ring or a heteroaryl ring; wherein the cycloalkyl ring and the heteroaryl ring wherever they occur are optionally and independently substituted with one or more substitutents selected from the group consisting of alkyl, aryl, haloaryl, arylalkyl and heterocyclo; and

R⁶ is selected from the group consisting of hydrogen, hydroxy, -ONO₂, halogen, nitroxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms, wherein each of hydroxy, nitroxyalkylcarbonyl, thiol, haloalkyl, alkoxy, alkylsilyloxy, alkyl, and a 3 to 7 membered ring containing 1 to 3 heteroatoms are independently and optionally substituted with a radical selected from the group consisting of hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, amino, nitro, cyano, carboxyl and haloalkyl; or

R⁶ is a group of the formula OCO-R⁷ wherein R⁷ is selected from the group consisting of carboxyalkyl, alkyl, alkenyl, alkynyl, and alkoxy; wherein the amount of the compound is effective for the treatment or prevention of the COX-2 mediated disorder.

21. A method of Claim 20 wherein the COX-2 mediated disorder is an inflammatory disorder.