AU2014201375B2 - Omega-3 fatty acids, hydroxy polyunsaturated fatty acids, lipoxin compounds, or oxylipin compounds for the treatment of ophthalmic conditions - Google Patents

Abstract

Abstract The invention relates to methods of treating ophthalmic conditions comprising administering a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound.

Description

Omega-3 fatty acids, hydroxy polyunsaturated fatty acids, lipoxin compounds, or oxylipin compounds for the treatment of ophthalmic conditions The present application is a divisional application of Australian Application No. 2008312006, which is incorporated in its entirety herein by reference. 5 This application claims the benefit of priority to U.S. Provisional Patent Application No. 60/998,677, filed October 12, 2007, and U.S. Provisional Patent Application No. 61/125,463, filed April 25, 2008, which applications are hereby incorporated by reference in their entirety. Background 10 Approximately one of every 247 people (over 1.1 million people) in the United States is legally blind. Worldwide, it is estimated that 42,000,000 people are affected by blindness. A further large population suffers from other severe retinal disorders. A study of blindness in India reveals that 62% is caused by cataracts, 19% by refractive error, and 5.8% by untreated glaucoma. However, retinal disorders, including 15 without limitation, diabetic retinopathy, retinitis pigmentosa (RP), wet and dry age related macular degeneration (ARMD), inflammatory disease including macular edema, cen-ral vein occlusion, uveitis affecting the retina, and proliferative vitreoretinopathy are much more prevalent causes of blindness in the Western world. Diabetic retinopathy is another common form of retinal disease. While diet, 20 exercise, and drug therapy can do much to lessen the ocular effects of diabetes on the retina, there is no specific cure or prophylactic for diabetic retinopathy. Similarly, glaucoma is a condition that is most commonly (though not exclusively) characterized by high intraocular pressure and which also involves degeneration of the retinal and optic nerve. While high intraocular pressure is 25 susceptible to management with, for example, 13-adrenergic receptor antagonists such as timolol, and a-adrenergic receptor agonists such as brimonidine, the neural degeneration that accompanies glaucoma is neither reversible nor can it be definitively halted by lowering intraocular pressure alone. In the developed world, the most prevalent retinal disease causing blindness in 30 adults over 60 is age related macular degeneration (AMD). With the segment of the population within this age range steadily increasing in the United States, the number of cases of AMD are likely to increase by the same rate without an effective treatment for the condition. AMD progressively decreases the function of specific neural and epithelial layers of the retinal macula. The clinical presentation of the condition includes the presence of drusen, hyperplasia of the retinal pigmented epithelium 5 (RPE), geographic atrophy, and choroidal neovascularization (CNV). Atrophic AMD is characterized by outer retinal and RPE atrophy and subadjacent choriocapillaris degeneration, and accounts for about 25% of cases with severe central visual loss. Exudative (or "wet") AMD is characterized by CNV growth. under the RPE and retina, and subsequent hemorrhage, exudive retinal detachment, diciform scarring, 10 and retinal atrophy. Pigment epithelial detachment can also occur. Exudative AMD accounts for about 75% of AMD cases with severe central vision loss. Currently most treatment for this disease involves therapies that are most helpful to patients who are suffering from relatively advanced symptoms of the disease. These therapies include laser photocoagulation, photodynamic therapy and surgery in cases where CNV is 15 involved. However, there is no currently effective therapy for the early stages of the disease. There remains a need for additional therapies for this and other ophthalmic conditions. Dry eye, or keratoconjunctivitis sicca, is a common ophthalmological disorder that affects a significant proportion of the worldwide population. Some of these 20 individuals suffer from Sjogren's disease. Women of post-menopausal age comprise another segment of the dry eye population. Dry eye may afflict individuals with differing severity. In mild cases, a patient may experience burning, a feeling of dryness, and other symptoms of ocular discomfort. In severe cases, vision may be substantially impaired. 25 Although dry eye may have a variety of unrelated pathogenic causes, all share as a common effect the breakdown of the ocular tear film, with dehydration of and subsequent damage to the exposed outer ocular surfaces. Individuals afflicted with the systemic autoimmune disease known as Sjogren's syndrome typically suffer severe dry eye. In this disease, inflammation of 30 the lacrimal gland impairs normal secretory processes, resulting in abnormalities in the tear film. Changes to the ocular surface include the production and accumulation of a variety of mediators of inflammation. Prior therapies for dry eye have included both palliative agents, such as -2- -3 artificial tear formulations, and drugs, such as topical steroids, topical retinoids (e.g., Vitamin A), oral pilocarpine, and topical cyclosporin. In general, the palliative therapies are capable of providing short-term relief from some of the symptoms of dry eye, but frequent application of the palliative products to the eye is required to maintain this 5 relief, since these products generally do not eliminate the physiological sources of the dry eye conditions. These drug therapies have had limited success in treating dry eye conditions, typically attributed to the inability of the drug to eliminate or reduce the root causes of the dry eye condition, side effects from the drugs that threaten the overall ocular health of the patient, or result in poor patient compliance, or a combination of 10 these factors. For example, certain glucocorticoids have a greater potential for elevating intraocular pressure ("lOP") than other compounds in this class. One such compound, prednisolone, a very potent ocular anti-inflammatory agent, has a greater tendency to elevate IOP than fluorometholone, which has moderate ocular anti-inflammatory 15 activity. The risk of IOP elevations associated with the topical ophthalmic use of glucocorticoids increases over time. In other words, the chronic (i.e., long-term) use of these agents increases the risk of significant IOP elevations. Unlike bacterial infections or acute ocular inflammation associated with physical trauma, which require short-term therapy on the order of a few weeks, dry eye 20 conditions require treatment for extended periods of time, generally several months or more. This chronic use of corticosteroids significantly increases the risk of IOP elevation. Prolonged use of corticosteroids typically increases the risk of cataract formation. Accordingly, more effective ophthalmic therapies are needed. 25 Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field. Summary of Invention 30 According to a first aspect, the present invention provides a method of treating the ophthalmic condition post-operative inflammation in a subject, said method comprising administering to said patient a compound of formula 43, having the structure: - 3a Re Ri ORf ORe O R , 1 R , E 43 wherein: Re, Rf, Ri, R 8 and R 9 are each hydrogen; 5 E is hydroxyl or alkoxyl; and

R

5 is CH 2

CH

2

CH

2 , or a pharmaceutically acceptable salt thereof. According to a second aspect, the present invention provides use of a compound of formula 43, having the structure: Re R i ORf OReO 10 43 wherein: Re, Rf, Ri, R 8 and R 9 are each hydrogen; E is hydroxyl or alkoxyl; and

R

5 is CH 2

CH

2

CH

2 , 15 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating the ophthalmic condition post-operative inflammation in a patient. According to a third aspect, the present invention provides a compound when used in the treatment of the ophthalmic condition post-operative inflammation in a 20 patient, wherein said compound is formula 43, having the structure: Re Ri ORf ORO O UR E 43 wherein: Re, Rf, Ri, R 8 and R 9 are each hydrogen; E is hydroxyl or alkoxyl; and 25 R 5 is CH 2

CH

2

CH

2

,

- 3b or a pharmaceutically acceptable salt thereof. Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the 5 sense of "including, but not limited to". The present invention provides a method of treating an ophthalmic condition in a patient, comprising administering to said patient a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid.

Detailed Description of the Drawings Figure 1 shows the inhibition of hypertonicity-induced release of inflammatory mediators such as IL-6 (a) and IL-8 (b) upon treatment with compound X. 5 Figure 2 shows the inhibition of hypertonicity-induced release of inflammatory mediators such as IL-6 (a) and IL-8 (b) upon treatment with compound Z. Figures 3a and 3b show the prevention of goblet cell loss in the murine dry eye model upon treatment with compounds V or W. 10 Figures 4a and 4b show the reduction of corneal staining and preservation of corneal integrity in the murine dry eye model upon treatment with compounds V or W. Figure 5 shows the block in over-expression of the pro-inflammatory enzymes Arginase (a) and Cox-2 (b) in the murine dry eye model upon treatment with 15 compounds V or W. Figure 6 shows the in vitro inhibition of oxidative stress-induced apoptosis in retinal pigment-epithelial cells upon treatment with compounds X or Z. Figure 7 shows the reduction of choroidal vascular leakage on days 7 and 14 in experimental choroidal neovascularization upon treatment with compounds X, Z, or 20 48a. Figure 8 shows the reduction of choroidal vascular leakage on day 7 in experimental choroidal neovascularization upon treatment with compounds X or Z. Figure 9 shows the reduction of choroidal vascular leakage on day 14 in experimental choroidal neovascularization upon treatment with compounds X or Z. 25 Figure 10 shows the reduction of choroidal vascular leakage on days 7 and 14 in experimental choroidal neovascularization upon treatment with compounds 48a. Figures I Ia and I lb shows the reduction of choroidal lesion size at day 14 in experimental choroidal neovascularization upon treatment with compounds X, Z, or 48a. -4- Detailed Description of the Invention The present invention provides a method of treating an ophthalmic condition in a patient, comprising administering to said patient a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, 5 or a combination of aspirin and an omega-3 fatty acid. Examples of ophthalmic conditions that may be treated by administration of a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid, irclude AIDS-related retinal disorders; age-related macular degeneration; 10 alkaline erosive keratoconjunctivitis; allergic keratitis; anterior ischemic optic neuropathy; anterior uveitis (iridocyclitis); Behcet's disease; blepharitis; seborrheic blepharitis; canaliculitis; cataract; central serous chorioretinopathy; chorioiditis; chronic uveitis; Coats' disease; conjunctivitis (e.g., infectious conjunctivitis, neonatal conjunctivitis, non-infectious conjunctivitis, and allergic conjunctivitis); contact lens 15 induced keratoconjunctivitis; contact eczema; corneal ulcer (e.g., Mooren's ulcer, comeal ulcer subsequent to chronic rheumatoid arthritis or collagen disease, Terrien's marginal degeneration, catarrhal corneal ulcer, infectious corneal ulcer); crystalline retinopathy; cyclitis; edema (e.g., cystoid macular edema); dacryoadenitis; dacryocystitis; degenerative myopia; degenerative retinoschisis; diabetic 20 keratophathy; diabetic macular edema; diabetic retinopathy; dry eye disease (e.g., dry eye of the lacrimal system or dry eye of the cornea); dry age-related macular degeneration; endophthalmitis; episcleritis; exudative macular edema; Fuchs' Dystrophy; giant cell arteritis; giant papillary conjunctivitis; glaucoma (e.g., primary open angle glaucoma, primary angle closure glaucoma, secondary open angle 25 glaucoma, secondary angle closure glaucoma, and childhood glaucoma); glaucoma surgery failure; graft versus host disease of the eye (often a form of dry eye); herpes zoster (shingles); hypertensive retinopathy; inflammation after cataract surgery; iridocorneal endothelial syndrome; iridocytis; iritis; keratitis (e.g., infectious keratitis, non-infectious keratitis, and neuroparalytic keratitis); keratoconjunctiva sicca; 30 keratoconjunctival inflammatory disease; keratoconus; keratopathy; lattice dystrophy; map-dot-fingerprint dystrophy; necrotic keratitis; neovascular diseases involving the -5retina, uveal tract or cornea such as neovascular glaucoma, corneal neovascularization (inflammatory, transplantation, developmental hypoplasia of the iris), neovascularization resulting following a combined vitrectomy and lensectomy, neovascularization of the optic nerve, and neovascularization due to penetration of the 5 eye or contusive ocular injury; non-infectious uveitis; ocular herpes; ocular rosacea; ophthalmic infections (e.g., corneal herpes, bacterial keratitis, bacterial conjunctivitis, mycotic keratitis, acanthamebic keratitis, infectious endophthalmitis, infectious corneal ulcer, inflammation of the conjunctiva or cornea by staphylococci, streptococci, enterococci, euterococci, bacillus, corynebacterium, chlamydia, and 10 neisseria); ophthalmic pemphigoid; optic disc drusen; optic neuritis; panuveitis; papilledema; papillitis; pars planitis; persistent macular edema; phacoanaphylaxis; posterior uveitis (chorioentinitis); post-operative inflammation (e.g., post-LASIK inflammation of the cornea); proliferative diabetic retinopathy; proliferative sickle cell retinopathy; proliferative vitreoretinopathy; retinal artery occlusion; retinal 15 detachment;'retinal vasculitis; retinal vein occlusion; retinitis pigmentosa; retinopathy of prematurity; rubeosis iritis; scleritis; Stevens-Johnson syndrome (erythema multiforme major); sympathetic ophthalmia; temporal arteritis; toxic retinopathy; uveitis (e.g., anterior uveitis or posterior uveitis); vernal conjunctivitis; vitamin A insufficiency-induced keratomalacia; vitreitis; and wet age-related macular 20 degeneration. In certain embodiments, the ophthalmic conditions that may be treated by administration of a compound of formula A, a compound of any one of formulae I 49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid, include AIDS-related retinal disorders; anterior ischemic optic 25 neuropathy; Behcet's disease; blepharitis; seborrheic blepharitis; canaliculitis; cataract; central serous chorioretinopathy; chorioiditis; Coats' disease; contact eczema; corneal ulcer (e.g., Mooren's ulcer, corneal ulcer subsequent to chronic rheumatoid arthritis or collagen disease, Terrien's marginal degeneration, catarrhal corneal ulcer, infectious corneal ulcer); crystalline retinopathy; cyclitis; edema (e.g., 30 cystoid macular edema); dacryoadenitis; dacryocystitis; degenerative myopia; diabetic keratophathy; diabetic macular edema; dry eye disease (e.g., dry eye of the lacrimal system or dry eye of the cornea); endophthalmitis; episcleritis; exudative macular edema; Fuchs' Dystrophy; giant cell arteritis; glaucoma (e.g., primary open angle -6glaucoma, primary angle closure glaucoma, secondary open angle glaucoma, secondary angle closure glaucoma, and childhood glaucoma); glaucoma surgery failure; graft rejection; herpes zoster (shingles); hypertensive retinopathy; inflammation after cataract surgery; iridocomeal endothelial syndrome; iridocytis; 5 keratitis (e.g., infectious keratitis, non-infectious keratitis, and neuroparalytic keratitis); keratoconjunctiva sicca; keratoconjunctival inflammatory disease; keratoconus; keratopathy; lattice dystrophy; map-dot-fingerprint dystrophy; necrotic keratitis; neovascular diseases involving the retina, uveal tract or cornea such as neovascular glaucoma, comeal neovascularization (inflammatory, transplantation, 10 developmental hypoplasia of the iris), neovascularization resulting following a combined vitrectomy and lensectomy, neovascularization of the optic nerve, and neovascularization due to penetration of the eye or contusive ocular injury; non infectious uveitis; ocular herpes; ocular rosacea; ophthalmic infections (e.g., corneal herpes, bacterial keratitis, mycotic keratitis, acanthamebic keratitis, infectious 15 endophthalmitis, infectious corneal ulcer, inflammation of the conjunctiva or cornea by staphylococci, streptococci, enterococci, euterococci, bacillus, corynebacterium, chlamydia, and neisseria); ophthalmic pemphigoid; optic disc drusen; optic neuritis; panuveitis; papilledema; papillitis; pars planitis; persistent macular edema; phacoanaphylaxis; post-operative inflammation (e.g., post-LASIK inflammation of 20 the cornea); proliferative sickle cell retinopathy; retinal artery occlusion; retinal detachment; retinal vasculitis; retinal vein occlusion; retinitis pigmentosa; retinopathy of prematurity; Stevens-Johnson syndrome (erythema multiforme major); sympathetic ophthahmia; temporal arteritis; toxic retinopathy; vitamin A insufficiency-induced keratomalacia; and vitreitis. 25 Diseases caused by dry eye include Riley-Day syndrome, Shy-Drager syndrome, Sjogren syndrome, sarcoidosis, amyloidosis, sequela of radiotherapy, lagophthalmia, avitaminosis A, Stevens-Johnson syndrome, ocular pemphigoid, marginal blepharitis, meibomitis, sequela of intraocular surgery, contact-lens affection, diabetic corneal epitheliopathy, dry eye due to VDT operation, and the like. 30 Disorders caused by corneal infective disease include, for example, viral epitheliopathy and the like. Stem cell depletion syndromes include Stevens-Johnson syndrome, ocular pemphigoid, thermal or chemical burn, drug toxicity of idoxuridine (IDU) and therapeutic agents for glaucoma, and the like. The present invention -7provides a method of inhibiting COX-2 or TNF in the eye in a patient comprising administering to said patient a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid. The present invention further provides a method of 5 protecting against goblet cell loss in the eye in a patient comprising administering to said patient a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega 3 fatty acid. Compounds as described herein have also demonstrated inhibition of 10 inflammatory mediators in the cornea including TNF, IL-1a, IL-lb, IL-6, and IL-8. Accordingly, these compounds may be useful in the treatment of dry eye diseases, age-related macular degeneration, retinopathy of prematurity, uveitis, and glaucoma. Compounds as described herein have also demonstrated COX-2 inhibition in the cornea. Accordingly, these compounds may be useful in the treatment of dry eye 15 diseases. Compounds as described herein have also demonstrated prevention of goblet cell loss. Accordingly, these compounds may be useful in the treatment of dry eye diseases, age-related macular degeneration, retinopathy of prematurity, retinitis pigmentosa, and glaucoma. Compounds as described herein have also demonstrated 20 significant increases in tear production and density of superficial epithelial cells, two endpoints relevant to the treatment of dry eye. Compounds as described herein inhibit CDI lb+ cells. Animal models of dry eye show an increase in CDI1 Ib+ cells suggesting the increased presence of leukocytes in corneas. Accordingly, these compounds may be useful in the treatment 25 of dry eye by decreasing the arrival of leukocytes induced by dry eye. Compounds as described herein have also demonstrated prevention of pigmented retinal epithelium destruction. Accordingly, these compounds may be useful in the treatment of age-related macular degeneration, retinopathy of prematurity, retinitis pigmentosa, and glaucoma. 30 Compounds suitable for use in methods of the invention include those of Formula A, -8- X'-Y' 'V1,V 2 "v-W'-G' wherein: each of W' and Y is a bond or a linker independently selected from a ring containing up to 20 atoms or a chain of up to 20 atoms, provided that W' and Y' can 5 independently include one or more nitrogen, oxygen, sulfur or phosphorous atoms, further provided that W' and Y' can independently include one or more substituents independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio, 10 alkylsulfonate, arylsulfonate, phosphoryl, or sulfonyl, further provided that W' and Y' can independently contain one or more fused carbocyclic, heterocyclic, aryl or heteroaryl rings, and further provided that when o' is 0, and V, is RWoo1/ Ra' ,Y'is connected to V, via a carbon atom;

R

1001 Ra' R V, is selected from / , R100 1 Ra R102 R R01 R1002 Rb R 15 ,cRRbor Rb R 1 2 R' R 1 001, wherein when q' is 0 and V3 is a bond, n' is 0 or 1; otherwise n is 1; R1001 Ra'

V

2 is selected from a bond, L , -9- R1002 Rb R 100 2 Rb' or Ra R1a0o R01 Ra' or i , or wherein: L' is selected from -C(R 003 )(R 14)-, wherein each of R 10 3 and R'004 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, 5 alkoxy, aryl or heteroaryl, or R'00 3 and R'00 4 are connected together to form a R1001 Ra' carbocyclic or heterocyclic ring; when V 3 is , L' is additionally selected from W'; and n' is 0 or 1; R1001 Ra'

V

3 is selected from a bond or wherein: 10 each R' 00 'and R'00 2 is independently for each occurrence selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxy, or halo, wherein said alkyl- or aryl-containing moiety is optionally substituted with up to 3 independently selected substituents; each of R" and RbV is independently for each occurrence selected from 15 -OR' or -N(R') 2 , or adjacent R" and Rb' are taken together to form an epoxide ring having a cis or trans configuration, wherein each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl, aminoacyl, aminocarbonyl, alkoxycarbonyl, or a protecting group; Rb' R 1 ao 2 V1 001 Ra Ra'~o R100 or when V 1 is and V2 is 20 R 00 2 and Rb are both hydrogen; X' is selected from -CN, -C(NH)N(R")(R"), -C(S)-A', -C(S)R", -C(O)-A', -C(O)-R", -C(O)-SR", -C(O)-NH-S(O) 2 -R", -S(O) 2 -A', -S(O) 2 -R", S(O) 2 N(R")(R"),

-P(O)

2 -A', -PO(OR")-A', -tetrazole, alkyltetrazole, or -CH- 2 OH, wherein A' is selected from -OR", -N(R")(R") or -OM'; - 10each R" is independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or a detectable label molecule, wherein any alkyl-, aryl- or heteroaryl-containing moiety is optionally substituted with up to 3 independently selected substituents; and 5 M' is a cation; G' is selected from hydrogen, halo, hydroxy, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido or a detectable label molecule, wherein any alkyl-, aryl- or heteroaryl-containing moiety is optionally substituted with up to 3 independently 10 selected substituents; o' is 0, 1, 2, 3, 4, or 5; p'is 0, 1, 2, 3, 4, or 5; q' is 0, 1, or 2; and o'+p'+q'is 1, 2, 3,4,5or6; 15 wherein: if V 2 is a bond, then q' is 0, and V 3 is a bond; RR101 Ra if V 3 is ,then o' is 0, Vi is , p' is l and

R

100 1 Ra'

V

2 is / any acyclic double bond may be in a cis or a trans configuration or is 20 optionally replaced by a triple bond; and either one portion of the compound, if present, is optionally replaced by or one portion of the compound, if present, is optionally - II -

Q'

replaced by, wherein Q' represents one or more substituents and each Q' is independently selected from halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, carboxyl, alkoxycarbonyloxy, 5 aryloxycarbonyloxy or aminocarbonyl.

R

1 001

R

3 In certain embodiments, V, is selected from R100 Ra' R ,or

R

1001 Ra' In certain embodiments, V 2 is selected from a bond, L , RbR R 1 00 2 or 10 In certain embodiments, when q' is 0 and V 3 is a bond, n' is 0 or 1; otherwise n t is 1. In certain embodiments, p' is 0, 1, 2, 3, or 5. In certain embodiments, q' is 0 or 1.

R

1 001 Ra' In certain embodiments, if V, is R1,2 Rb' then o' is 0 or R1001 R"' 15 1, p' is I or 2, o'+ p' is l or 2, V 2 is and V 3 is a bond. - 12- 1001 Ra In certain embodiments, if V, is , then o' is 3, 4 or 5, p' is 0, I or 2, o' + p' is 4 or 5, and V 2 is a bond. In certain embodiments, if V 2 is a bond, then o' is 0, 3, 4 or 5; p' is 0, 1, 2 or 5, o'+ p' is 4 or 5, q' is 0, and V3 is a bond. 5 In certain embodiments, each of W' and Y' is independently selected from a bond or lower alkyl or heteroalkyl optionally substituted with one or more substituents independently selected from alkenyl, alkynyl, aryl, chloro, iodo, bromo, fluoro, hydroxy, amino, or oxo. In certain embodiments, the compound of formula A is other than a compound 10 of formulae 48, 48a, 48b, 48c, or 48d.

R

1 00 1 Ra' In certain embodiments of Formula A, when o'is 2, V, is 1001 Ra' p', is s LV is q'island V is a bond, at least one occurrence of R 1001 is other than hydrogen. Compounds suitable for use in methods of the invention include those of 15 Formula 1, Ri CR" h ORO J-I b'GIc' d' Rj ORg wherein: Carbons a' and b' are connected by a double bond or a triple bond; Carbons c' and d' are connected by a double bond or a triple bond; 20 Re, Rf, and Rg are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl, alkoxycarbonyl, or silyl; - 13 - Rh, Ri and Rj are independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl; I is selected from -C(O)-E, -S0 2 -E, -PO(OR)-E, where E is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or arylamino; and R is hydrogen or alkyl; 5 J, L and H are linkers independently selected from a ring containing up to 20 atoms or a chain of up to 20 atoms, provided that J, L and H can independently include one or more nitrogen, oxygen, sulfur or phosphorous atoms, and further provided that J, L and H- can independently include one or more substituents selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, 10 bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, arylsulfonate, phosphoryl, and sulfonyl, and further provided that J, L and H can also contain one or more fused carbocyclic, heterocyclic, aryl or heteroaryl rings, and provided that linker J is connected to 15 the adjacent C(R)OR group via a carbon atom; G is selected from hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, or carboxamido; or pharmaceutically acceptable salts thereof 20 in certain embodiments, a pharmaceutically acceptable salt of the compound is formed by derivatizing E, wherein E is -OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn. In certain embodiments, a compound of formula 1 is represented by formula 2, OR( ORe 0 E 2 ORg 25 wherein: E, Re, Rf, and Rg are as defined above. In certain embodiments, a pharmaceutically acceptable salt of the compound is forced by derivatizing E, wherein E is -OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn. - 14- Exemplary compounds of formula 2 include compound 2a, OH OH 0 OCH3 OH (2a). In certain embodiments, a compound of formula I is represented by formula 3, ORf ORe 0 ORg 5 wherein: E, Re, Rf, and Rg are as defined above. In certain embodiments, a pharmaceutically acceptable salt of the compound is formed by derivatizing E, wherein E is -OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn. 10 Exemplary compounds of formula 3 include compound 3a, C(cH3)3

C(CH

3

)

3 11-" OCH, 0 Si----

C(CH

3 h (3a) and compound 3b, OH OH0 OCHa OH (3b). - 15- Further exemplary compounds of formula I include Compound X, OH OH 0 (X), and pharmaceutically acceptable salts and esters thereof Other compounds suitable for use in methods of the invention include those of 5 Formula 4, R, O03P, R2 OP2 4 wherein: A is H or-OP 4 ;

PI,P

2 and P 4 each individually is a protecting group or hydrogen atom; 10 R, and R 2 each individually is a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, or alkynyl group, substituted or unsubstituted aryl group, substituted or unsubstituted, branched or unbranched alkylaryl group, halogen atom, hydrogen atom; Z is -C(O)ORd, -C(O)NRCRC, -C(O)H, -C(NH)NRcRc, -C(S)H, -C(S)ORd, 15 -C(S)NRcRc, -CN, preferably a carboxylic acid, ester, amide, thioester, thiocarboxamide or a nitrile; each R', if present, is independently selected from hydrogen, (Cl -C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-Cl 1) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C 16) arylalkyl, benzyl, 2-6 20 membered heteroalkyl, 3-8 membered heterocyclyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-1 1 membered heterocyclylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each Rb, if present, is a suitable group independently selected from =0, -ORd, (Cl C3) haloalkyloxy, -OCF 3 , =S, -SR , =NRd, =NORd, -NRcRc, halogen, -CF 3 , d d 25 -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N2, -N 3 , -S(O)R , -S(O)2R ,

-S(O)

2 0Rd', -S(O)NRcRc, -S(O) 2 NRcRc, -OS(O)Rd, -OS(O) 2 R, -OS(O) 2 ORd, - 16-

-OS(O)

2 NRcRc, -C(O)Rd, -C(O)OR', -C(O)NRcRc, -C(NH)NRcRc, -C(NR")NRcRc, -C(NOH)Ra, -C(NOH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc, -OC(NH)NRcRc, -OC(NRa)NRcRc, -[NHC(O).Rd,

-[NR"C(O))

1 Rd, -[NHC(O)],ORd, -[NRaC(O)]ORd, [NHC(O)]nNRCRC, 5 -[NRaC(O)]nNRRC, -[NHC(NH)]NR'Rc and -[NR"C(NRa)]NRcRc; each Rc, if present, is independently a protecting group or R', or, alternatively, two R' taken together with the nitrogen atom to they are bonded form a 5 to 8 membered heterocyclyl or heteroaryl which optionally including one or more additional heteroatoms and optionally substituted with one or more of the 10 same or different R' or suitable Rb groups; each n independently is an integer from 0 to 3; each Rd independently is a protecting group or R'; or pharmaceutically acceptable salts thereof Exemplary compounds of formula 4 include compound 4a, OH CO 2 H 15 OH (4a), compound 4b, OH CO 2 H OH (4b), and pharmaceutically acceptable salts and esters thereof Other compounds suitable for use in methods of the invention include those of Formula 5, 20 P20 OP3 or pharmaceutically acceptable salts thereof, wherein: the stereochemistry of the carbon ii' to carbon jj' bond is cis or trans;

P

3 is a protecting group or hydrogen atom; and -17- PI, P2, R, and Z are as defined above in formula 4. In certain embodiments, the stereochemistry of the carbon ii' to carbon jj' bond is trans. Exemplary compounds of formula 5 include compound 5a, OH O0H 5 HO OH (Sa), compound 5b, OH OH HO OH (5b), and pharmaceutically acceptable salts and esters thereof. Other compounds suitable for use in methods of the invention include those of Formula 6, P20 X X 0P, hh' z 10 R , 6 or pharmaceutically acceptable salts thereof, wherein: the stereochemistry of the carbon gg' to carbon hh' bond is cis or trans; each X represents hydrogen or taken together both X groups represent one substituted or unsubstituted methylene, an oxygen atom, a substituted or unsubstituted N 15 atom, or a sulfur atom such that a three-membered ring is formed; and Pi, P 2 , P 3 , R 1 and Z are as defined above. In certain embodiments, the stereochemistry of the carbon gg' to carbon hh' bond is trans. - 18- Exemplary compounds of formula 6 include compound 6a, HO OH OH (6a), compound 6b, OH OH (6b), and pharmaceutically acceptable salts and esters thereof 5 Other compounds suitable for use in methods of the invention include those of Formula 7, R12 R11 OP1 P2O g' Z Z. h' T' f' e' R13 OP3 7 or pharmaceutically acceptable salts thereof, wherein: Carbons e' and f are connected by a double bond or a triple bond, and when carbon e' 10 is connected to carbon f through a double bond the stereochemistry is cis or trans; Carbons g' and h' are connected by a double bond or a triple bond and when carbon g' is connected to carbon h' through a double bond the stereochemistry is cis or trans; 15 m is 0 or 1; - 19 - T' is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C5-C14) aryl, (C6 C16) arylalkyl, 5-14 membered heteroaryl, 6-16 membered heteroarylalkyl, or

-CH=CHCH

2

CH

3 ; T is -(CH2)q- or -(CH2),-O-, where q is an integer from 0 to 6; 5 Z' is (C] -C6) alkylene optionally substituted with 1, 2, 3, 4, 5 or 6 of the same or different halogen atoms, -(CH 2

)-O-CH

2 - or -(CH2)m-S-CH2-, wherep is an integer from 0 to 4; R, , R 1 2 and R 13 each individually is substituted or unsubstituted, branched or unbranched alkyl, alkenyl, or alkynyl group, substituted or unsubstituted aryl 10 group, substituted or unsubstituted, branched or unbranched alkylaryl group, Ci4alkoxy, halogen atom, -CH- 2

R

1 4 , -CHR 4

R

1 4 , -CR 1 4

R

14

R

1 4 , or a hydrogen atom; R1 4 is independently for each occurrence selected from -CN, -NO 2 or halogen; PI, P 2 , P 3 , and Z are as defined above. 15 In certain embodiments, carbons e' and f are connected by a cis double bond. In certain embodiments, carbons g' and h' are connected by a double bond. In certain embodiments, carbons e' and f are connected by a cis double bond and carbons g' and h' are connected by a double bond. Exemplary compounds of formula 7 include compound 7a, OH H CO2H O6DH 20 HO (7a), compound 7b, OH H CO2H 0H HO -(7b), and pharmaceutically acceptable salts and esters thereof. -20 - Other compounds suitable for use in methods of the invention include those of Formula 8, z R, P 1 R2 OP 2 or pharmaceutically acceptable salts thereof, wherein: 5 the stereochemistry of the carbon i' to carbon j' bond is cis or trans; m is 0 or 1; D' is CH 3 , -CH=CHCH 2 U or -CH=CHCH 2

CH

2 A; U is a branched or unbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, 10 aryloxycarbonyl, alkoxycarbonyloxy, and aryloxycarbonyloxy group; A is H or -OP 4 ;

P

1 , P 2 , P 4 , R 1 , R 2 and Z are as defined above. In certain embodiments, the stereochemistry of the carbon i' to carbon j' bond is cis. 15 Exemplary compounds of formula 8 include compound 8a, OH C0 2 H OH (8a), compound 8b, OH - - CO 2 H OH (8b), compound Sc, OH CO 2 H OH (8c), and pharmaceutically acceptable salts and esters thereof -21 - Other compounds suitable for use in methods of the invention include those of Formula 9, x P1 M. X --- OP2 RI or pharmaceutically acceptable salts thereof, wherein: 5 Carbons k' and 1' are connected by a double bond or a triple bond, and when carbon k' is connected to carbon l' through a double bond the stereochemistry is cis or trans; the stereochemistry of the carbon m' to carbon n' double bond is cis or trans; m is 0 or 1; 10 D is -CH 3 or -CH=CHCH 2

CH

3 ;

P

1 , P2, P 3 , R 1 , X, and Z are as defined above. In certain embodiments, the stereochemistry of the carbon m' to carbon n' double bond is cis. In certain embodiments, carbons k' and ' are connected by a cis double bond. 15 In certain embodiments, the stereochemistry of the carbon in' to carbon n' double bond is cis and carbons k' and ]' are connected by a cis double bond. Exemplary compounds of formula 9 include compound 9a,

OH

OH C 2H OH (9a), compound 9b, OH C02H OH OH (9b), and pharmaceutically 20 acceptable salts and esters thereof. - 22 - Other compounds suitable for use in methods of the invention include those of Formula 10, z

P

1 0 R 1 10 or pharmaceutically acceptable salts thereof, wherein: 5 PI, P2, P3, R, and Z are as defined above; and Q represents one or more substituents and each Q individually, if present, is a halogen atom or a branched or unbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, carboxyl, 10 alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl group. Other compounds suitable for use in methods of the invention include those of Formula 11, z P10

OP

2 R, OP3 or phaniaceutically acceptable salts thereof, wherein: 15 PI, P' 2 , P 3 , RI, and Z are as defined above. Other compounds suitable for use in methods of the invention include those of Formula 12, - 23 z P10 oP 2 12 0 R, OP3 or pharmaceutically acceptable salts thereof, wherein PI, P2, P 3 , Q, Ri, and Z are as defined above. Other compounds suitable for use in methods of the invention include those of 5 Formula 13,

P

1 0 z Ri R2

P

2 0 U 13 or pharmaceutically acceptable salts thereof, wherein: Pr, P 2 , RI, R2, U, and Z are as defined above. Other compounds suitable for use in methods of the invention include those of 10 Formula 14, Z 14 P1 or pharmaceutically acceptable salts thereof, wherein: - 24 -

P

1 , P 2 , RI, R 2 , Q, and Z are as defined above. Other compounds suitable for use in methods of the invention include those of Formula 15, OP1 z 5 or pharmaceutically acceptable salts thereof, wherein: PI, P 2 , and Z are as defined above. Other compounds suitable for use in methods of the invention include those of Formula 16, OP1 16 10 or pharmaceutically acceptable salts thereof, wherein: P, and Z are as defined above. Other compounds suitable for use in methods of the invention include those of Formula 17, oPi q. P' ' O22 17 15 or pharmaceutically acceptable salts thereof, wherein: Carbons o and p' are connected by a single or a double bond (e.g., a cis or trans double bond); Carbons q' and r' are connected by a single or a double bond (e.g., a cis or trans double bond); and 20 PI, P 2 , and Z are as defined above. - 25 - Other compounds suitable for use in methods of the invention include those of Formula 18, R2 OP2 g or pharmaceutically acceptable salts thereof, wherein: 5 the stereochemistry of the carbon s' to carbon t' double bond is cis or trans; the stereochemistry of the carbon u' to carbon V double bond is cis or trans; and

P

1 , P 2 , R 1 , R 2 , and Z are as defined above. Other compounds suitable for use in methods of the invention include those of Formula 19, OP, Yt z 10 P2 19 or pharmaceutically acceptable salts thereof, wherein: Carbons w' and x' are connected by a single or a double bond; Carbors y' and z' are connected by a single or a double bond; and

P

1 , P 2 , and Z are as defined above. 15 In certain embodiments of formulae 4 to 19, each Rb, if present, is a suitable group independently selected from =0, -ORd, (CI-C3) haloalkyloxy, -OCF 3 , =S, -SR , =NRd, =NORd, -NR'Rc, halogen, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 ,

=N

2 , -N 3 , -S(O)Rd, -S(O) 2 Rd, -S(0)2ORd, -S(O)NRcRc, -S(0) 2 NRcRc, -OS(O)Rd,

-OS(O)

2 Rd, -OS(0) 2 0Rd', -OS(O) 2 NRcRc, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, 20 -C(NH)NRcRc, -C(NRa)NRcRc, -C(NOH)R", -C(NOH)NRRc, -OC(O)Rd,

-OC(O)OR

4 , -OC(O)NRcRc, -OC(NH)NRRc, -OC(NR")NRcRc, -[NHC(O)]Rd, -[NR"C(O)],Rd, -[NHC(O)] 1 ORd, [N HC(O)]IN RCRC, -[N R"C(O)],,N RRc,

-[NHC(NH)]

1 NRcRc and -[NRaC(NR")],NRcRc. - 26 - Other compounds suitable for use in methods of the invention include those of Formula 20, C- C 2 R 20 OP Formula 21, OP 5 21 Formula 22, PO OP CO2R OP 22 Formula 23, cOg PO 23 10 Formula 24, 24 OP Fonnula 25, Co 2 R Po 25 - 27 - Formula 26, CO2R OP 26 Formula 27,

CO

2 R 27 PO 5 or Formula 28,

CO

2 R 28 OP , or pharmaceutically acceptable salts of any of the above, wherein each P is individually selected from H or a protecting group; and R is H, CI- 6 alkyl (e.g., methyl, ethyl, glycerol), C2-6alkenyl or C2.6alkynyl. 10 Exemplary compounds of formula 21 include compound 21 a, __ CO 2 H OH (21 a), and pharmaceutically acceptable salts and esters thereof. Other compounds suitable for use in methods of the invention include those of Formula 29, R, OH

R

10

OH

0 12 DE 1 5 A 1

W

1 F1,G 1

R

103 OH 15 29 and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: Di-Ei and F-G, are independently are cis or trans -C=C-or -C=C-; -28-

R

1 o, Ro 2 and R 103 are independently selected from hydrogen, (CI -C4) straight chained or branched alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (CI -C4) alkoxy, -CH2Ro4, -CHRI,4R, 9 4 and -CRIo 4 Rio 4 Rjo4; each Ri 0 4 is independently selected from CN, -NO 2 and halogen; 5 Wi is selected from-RI 05 , -ORios, -SRio 5 and -NRs 05 Ro 5 ; each Ros is independently selected from hydrogen, (CI -C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl optionally substituted with one or more of the same or different R groups, (C5-C14) aryl optionally substituted with one or more of the same or different R groups, phenyl optionally substituted with one or more 10 of the same or different R groups, (C6-C 16) arylalkyl optionally substituted with one or more of the same or different R groups, 5-14 membered heteroaryl optionally substituted with one or more of the same or different R groups, 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R groups and a detectable label molecule; 15 A, is selected from (CI -C6) alkylene optionally substituted with 1, 2, 3, 4, 5 or 6 of the same or different halogen atoms, -(CH2).-O-CH2- and -(CH2)-S-CH2-, where m is an integer from 0 to 4; X, is selected from -(CH 2 ),- and -(CH 2 )n-O-, where n is an integer from 0 to 6;

Y

1 is selected from hydrogen, (Cl-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl, 20 optionally substituted with one or more of the same or different RIO, groups, (C5-C 14) aryl optionally substituted with one or more of the same or different R 100 groups, phenyl, optionally substituted with one or more of the same or different R 100 groups, (C6-C 16) arylalkyl optionally substituted with one or more of the same or different R 1 oo groups, 5-14 membered heteroaryl 25 optionally substituted with one or more of the same or different R 100 groups, 6 16 membered heteroarylalkyl optionally substituted with one or more of the same or different R 00 groups and a detectable label molecule; each R 100 is independently selected from an electronegative group, =O, -OR" (Cl-C3) haloalkyloxy, =S, -SR"', =NR', =NONR"', -NRc'Rc, halogen, -CF 3 , 30 -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R"', -S(O)2R", -S(0) 2 0R"', -S(O)2NRcRcI, -OS(O)Rul, -OS(O)R", -OS(O) 2 0R"',

-OS(O)

2 NRcI Rd, -C(O)Ra', -C(O)ORaI, -C(O)NRI R', -C(NH)NRc' Re, -29- -OC(O)Ra', -OC(O)ORaI, -OC(O)NRc'R 1 , -OC(NH)NR' Rc', -NHC(O)RaI, -NHC(O)ORaI, -NHC(O)NRc'R' and -NHC(NH)NRcl R"; each Ra is independently selected from hydrogen, (CI -C4) alkyl, (C2-C4) alkenyl or (C2-C4) alkynyl; and 5 each Re' is independently an R" or, alternatively, RCIRC' taken together with the nitrogen atom to which it is bonded forms a 5 or 6 membered ring. In certain embodiments of Formula 29, when XI-Yi is -CH 2

CH

3 , then at least one of RIO,, R 1 02 or RJ 03 is other than hydrogen. In certain embodiments, a compound of Formula 29 is represented by Formula 10 30, R OH R1- OH 0 D 1E 1 Al W 1

F

1 G, X

R

103 OH 30 and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein: DI-E, and FI-GI are independently are cis or trans -C=C-or -C=C-; and Rioi, R102, R10 3 , R 1 04 , Wi, Rios, A,. X1, n, Y i, Roo, Ra', and Rd are as defined above. 15 Other compounds suitable for use in methods of the invention include those of Formulae 31 to 37 - 30 - H OH HR OH 0 R1OH HOH 0 HN R~R1R7 OH 321 OH 36 O H OH HH 3 3 H, OH H OH OH 36 H OH OH 333 H/. OH H0 H 0OHf H 0 H OH 107O 34 and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein:

R

106 is -OH, -OCH 3 , -OCH(CH 3

)

2 or -NHCH 2

CH

3 ; and {-I \ F or 5 R 1 07 is Other compounds suitable for use in methods of the invention include those of Formula 38, Rs mt ORr Rhi 0~ ----- RS E bbcc' dd' 0 0 R0 Rj ORg wherein: -31- Carbons aa' and bb' are connected by a double bond or a triple bond; Carbons cc' and dd' are connected by a double bond or a triple bond; Re, Rf, and Rg are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl, 5 alkoxycarbonyl, or silyl; E is hydroxyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or arylamino; Rh, Ri and Rj are independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl;

R

4 is selected from hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, 10 fluoro, hydroxyl, alkoxy, aryloxy;

R

5 is selected from i-iv as follows: i) CH 2

CH(R

6

)CH

2 , where R 6 is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro, hydroxyl or alkoxy; ii) CH 2

C(R

6 R7)CH 2 , where R 6 and R 7 are each independently alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, or fluoro, or R 6 and R 7 are connected together to 15 form a carbocyclic or heterocyclic ring; iii) CH 2 0CH 2 , CH 2

C(O)CH

2 , or CH2CH 2 ; or iv) R 5 is a carbocyclic, heterocyclic, aryl or heteroaryl ring; and

R

8 and R 9 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or heteroaryl, or R 8 and R 9 are connected together to form a carbocyclic or heterocyclic ring; 20 or pharmaceutically acceptable salts thereof In certain embodiments R8 and R 9 are hydrogen. In certain embodiments, a pharmaceutically acceptable salt of the compound is formed by derivatizing E, wherein E is -OM,' where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn. 25 Other compounds suitable for use in methods of the invention include those of Formulae 39-44, 39 - 32 - ORf ORe E SiRa 40 ORf ORe R5 E 41 SiR4 R R ORf ORe -5 E and pharmaceutically acceptable salts thereof, wherein: Re, Rf, E, Ri, R 5 , R 8 and Rg are as defined above. Exemplary compounds of formulae 39, 41, and 43 include: OH 4s .,and pharmaceutically 10 acceptable salts and esters thereof - 33 - In certain embodiments, a pharmaceutically acceptable salt of the compound is formed by derivatizing E, wherein E is -OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn. Examples of such compounds include compound Z, OH OH 0 ONa Other compounds suitable for use in methods of the invention include those of Formula 46, R2 R3 - R4 12 5 18 R1 46 or a pharmaceutically acceptable salt or prodrug thereof, wherein: 10 each -~ independently designates a double or triple bond; R', R 2 , and R 3 are each independently OR, OX', SR, SX 2 , N(R) 2 , NHX 3 , NRC(O)R,

NRC(O)N(R)

2 , C(O)OR, C(O)N(R) 2 , SO 2 R, NRSO 2 R, C(O)R, or SO 2

N(R)

2 ; each R is independently selected from hydrogen or an optionally substituted group selected from C 1

.

6 aliphatic, a 3-8 membered saturated, partially unsaturated, 15 or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or; two R on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 20 each X' is independently a suitable hydroxyl protecting group; each X 2 is independently a suitable thiol protecting group; each X 3 is independently a suitable amino protecting group; and

R

4 is NRC(O)R, NRC(O)N(R) 2 , C(O)OR, C(O)N(R) 2 , SO 2 R, NRSO 2 R, C(O)R, or S0 2 N (R) 2 . 25 -34- Other compounds suitable for use in methods of the invention include those of Formula 47, HOY i- kk' PP (47) or a pharmaceutically acceptable salt or prodrug thereof, wherein: 5 the stereochemistry of the carbon kk' to carbon 11' double bond is cis or trans; the stereochemistry of the carbon mm' to carbon nn' double bond is cis or trans; the stereochemistry of the carbon oo' to carbon pp' double bond is cis or trans; Y' is a bond or a linker selected from a ring containing up to 20 atoms or a chain of up to 20 atoms, provided that Y' can include one or more nitrogen, oxygen, sulfur 10 or phosphorous atoms, further provided that Y can include one or more substituents independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, arylsulfonate, 15 phosphoryl, or sulfonyl, further provided that Y' can contain one or more fused carbocyclic, heterocyclic, aryl or heteroaryl rings; Z' is selected from -CN, -C(NH)N(R")(R"), -C(S)-A', -C(S)R", -C(O)-A', -C(O)-R", -C(O)-SR", -C(O)-NH-S(O)2-R", -S(0)2-A', -S(O)2-R", S(O)2N(R")(R"),

-P(O)

2 -A', -PO(OR")-A', -tetrazole, alkyltetrazole, or -CH 2 OH, wherein 20 A' is selected from -OR", -N(R")(R") or -OM'; each R" is independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or a detectable label molecule, wherein any alkyl-, aryl- or heteroaryl-containing moiety is optionally substituted with up to 3 independently selected substituents; and 25 M' is a cation. - 35 - In certain embodiments, a compound of formula 47 is represented by formula 48, HO kk,

CO

2 H MM . nn' OH (48), or pharmaceutically acceptable salts and esters thereof, wherein: 5 the stereochemistry of the carbon kk' to carbon I' double bond is cis or trans; the stereochemistry of the carbon mm' to carbon nn' double bond is cis or trans; the stereochemistry of the carbon oo' to carbon pp' double bond is cis or trans. In certain embodiments, the stereochemistry of the carbon kk' to carbon 11' double bond is trans. 10 In certain embodiments, the stereochemistry of the carbon mm' to carbon nn' double bond trans. In certain embodiments, the stereochemistry of the carbon oo' to carbon pp' double bond is cis. In certain embodiments, the stereochemistry of the carbon kk' to carbon l1' 15 double bond is trans, the stereochemistry of the carbon mm' to carbon nn' double bond trans, and the stereochemistry of the carbon oo' to carbon pp' double bond is cis. In certain embodiments, a compound of formula 47 is represented by HO

CO

2 H compound 48a, (48a), compound 48b, -36-

HO

4 HO

CO

2 H CO 2 H - OH OH (48b), compound 48c, (48c), or pharmaceutically acceptable salts and esters thereof In certain embodiments, a compound of formula 47 is represented by formula HO 1 kk C02H 00.. pp 48d, (48d), or pharmaceutically acceptable salts and 5 esters thereof, wherein: the stereochemistry of the carbon kk' to carbon ll' double bond is cis or trans; the stereochemistry of the carbon mm' to carbon nn' double bond is cis or trans; the stereochemistry of the carbon oo' to carbon pp' double bond is cis or trans. In certain embodiments, the compound of formula 47 is other than a 10 compound of formula 48, 48a, 48b, 48c, or 48d. Other compounds suitable for use in methods of the invention include those of Formula 49, Y' R" (49), or a pharmaceutically acceptable salt or prodrug thereof, wherein: 15 Y' is a bond or a linker selected from a ring containing up to 20 atoms or a chain of up to 20 atoms, provided that Y' can include one or more nitrogen, oxygen, sulfur or phosphorous atoms, further provided that Y' can include one or more substituents independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, -37carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, arylsulfonate, phosphoryl, or sulfonyl, further provided that Y' can contain one or more fused carbocyclic, heterocyclic, aryl or heteroaryl rings; 5 Z' is selected from -CN, -C(NH)N(R")(R"), -C(S)-A', -C(S)R", -C(O)-A', -C(O)-R", -C(O)-SR", -C(O)-NH-S(O) 2 -R", -S(O) 2 -A', -S(O) 2 -R", S(O) 2 N(R")(R"),

-P(O)

2 -A', -PO(OR")-A', -tetrazole, alkyltetrazole, or -CH 2 OH, wherein A' is selected from -OR", -N(R")(R") or -OM'; each R" is independently selected from hydrogen, alkyl, aryl, arylalkyl, 10 heteroaryl, heteroarylalkyl or a detectable label molecule, wherein any alkyl-, aryl- or heteroaryl-containing moiety is optionally substituted with up to 3 independently selected substituents; and M' is a cation; and each of R" and Rb is independently for each occurrence selected from -OR', or 15 adjacent R" and Rb' are taken together to form an epoxide ring having a cis or trans configuration, wherein each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl, aminoacyl, aminocarbonyl, alkoxycarbonyl, or a protecting group. Exemplary compounds of formula 49 include compound 49a, OH CO 2 H 20 OH (49a), compound 49b, C0 2 H "60 (49b), or pharmaceutically acceptable salts and esters thereof. The compounds above (e.g., compounds of formula A or formulae 1 to 49) are known to be useful in the treatment or prevention of inflammation or inflammatory 25 disease. Examples of such compounds are disclosed in the following patents and applications: US 2003/0191184, WO 2004/014835, WO 2004/078143, US 6670396, US 2003/0236423, US 2005/0228047, US 2005/0238589 and US2005/0261255. These compounds are suitable for use in methods of the present invention. - 38 - Other compounds useful in this invention are compounds that are chemically similar variants to any of the compounds of formula A or formulae 1-49 set forth above. The term "chemically similar variants" includes, but is not limited to, replacement of various moieties with known biosteres; replacement of the end groups 5 of one of the compounds above with a corresponding end group of any other compound above, modification of the orientation of any double bond in a compound, the replacement of any double bond with a triple bond in any compound, and the replacement of one or more substituents present in one of the compounds above with a corresponding substituent of any other compound. 10 Lipoxin compounds suitable for use in this invention include those of formula 50:

HQ

4 0 3 H R 302 R304 R305 R303

R

305 Y301 , wherein: X is R 3 01 , OR 3 0 i, or SR 30 1 ;

R

3 01 is 15 (a) a hydrogen atom; (b) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched; (c) a cycloalkyl of 3 to 10 carbon atoms; (d) an aralkyl of 7 to 12 carbon atoms; 20 (e) phenyl; zi Zu Zi (f) substituted phenyl Zv Ziv wherein Zi Zii, Zii, Zi, and Z, are each independently selected from

-NO

2 , -CN, -C(=0)-R 301 , -S0 3 H, a hydrogen atom, halogen, methyl, -OR,, wherein R, is I to 8 carbon atoms, inclusive, which may be a 25 straight chain or branched, and hydroxyl, wherein when any of Zi Zi, -39- Zii, Zi, or Z, is C(=0)-R 30 1 , said Zi Zsi, Z;;;, Zi, or Z, is not substituted with another C(=O)-R 3 01. (g) a detectable label molecule; or (h) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive; 5 Q1 is (C=O), SO 2 or (CN), provided when Q, is CN, then X is absent; Q3 and Q4 are each independently 0, S or NH; one of R3 0 2 and R 303 is a hydrogen atom and the other is: (a) H; (b) an alkyl of I to 8 carbon atoms, inclusive, which may be a straight 10 chain or branched; (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive; (d) an alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched; or (e) RkQ2RI wherein Q2 is -0- or -S-; wherein Rk is alkylene of 0 to 6 15 carbons atoms, inclusive, which may be straight chain or branched and wherein R, is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R, is 0, then R is a hydrogen atom;

R

30 4 is 20 (a) H; (b) an alkyl of I to 6 carbon atoms, inclusive, which may be a straight chain or branched; Zi Zi ZM'

R

30 5 is z Ziv , wherein Zi Zi;, Ziii, Zi4 and Zy are defined as above; 25 R 306 is (a) H; (b) an alkyl from I to 4 carbon atoms, inclusive, straight chain or branched; -40wherein Y 30 1 is -OH, methyl, -SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of I to 4 carbon atoms, inclusive, or (CH)p(Z)q, where p+q=3, p=O to 3, q=0 to 3 and Z is cyano, nitro or a halogen; and T is 0 or S, and pharmaceutically acceptable salts thereof 5 Lipoxin compounds suitable for use in this invention include those of formulae 51, 52, 53 or 54:

R

318

R

316

R

3 15

R

3 13

R

311

R

307 0 R3R OR2r R 317

R

31 4

R

3

R

2

OR

307 (51)

R

318

R

316

R

315

R

313

R

31 1

R

3 0 yO

OR

307

R

3 1 7

R

3 14

R

3 12

OR

30 7 (52),

R

3 18

R

3 16

R

3 15

R

3 13

R

3 11

R

3 07 0 319,R3390

OR

30 7

R

3 17

R

3 14

R

3 12

OR

30 7 (53),

R

3 18

R

3 16

R

315

R

3 13

R

311

R

307 O R320R 3309 10 OR 307

R

317

R

3 14 R 312

OR

307 (54), wherein: each R 30 7 is independently selected from hydrogen and straight, branched, cyclic, saturated, or unsaturated alkyl having from 1 to 20 carbon atoms;

R

3 0 8 , R 309 , R 310 , R 319 , and R 3 20 are independently selected from: (a) hydrogen; 15 (b) straight, branched, cyclic, saturated, or unsaturated alkyl having from l to 20 carbon atoms; (c) substituted alkyl having from I to 20 carbon atoms, wherein the alkyl is substituted with one or more substituents selected from halo, hydroxy, lower alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylarnino, 20 arylamino, hydroxyamino, alkoxyamino, alkylthio, arylthio, carboxy, carboxamido, carboalkoxy, aryl, and heteroaryl; -41 - (d) substituted aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with one or more substituents selected from alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and carboxamido; and (e) Z-Y, wherein: 5 Z is selected from a straight, branched, cyclic, saturated, or unsaturated alkyl having from I to 20 carbon atoms; substituted lower alkyl, wherein the alkyl is substituted with one or more substituents selected from halo, hydroxy, lower alkoxy, aryloxy, amino, alkyl amino, dialkylamino, acylamino, arylamino, hydroxyamino, alkoxyamino, alkylthio, arylthio, carboxy, carboxamido, carboalkoxy, aryl, and 10 heteroaryl; and substituted aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with one or more substituents selected from alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and carboxamido; and Y is selected from hydrogen; alkyl; cycloalkyl; carboxyl; carboxamido; aryl; heteroaryl; substituted aryl or heteroaryl, wherein the aryl or heteroaryl is 15 substituted with one or more substituents selected from alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and carboxamido; and

R

311 to R 318 are independently selected from: (a) hydrogen; (b) halo; 20 (c) straight, branched, cyclic, saturated, or unsaturated alkyl having from 1 to 20 carbon atoms; (d) substituted alkyl having from 1 to 20 carbon atoms, wherein the alkyl is substituted with one or more substituents selected from halo, hydroxy, lower alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, 25 arylamino, hydroxyamino, alkoxyamino, alkylthio, arylthio, carboxy, carboxamido, carboalkoxy, aryl, and heteroaryl; (e) substituted aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with one or more substituents selected from alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and carboxamido; or 30 R308 to Rno are independently a bond that forms a carbon-carbon double bond, a carbon-carbon triple bond, or a ring with the lipoxin backbone; or - 42 any two of R 30 7 to R 320 are taken together with the atoms to which they are bound and optionally to I to 6 oxygen atoms, 1 to 6 nitrogen atoms, or both 1 to 6 oxygen atoms and I to 6 nitrogen atoms, to form a ring containing 3 to 20 atoms. Lipoxin compounds suitable for use in this invention include those of formula 5 55: > R401 R402 (55) wherein: R4o, is selected from: HO Q 3 H R 4 12

R

412 0

(CH

2 )

OR

4 11 R414 R413 R413a R413b OH R 412 0 HO OH 0 Y4021,,.

(CH

2 )n OR 421

OR

42 1 , or R413a R413b 10 R 402 is selected from:

R

4 1 5 R415 R415 R416

-

. Y402 Y402 401 402 Y401 Y 4 ,1

R

42

.

42 R41 2 R415 R 2 6 R422 or (forms ring)

R

424

RR

425 R4 22

R

423 2 - 43 - XIo is R411, OR 4 ii, or SR 4 11 ;

R

4 1 is (a) a hydrogen atom; (b) an alkyl of I to 8 carbons atoms, inclusive, which may be 5 straight chain or branched; (c) a cycloalkyl of 3 to 10 carbon atoms; (d) an aralkyl of 7 to 12 carbon atoms; (e) phenyl; z Zii ; 4i (f) substituted phenyl Z' zi, 10 wherein Zi Zii, Ziii, Zi, and Zv are each independently selected from -NO 2 , -CN, -C(=O)-R 4

,

1 , -SO 3 H, a hydrogen atom, halogen, methyl, -OR., wherein R, is I to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl; wherein when any of Zi Zj 1 , Z j, Z;v or Zv is 15 C(=O)-R 4 1 , said Zi Z, Zi, Ziv or Z, is not substituted with another C(=O)-R 4 1 . (g) a detectable label molecule; or (h) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive; 20 Q I is (C=O), SO 2 or (CN); Q3 is O, S or NH; one of R412 and R41 3 is a hydrogen atom and the other is selected from: (a) H; (b) an alkyl of I to 8 carbon atoms, inclusive, which can be straight 25 chain or branched; (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive; (d) an alkenyl of 2 to 8 carbon atoms, inclusive, which can be straight chain or branched; or - 44 - (e) R 431

Q

2

R

4 32 wherein Q2 is -0- or -S-; wherein R43i is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched and wherein R 4 3 1 is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched; 5 R4E3, and R4I3b are each independently: (a) H; (b) an alkyl of I to 8 carbon atoms, inclusive, which can be straight chain or branched; (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive; 10 (d) an alkenyl of 2 to 8 carbon atoms, inclusive, which can be straight chain or branched; or (e) R 43

|Q

2 R4 3 2 wherein R 431 , Q2, and R432 are as defined above;

R

4 14 is (a) H; 15 (b) an alkyl of I to 6 carbon atoms, inclusive, can be straight chain or branched; Ra1s is (a) an alkyl of I to 9 carbon atoms which can be straight chain or branched; 20 (b) -(CH 2 )-Rs wherein n=O to 4 and R; is (i) a cycloalkyl of 3 to 10 carbon atoms, inclusive; (ii) a phenyl; or Zi Z4 i (iii) substituted phenyl Zv ziv , wherein Zi 25 through Z, are as defined above; (b) R43,Q2R432, wherein R431, Q2, and R432 are as defined above; (c) -C(Riii)(Ri,)-R;, wherein Ri;; and R;, are each independently: (i) a hydrogen atom; - 45 - (ii) (CH),(Z)q, wherein Z, p, and q are as defined above; (e) a haloalkyl of I to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched;

R

4 6 is 5 (a) H; (b) an alkyl from I to 4 carbon atoms, inclusive, straight chain or branched; (c) a halogen; one of Y 40 1 or Y4a 2 is -OH, methyl, or -SH, and wherein the other is selected 10 from: (a) H; (b) (CH)p(Z)q where p+q=3, p=0 to 3, q=0 to 3 and each Z, independently, is cyano, nitro or a halogen; (c) an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or 15 branched; or (d) an alkoxy of 1 to 4 carbon atoms, inclusive, or Y 401 and Y 402 taken together are: (d) =NH; or (e) =0; 20 one of Y 4 03 or Y 4 04 is -OH, methyl, or -SH, and wherein the other is selected from: (a) H; (b) (CH)p(Z)q wherein Z, p, and q are as defined above; (c) an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or 25 branched; or (d) an alkoxy of I to 4 carbon atoms, inclusive, or Y 401 and Y 40 2 taken together are: (a) =NH; or (b) =0; 30 one of Y 40 5 or Y 406 is -OH, methyl, or -SH, and wherein the other is selected from: (a) H (b) (CH)p(Z), wherein Z, p, and q are as defined above; - 46 - (c) an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched; or (d) an alkoxy of I to 4 carbon atoms, inclusive, or Y401 and Y4o2 taken together are: 5 (a) =NH; or (b) =0;

R

4 21 is (a) H; or (b) alkyl of I to 8 carbon atoms; 10 R 4 22 and R423 are each independently: (a) H; (b) a hydroxyl, or a thiol; (c) a methyl or a halomethyl; (d) a halogen; or 15 (e) an alkoxy of 1 to 3 carbon atoms;

R

424 and R 425 are each independently: (a) H; (b) a hydroxyl, or a thiol; (c) a methyl or a halomethyl; 20 (d) a halogen; (e) an alkoxy of 1 to 3 carbon atoms; or (f) an alkyl or haloalkyl of 2 to 4 carbon atoms inclusive, which can be straight chain or branched; and

R

426 is Zi Zii zi~ 25 (a) a substituted phenyl z ziv , wherein Z; through Z, are as defined above; -47- Zi Zii (b) a substituted phenoxy Z' Ziv wherein Zi through Z, are as defined above; or Zi Zi (c) z Ziv wherein Zi through Z, are as defined above. 5 Lipoxin compounds suitable for use in this invention include those of formula 56:

R

502 0 OR 50 1 0 E n R5030 W (56), wherein: E is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, and the 10 cations of sodium, potassium, magnesium and zinc; W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide; each of R 501

-RS

03 are independently selected from hydrogen, alkyl, 15 aryl, acyl or alkoxyacyl; nisO, 1 or2; m is 1 or 2; and the two substituents on the phenyl ring are ortho, meta, or para. - 48 - Lipoxin compounds suitable for use in this invention include those of formula 57: ORr ORe R604 R0R601 R6o5 G R0os OR (57), wherein: I is selected from: -C(O)-E, -SO2-E, -PO(OR)-E, where E is hydroxy, 5 alkoxy, aryloxy, amino, alkylamino, dialkylamino, or -OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn; and R is hydroxyl or alkoxy J' and K' are linkers independently selected from a chain of up to 20 atoms and a ring containing up to 20 atoms, provided that J' and K' can independently 10 include one or more nitrogen, oxygen, sulfur or phosphorous atoms, and further provided that J' and K' can independently include one or more substituents selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, 15 arylsulfonate, phosphoryl, and sulfonyl, and further provided that J' and K' can also contain one or more fused carbocyclic, heterocyclic, aryl or heteroaryl rings, and provided that linkers J' and K' are connected to the adjacent C(R)OR group via a carbon atom or a C-heteroatom bond where the heteroatom is oxygen, sulfur, phosphorous or nitrogen; 20 G is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, and carboxamido. Re, Rf and Rg, are independently selected from hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl; 25 R 601 , R 602 and R 603 are independently selected from hydrogen, alkyl, aryl and heteroaryl, provided that R 6 01 , R 602 and R 603 can independently be connected to linkers ' or K'; -49 -

R

60 4 and R6os are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, fluoro, and provided that R 604 and R6os can be joined together to form a carbocyclic, heterocyclic or aromatic ring, and further provided that R6o4 and R6os can be replaced by a bond to form a triple bond. 5 Other compounds suitable for use in methods of the invention are the oxylipins described in international applications WO 2006055965, WO 2007090162, and W02008103753 the compounds in which are incorporated herein by reference. Examples of such compounds are those of formulae 58-1 15, as shown in Table 1, These compounds include long chain omega-6 fatty acids, docosapentaenoic acid 10 (DPAn-6) (compounds 58-73) and docosatetraenoic acid (DTAn-6) (compounds 74 83), and the omega-3 counterpart of DPAn-6, docosapentaenoic acid (DPAn-3) (compounds 84-97). Further compounds are the docosanoids 98-115, the y-linolenic acids (GLA) (compounds 116-122), and the stearidonic acids (SDA) (compounds 123-132). 15 Table I 10,17-Dihydroxy DPAn-6 (58) OH CO2H OH 16,17-Dihydroxy DPAn-6 (59)

.

__. CO 2 H HO OH 4,5-Dihydroxy DPAn-6 (60) HO OH -_ CO 2 H -50- 7,17-Dihydroxy DPAn-6 OH (61) -oDCO2H OH 7-Hydroxy DPAn-6 (62) OH

CO

2 H 10-hydroxy DPAn-6 (63) OH

CO

2 H 13-Hydroxy DPAn-6 (64) CO2H HO 17-hydroxy DPAn-6 (65) CO 2 H OH - 5! - 4,5,17-Trihydroxy DPAn-6 HO OH (66) CO2H OH 7,16,17-Trihydroxy DPAn 6(67) CO2H HO OH 8-Hydroxy DPAn-6 (68) HO C0 2 H 14-Hydroxy DPAn-6 (69) CO 2 H OH 13,17-Dihydroxy DPAn-6 (70) CO 2 H HO OH - 52 - 7,14-Dihydroxy DPAn-6 (71) OH C02H OH 8,14-Dihydroxy DPAn-6 HO (72) CO2H OH 11 -Hydroxy DPAn-6 (73) HO CO 2 H 10,1 7-Dihydroxy-DTAn-6 (74) OH CO2H OH 16,17-Dihydroxy-DTAn-6 (75)

CO

2 H HO OH -53- 4,5-Dihydroxy-DTAn-6 (76) HO OH C0 2 H 7,17-Dihydroxy-DTAn-6 (77) OH CO2H OH 7-Hydroxy-DTAn-6 (78) OH

CO

2 H 10-Hydroxy-DTAn-6 (79)

-CO

2 H 13-Hydroxy-DTAn-6 (80)

CO

2 H HO 17-Hydroxy-DTAn-6 (81) CO2H OH -54- 4,5,17-Trihydroxy-DTAn-6 (82) HO OH -- CO2H OH 7,16,17-Trihydroxy-DTAn 6 (83) OH -- CO2H HO OH 10,1 7-Dihydroxy DPAn-3 (84) OH CO2 10,20-Dihydroxy DPAn-3 (85) OH OH 13,20-Dihydroxy DPAn-3 (86) --

CO

2 H HO OH - 55 - 16,17-Dihydroxy DPAn-3 (87)

-

CO

2 H HO OH 7,17-D~iydroxy DPAn-3 (88) OH CO2H OH 7-Hydroxy DPAn-3 (89) - CO 2 H OH

CO

2 H 13-Hydroxy DPAn-3 (91)

HCO

2 H HO -56- 17-Hydroxy DPAn-3 (92) CO2 H OH 7,16,17-Trihydroxy DPAn- OH 3(93) CO2H HO OH 16-Hydroxy DPAn-3 (94) CO 2 H HO 11-Hydroxy DPAn-3 (95) HO HO CO 2 H 14-Hydroxy DPAn-3 (96) -- CO2H OH - 57 - 8,14-Dihydroxy DPAn-3 HO (97) -- CO2H OH 10,11-Epoxy DHA (98) 0

CO

2 H 13,14-Dihydroxy DHA (99)

CO

2 H HO OH 13,14-Epoxy DHA (100) CO 2 H 0 19,20-Epoxy DHA (101)

CO

2 H 0 7,8-Epoxy DHA (102) O

CO

2 H - 58 - 4,5-Epoxy-17-OH DPA (103) O - --- CO2H OH 7,16,17-Trihydroxy DTAn 3(104) OH CO2H HO OH 16,17-Dihidroxy DTAn-3 C0 2 H (105) C HO OH 10,16,17-Trihydroxy OTRAn-6 (106) OH CO2H HO OH 16,17-Dihydroxy DTRAn-6 (107) CO 2 H HO OH 7,16,17-Trihydroxy DTRAn-6 (108) OH CO2H HO OH - 59 - 15-epi-lipoxin A4 (109) HO OH CO2H OH 16,17-epoxy DHA (110) CO 2 H 0 7,8-epoxy DPA (111) 0 CO 2 H 10,11 epoxy DPA (112) 0 C0 2 H 19,20 epoxy DPA (113) - -- CO 2 H 0 7-hydroxy DHA (114) OH CO2 - C 2 H - 60 - 13,14 epoxy DPA (115) C0 2 H 0 6-hydroxy GLA (116) OH / coo 10-hydroxy GLA (117)

COO

OH 7-hydroxy GLA (118) HO

COO

12-hydroxy GLA (119) HO 9-hydroxy GLA (120) HO 13-hydroxy GLA (121) COO - 6! - 6.13 dihydroxy GLA (122) OH / coo 6-hydroxy SDA (123) OH 10-hydroxy SDA (124) OH 7-hydroxy SDA (125) HO coor 12-hydroxy SDA (126) HO 9-hydroxy SDA (127) HO 13-hydroxy SDA (128) OH - 62 - 15-hydroxy SDA (129) - / _ _ C00 HO ___ 16-hydroxy SDA (130) \Coo OH 6,13 dihydroxy SDA (131) OH / coo O H 6,16 dihydroxy SDA (132) OH OH / Coo ____ ____ ____OH. Other oxylipin compounds that are suitable for use in methods of the invention include analogs of the compounds shown in Table 1. Such compounds include but are not limited to those analogs wherein one or more double bonds are replaced by 5 triple bonds, those wherein one or more carboxy groups are derivatized to form esters, amides or salts, those wherein the hydroxyl-bearing carbons are further derivatized (with, for example, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, or alkynyl group, substituted or unsubstituted aryl group, substituted or unsubstituted, branched or unbranched alkylaryl group, halogen atom) to form tertiary 10 alcohols (or ethers, esters, or other derivatives thereof), those wherein one or more hydroxyl groups are derivatized to form esters or protected alcohols, or those having combinations of any of the foregoing modifications. Further oxylipin compounds suitable for use in methods of the invention include the following: isolated docosanoids of docosapentaenoic acid (DPAn-6); 15 monohydroxy, dihydroxy, and trihydroxy derivatives of DPAn-6; isolated -63 docosanoids of docosapentaenoic acid (DPAn-3); monohydroxy, dihydroxy, and trihydroxy derivatives of DPAn-3; isolated docosanoids of docosapentaenoic acid (DTAn-6); or monohydroxy, dihydroxy, and trihydroxy derivatives of DTAn-6. The term "LASIK", as used herein, is an acronym for LAser in SItu 5 Keratomileusis. This is a type of refractive surgery in which the cornea is reshaped to change its optical power. Specifically, a disc of cornea is raised as a flap, then an excimer laser is used to reshape the middle layer of corneal tissue, producing surgical flattening. LASIK surgery may be used for correcting myopia, hyperopia, and astigmatism. 10 The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-. The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-. 15 The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-. The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. 20 The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term "alkenyl", as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having 25 substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, 30 carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. - 64 - In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g:, C-C 30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons 5 in the ring structure. Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon 10 backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a 15 sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, 20 phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl 25 substituted alkyls, -CF 3 , -CN, and the like. The term "C-y" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term "Cyalkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain 30 alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. CO alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms "C2-yalkenyl" and "C2-yalkynyl" refer to substituted or unsubstituted - 65 unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term "alkylamino", as used herein, refers to an amino group substituted with at least one alkyl group. 5 The term "alkylthio", as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyIS-. The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having 10 substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, 15 heterocyclyl, or heteroaryl groups is contemplated. The term "amide", as used herein, refers to a group 0 RIO N R1O wherein each R' 0 independently represent a hydrogen or hydrocarbyl group, or two RIO are taken together with the N atom to which they are attached complete a 20 heterocycle having from 4 to 8 atoms in the ring structure. The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by RIO R1O -N -N- RIO Rio or \RIO 25 wherein each R' 0 independently represents a hydrogen or a hydrocarbyl group, or two Rio are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. - 66 - The term "aminoalkyl", as used herein, refers to an alkyl group substituted with an amino group. The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group. 5 The term "aryl" as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5 to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is 10 aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term "carbamate" is art-recognized and refers to a group 0 0 /-O N R -N R R10 or 15 wherein each R1 0 independently represent hydrogen or a hydrocarbyl group, or both R10 groups taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. The terns "carbocycle", "carbocyclyl", and "carbocyclic", as used herein, refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring 20 is carbon. Preferably a carbocycle ring contains from 3 to 10 atoms, more preferably from 5 to 7 atoms. The term "carbocyclylalkyl", as used herein, refers to an alkyl group substituted with a carbocycle group. The term "carbonate" is art-recognized and refers to a group -OC0 2

-R'

0 , 25 wherein R' 0 represents a hydrocarbyl group. The term "carboxy", as used herein, refers to a group represented by the fonnula -CO2H. The term "ester", as used herein, refers to a group -C(O)OR' 0 wherein R' 0 represents a hydrocarbyl group. -67- The term "ether", as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O 5 heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl. The terms "halo" and "halogen" as used herein means halogen and includes chloro, fluoro, bromo, and iodo. The terms "hetaralkyl" and "heteroaralkyl", as used herein, refers to an alkyl 10 group substituted with a hetaryl group. The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent. The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted 15 aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5 to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings 20 wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term "heteroatom" as used herein means an atom of any element other 25 than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur. The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10 membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably 30 one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, - 68 cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. The term "heterocyclylalkyl", as used herein, refers to an alkyl group 5 substituted with a heterocycle group. The term "hydrocarbyl", as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and 10 trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof 15 The term "hydroxyalkyl", as used herein, refers to an alkyl group substituted with a hydroxy group. The term "lower" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. 20 A "lower alkyl", for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations 25 hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent). The terms "polycyclyl", "polycycle", and "polycyclic" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., 30 the rings are "fused rings". Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7. - 69 - The term "silyl" refers to a silicon moiety with three hydrocarbyl moieties attached thereto. The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that 5 "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all 10 permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen 15 may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a 20 phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, 25 if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants. The term "sulfate" is art-recognized and refers to the group -OSO 3 H, or a 30 pharmaceutically acceptable salt thereof. The term "sulfonamide" is art-recognized and refers to the group represented by the general formulae -70o 0 11 R10 1 tsN / AI R' 0 N N R1 0 Rio Ren or RIO wherein each R110 independently represents hydrogen or hydrocarbyl, or both R' groups taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.. 5 The term "sulfoxide" is art-recognized and refers to the group -S(O)-R", wherein R' 0 represents a hydrocarbyl. The term "sulfonate" is art-recognized and refers to the group SO 3 H, or a pharmaceutically acceptable salt thereof The term "sulfone" is art-recognized and refers to the group -S(O)rR', 10 wherein R 0 represents a hydrocarbyl. The term "thioalkyl", as used herein, refers to an alkyl group substituted with a thiol group. The term "thioester", as used herein, refers to a group -C(O)SR' 0 or -SC(O)R' 0 wherein R1 0 represents a hydrocarbyl. 15 The term "thioether", as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur. The term "urea" is art-recognized and may be represented by the general formula 0 20 wherein each R' 0 independently represent hydrogen or a hydrocarbyl, or two occurrences of R' 0 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. The term "prodrug" is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the 25 present invention (e.g., a compound of formula A or formulae 1-49, a lipoxin compound, or an oxylipin compound). A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic -71 conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, esters (e.g., esters of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of formula A, compounds of 5 any one of formulae 1-49, lipoxins, or oxylipins, all or a portion of a compound of formula A, compound of any one of formulae 1-49, lipoxin, or oxylipin in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl or carboxylic acid present in the parent compound is presented as an ester. 10 "Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3" Ed., 1999, John Wiley 15 & Sons, NY and Harrison et al., Compendium ofSynthetic Organic Methods, Vols. 1 8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2 trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, 20 allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro veratryloxycarbonyl ("NVOC") and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups), 25 glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers. The term Healthcaree providers" refers to individuals or organizations that provide healthcare services to a person, community, etc. Examples of "healthcare providers" include doctors, hospitals, continuing care retirement communities, skilled 3.0 nursing facilities, subacute care facilities, clinics, multispecialty clinics, freestanding ambulatory centers, home health agencies, and HMO's. The term "treating" refers to: preventing a disease, disorder or condition from occurring in a cell, a tissue, a system, animal or human which may be predisposed to - 72 the disease, disorder and/or condition but has not yet been diagnosed as having it; stabilizing a disease, disorder or condition, i.e., arresting its development; and relieving one or more symptoms of the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition. 5 As used herein, a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. 10 The synthesis of each of the compounds of formula A, compounds of any one of formulae 1-49, lipoxins, or oxylipins set forth above can be achieved by methods well-known in the art. For example, the synthesis of compounds of formula A or formulae 1-49 is set forth in US 2003/0191184, WO 2004/014835, WO 2004/078143, US 6670396, US 2003/0236423 and US 2005/0228047, all of which are herein 15 incorporated by reference. The synthesis of lipoxin compounds is set forth in US 2002/0107289, US 2004/0019110, US 2006/0009521, US 2005/0203184, US 2005/0113443, all of which are herein incorporated by reference. The preparation of oxylipin compounds is set forth in WO 2006/055965, WO 2007/090162, and WO 2008/103753, all of which are herein incorporated by reference. 20 The compositions and methods of the present invention may be utilized to treat an individual in need thereof In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of formula A, 25 compound of any one of formulae 1-49, lipoxin compound, oxylipin compound, or aspirin and/or an omega-3 fatty acid and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable 30 organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, the aqueous solution is pyrogen free, or substantially pyrogen free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The - 73 pharmaceutical composition can be in dosage unit form such as tablet, capsule, sprinkle capsule, granule, powder, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. A pharmaceutically acceptable carrier can contain physiologically acceptable 5 agents that act, for example, to stabilize or to increase the absorption of a compound such as a compound of formula A, compound of any one of formulae 1-49, lipoxin compound, oxylipin compound, or aspirin and/or an omega-3 fatty acid. Such physiclogically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, 10 chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound 15 of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope 20 of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid 25 filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, 30 and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) - 74 glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) 5 ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, 10 boluses, powders, granules, pastes for application to the tongue); sublingually; anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, 15 as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 20 4,172,896, as well as in patents cited therein. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of 25 administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most 30 preferably from about 10 percent to about 30 percent. Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of formula A, compound of any one of formulae 1-49, lipoxin compound, oxylipin compound, or - 75 aspirin and/or an omega-3 fatty acid, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by unifonnly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the 5 product. Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid 10 emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste. 15 To prepare solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for 20 example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, 25 for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar 30 type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. - 76 - A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked 5 sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules, pills and granules, may optionally be scored or prepared 10 with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be 15 sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a 20 certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms useful for oral administration include pharmaceutically 25 acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils 30 (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. - 77 - Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending 5 agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth, and mixtures thereof Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by 10 mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. 15 Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment. Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine. 20 Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The 25 active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, 30 starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and - 78 polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled 5 delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. 10 Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have 15 properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatable with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant). Formulations of the present invention can be administered in a manner 20 generally known to those skilled in the art. In certain embodiments, the formulation is administered using an eyedropper. The eyedropper can be constructed in any suitable way. It may be desirable to utilize a measured dose eyedropper of the type described within U.S. Patent No. 5,514,118 or an illuminated eyedropper device of the type described in U.S. Patent No. 5,584,823. A range of other eye droppers can also be 25 utilized of the type described within the following U.S. Patent Nos. 5,059,188; 4,834,727; 4,629,456; and 4,515,295. The patents cited here which disclose eyedroppers are incorporated herein by reference as are the various patents and publications cited and discussed within these patents. The phrases "parenteral administration" and "administered parenterally" as 30 used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, - 79 subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions 5 or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers that may be employed 10 in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case 15 of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the 20 like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow 25 the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is 30 accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsuled matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer - 80 employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. 5 For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. Methods of introduction may also be provided by rechargeable or 10 biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site. 15 Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the 20 activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and 25 prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of 30 the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. -81 - It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, 5 and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference). 10 In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. If desired, the effective daily dose of the active compound may be 15 administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally; in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily. 20 The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general. In certain embodiments, the method of treating an ophthalmic condition comprises conjointly administering a compound of formula A, compound of any one 25 of formulae 1-49, lipoxin compound, oxylipin compound, or combination of aspirin and an omega-3 fatty acid conjointly with another therapeutic agent. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body 30 (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. Thus, an individual who - 82 receives such treatment can benefit from a combined effect of different therapeutic compounds. In certain embodiments, different compounds of formulae A, compounds of any one of formulae 1-49, lipoxin compounds, or oxylipin compounds may be 5 conjointly administered with other agents suitable for the treatment of an ophthalmic condition. For example, the following agents or classes of agents may be conjointly administered with a compound of formula A, compound of any one of formulae 1-49, lipoxin compound, oxylipin compound, or combination of aspirin and an omega-3 fatty acid: doxocycline; decosahexanoic acid; angiogenesis inhibitors, e.g., VEGF 10 inhibitors, such as pegaptanib sodium, bevacizumab, ranibizumab, AV-951, vandetanib, semaxanib, CBO-P 11, axitinib, sorafenib, sunitinib, pazopanib, and TIMP3; anesthetics and pain killing agents such as lidocaine and related compounds and benzodiazepam and related compounds; anti-cancer agents such as 5-fluorouracil, adriamycin and related compounds; anti-inflammatory agents such as 6-mannose 15 phosphate; anti-fungal agents such as fluconazole and related compounds; anti-viral agents such as trisodium phosphomonoformate, trifluorothymidine, acyclovir, ganciclovir, DDI, DDC, and AZT; cell transport/mobility impending agents such as colchicine, vineristine, cytochalasin B, and related compounds; antiglaucoma drugs such as beta-blockers: timolol, betaxol, atenalol, etc; prostaglandins such as 20 latanoprost and travoprost, etc.; immunological response modifiers such as muramyl dipeptide and related compounds; peptides and proteins such as cyclosporin, insulin, growth hormones, insulin related growth factor, nerve growth factor (optionally in further combination with decosahexanoic acid), heat shock proteins and related compounds; estrogen treatments; corticosteroids such as dexamethasone, 25 dexamethasone 21-phosphate, fluorometholone, medrysone, betamethasone, triamcinolone, triamcinolone acetonide, triminolone, prednisone, prednisolone, prednisolone 21 -phosphate, prednisolone acetate, hydrocortisone, hydrocortisone acetate, prednicarbate, deflazacort, halomethasone, tixocortol, prednylidene (21 diethylaminoacetate), prednival, paramethasone, prednisolone, methylprednisolone, 30 meprednisone, mazipredone, isoflupredone, halopredone acetate, halcinonide, formocortal, flurandrenolide, fluprednisolone, flurprednidine acetate, fluperolone acetate, fluocortolone, fluocortin butyl, fluocinonide, fluocinolone, fluocinolone acetonide, flunisolide, flumethasone, fludrocortisone, fluclorinide, fluoromethalone, -83 enoxolone, difluprednate, diflucortolone, diflorasone diacetate, desoximetasone (desoxymethasone), desonide, descinolone, cortivazol, corticosterone, cortisone, cloprednol, clocortolone, clobetasone, clobetasol, chloroprednisone, cafestol, budesonide, beclomethasone, amcinonide, allopregnane acetonide, alclometasone, 21 5 acetoxypregnenolone, tralonide, diflorasone acetate, deacylcortivazol, RU-26988, budesonide, and deacylcortivazol oxetanone. All of the above-cited corticosteroids are known compounds. Further information about the compounds may be found, for example, in The Merck Index, Thirteenth Edition (2001), and the publications cited therein, the entire contents of which are hereby incorporated herein by reference. In 10 certain embodiments, the corticosteroid is selected from fluocinolone acetonide, triamcinolone acetonide, dexamethasone, and related compounds, or any combination thereof; and carbonic anhydaze inhibitors. FUrther examples of agents or classes of agents may be conjointly administered with a compound of formula A, compound of any one of formulae 1-49, 15 lipoxin compound, oxylipin compound, or combination of aspirin and an omega-3 fatty acid include: antioxidants such as OT-55 1; agents targeting the IL-2Ra receptor such as daclizumab; TNFa antagonists such as infliximab; antibiotics such as sirolimus; nicotonic antagonists such as mecamylamine; steroids such as anecortave acetate; photosensitizers with photodynamic therapy such as verteporfin; PGE I (e.g., 20 alprostadil); synthetic retinoids such as fenretinide; carbonic anhydrase inhibitors such as acetazolamide; P2Y2 receptor agonists such as denufosol tetrasodium and diquafosol; interferons such as interferon beta; NSAIDs such as bromfenac and nepafenac; anti-VEGF agents such as EYEOOI, VEGF-Trap, bevasiranib, and vatalanib; anti-VEGF agents/kinase mediators such as TGI00801; antiangiogenic 25 agents such as AG-013,958 and squalamine lactate; and siRNA's such as CANDS and AGN21 1745. Further examples of agents or classes of agents may be conjointly administered with a compound of formula A, compound of any one of formulae 1-49, lipoxin compound, oxylipin compound, or combination of aspirin and an omega-3 30 fatty acid include: DE-104; PF-04217329; PF-03187207; AL 37807; OPC-12759; chemotherapeutic agents such as mitomycin C; synthetic structural analogs of prostaglandin such as bimatoprost; alpha 2 agonists such as brimonidine; carbonic anhydrase inhibitors such as dorzolamide HCI; prostaglandin derivatives and analogs - 84 such as tafluprost and travoprost; NMDA antagonists such as memantine; hyaluronic acid (e.g., sodium hyaluronate); corticosteroids such as loteprednol etabonate, difluprednate and rimexolone; antibiotics such as doxycycline; agents that increase mucin such as ecabet and rebamipide; lubricants such as the combination of 5 carboxymethylcellulose sodium and glycerin; A3 adenosine receptor agonists such as CF- 101; immunomodulators such as thalidomide; TNFa antagonists such as etanercept; protein kinase C-b inhibitors such as ruboxistaurin; immunosuppressants such as sirolimus; PARP inhibitors such as AG-Ol 4699; neuroprotective thrombolytic agents such as microplasmin; hyaluronidase; oxidizing agents such as carbamide; 10 somatostatin analogs such as octreotide acetate; angiotensin I receptor antagonists such as candesartan cilexetil; disease-modifying antirheumatic drugs such as leflunomide; AEB071 ; TNF antagonists such as adalimumab; CD1I1 antagonists such as efalizumab; calcineurin inhibitors such as LX21 1; interferons such as interferon a 2a; and human alpha fetoproteins such as MM-093. 15 In addition to the above agents, other agents are suitable for administration to the eye and its surrounding tissues to produce a local or a systemic physiologic or pharmacologic beneficial effect. Such agents may be conjointly administered with a compound of formula A, compound of any one of formulae 1-49, lipoxin compound, oxylipin compound, or combination of aspirin and an omega-3 fatty acid. Examples 20 of such agents include neuroprotectants such as nimodipine and related compounds; antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamycin, and erythromycin; antibacterials such as sulfonamides, sulfacetamide, sulfamethizole, and sulfisoxazole; antivirals, including idoxuridine; other antibacterial agents such as nitrofurazone and 25 sodium propionate; antiallergenics such as antazoline, methapyriline, chlorpheniramine, pyrilamine, and prophenpyridamine; decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; miotics and anti-cholinesterase such as pilocarpine, eserine salicylate, carbachol, di-isopropyl fluorophosphate, phospholine iodine, and demecarium bromide; mydriatics such as atropine sulfate, 30 cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; sympathonimetics such as epinephrine; and prodrugs such as those described in Design of Prodrugs, edited by Hans Bundgaard, Elsevier Scientific Publishing Co., Amsterdam, 1985. Reference may be made to any standard - 85 pharmaceutical textbook such as Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, Pa., USA 1985) for the identify of other agents. In certain embodiments, different compounds of formulae A, compounds of 5 any one of formulae 1-49, lipoxin compounds, or oxylipin compounds may be conjointly administered with non-chemical methods suitable for the treatment of an ophthalmic condition. In certain embodiments, different compounds of formulae A, compounds of any one of formulae 1-49, lipoxin compounds, or oxylipin compounds may be conjointly administered with laser treatment (e.g., photocoagulation or 10 photodynamic therapy), macular translocation surgery or with devices (e.g., brimonidine tartrate implant). In certain embodiments, different compounds of formulae A, compounds of any one of formulae 1-49, lipoxin compounds, or oxylipin compounds may be conjointly administered with one another. Moreover, such combinations may be 15 conjointly administered with other therapeutic agents, such as other agents suitable for the treatment of an ophthalmic condition, such as the agents identified above. In embodiments where a combination of aspirin and an omega-3 fatty acid are administered, the aspirin and omega-3 fatty acid can be administered simultaneously, e.g., as a single formulation comprising both components or in separate formulations, 20 or can be administered at separate times, provided that, at least at certain times during the therapeutic regimen, both the aspirin and omega-3 fatty acid are present simultaneously in the patient at levels that allow the omega-3 fatty acid to be metabolized as described in Serhan, et. al., 2002, J. Exp. Med., 196: 1025-1037. In certain such embodiments, the omega-3 fatty acid is provided in the form of a 25 partially purified natural extract, such as fish oil, while in other embodiments, the omega-3 fatty acid may be provided as a substantially pure preparation of one or more omega-3 fatty acids, such as a C 18:3, C20:5, or C22:6 fatty acid, particularly eicosapentaenoic acid or docosahexaenoic acid. A substantially pure preparation of one or more omega-3 fatty acids refers to a composition wherein the fatty acid 30 component is at least 90%, at least 95%, or even at least 98% of one or more omega-3 fatty acids, such as one or more specified omega-3 fatty acids. Non-fatty acid components, such as excipients or other materials added during fornmulation, are not - 86 considered for the purpose of determining whether the fatty acid component meets the desired level of purity. In certain embodiments, a COX-2 inhibitor other than aspirin, such as celecoxib, rofecoxib, valdecoxib, lumiracoxib, etoricoxib, NS-398, or parecoxib, may 5 be used in combination with an omega-3 fatty acid for the treatment of an ophthalmic condition in any of the various embodiments discussed herein. In certain embodiments, a non-selective NSAID other than aspirin, such as diclofenac, diflunisal, etodolac, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, 10 sulindac, or tolmetin, may be used in combination with an omega-3 fatty acid for the treatment of an ophthalmic condition in any of the various embodiments discussed herein. The combination of different COX-2 inhibitors or non-selective NSAIDs with an omega-3 fatty acid may result in the production of different subsets or proportions of active omega-3 metabolites. 15 This invention includes the use of pharmaceutically acceptable salts of compounds of formula A, compounds of any one of formulae 1-49, lipoxin compounds, or oxylipin compounds in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated 20 salts of the invention include Na, Ca, K, Mg, Zn or other metal salts. The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or 25 crystallization, or adventitious to such solvent. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. 30 Examples of phannaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene - 87 - (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. The present invention provides a kit comprising: 5 a) a pharmaceutical formulation comprising a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid; and b) instructions for the administration of the pharmaceutical formulation for treating an ophthalmic condition. 10 In certain embodiments, the kit further comprises instructions for the administration of the pharmaceutical formulation comprising a compound of formula A, compound of any one of formulae 1-49, lipoxin compound, oxylipin compound, or combination of aspirin and an omega-3 fatty acid conjointly with an agent or non chemical method suitable for the treatment of an ophthalmic condition as mentioned 15 above. In certain embodiments, the kit further comprises a second pharmaceutical formulation comprising an agent suitable for the treatment of an ophthalmic condition as mentioned above. The present invention provides a kit comprising: a) one or more single dosage forms each comprising a compound of formula A, a 20 compound of any one of formulae 1-49, a lipoxin- compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid and a pharmaceutically acceptable excipient; and b) instructions for administering the single dosage forms for the treatment of an ophthalmic condition. 25 In certain embodiments, the kit further comprises instructions for the administration of the one or more single dosage forms each comprising a compound of formula A, compound of any one of formulae 1-49, lipoxin compound, oxylipin compound, or combination of aspirin and an omega-3 fatty acid conjointly with an agent or non-chemical method suitable for the treatment of an ophthalmic condition as 30 mentioned above. In certain embodiments, the kit further comprises one or more single dosage fonrs of an agent suitable for the treatment of an ophthalmic condition as mentioned above. In certain embodiments, the present invention provides a kit comprising: - 88 a) one or more single dosage forms each comprising an agent suitable for the treatment of an ophthalmic condition as mentioned above; and b) instructions for the administration of the one or more single dosage forms with a compound of formula A, compound of any one of formulae 1-49, lipoxin 5 compound, oxylipin compound, or combination of aspirin and an omega-3 fatty acid for treating or preventing an ophthalmic condition. The present invention provides a kit comprising: a) a first pharmaceutical formulation comprising an agent suitable for the treatment of an ophthalmic condition as mentioned above; and 10 b) instructions for the administration of the first pharmaceutical formulation and a second pharmaceutical formulation comprising a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid for treating or preventing an ophthalmic condition. 15 In certain embodiments, the invention relates to a method for conducting a pharmaceutical business, by manufacturing a formulation of a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid, or a kit as described herein, and marketing to healthcare providers the benefits of using the 20 formulation or kit in the treatment of an ophthalmic condition. In certain embodiments, the invention relates to a method for conducting a pharmaceutical business, by providing a distribution network for selling a formulation of a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty 25 acid, or kit as described herein, and providing instruction material to patients or physicians for using the formulation to treat an ophthalmic condition. In certain embodiments, the invention comprises a method for conducting a pharmaceutical business, by determining an appropriate formulation and dosage of a compound of formula A, a compound of any one of formulae 1-49, a lipoxin 30 compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid in the treatment of an ophthalmic condition, conducting therapeutic profiling of identified formulations for efficacy and toxicity in animals, and providing a distribution network for selling an identified preparation as having an acceptable - 89 therapeutic profile. In certain embodiments, the method further includes providing a sales group for marketing the preparation to healthcare providers. In certain embodiments, the invention relates to a method for conducting a pharmaceutical business by determining an appropriate formulation and dosage of a 5 compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid in the treatment of an ophthalmic condition, and licensing, to a third party, the rights for further development and sale of the formulation. Exemplification 10 The biological activity of one or more of a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid can be assessed using techniques well known in the art, such as those discussed below. Example 1: Compounds X and Z Inhibit Hypertonicity-induced Proinflammatory 15 Cytokine Release in Human Comeal Epithelial Cells. Dry eye is commonly associated with tear film hypertonicity which may induce ocular surface inflammation and erosion. Accordingly, it is clinically relevant to identify novel approaches to suppress these stress responses. Compounds of formula A, compounds of any one of formulae 1-49, lipoxin compounds, oxylipin 20 compounds, and the combination of aspirin and an omega-3 fatty acid, are highly potent and efficacious immune response regulators as shown in models of acute and chronic inflammation. Hurnan corneal epithelial cells (HCEC) were used to OH OH 0 ONa investigate if compounds X, OH and its analog compound Z, -90- OH OH 0 ONa z , could suppress a hypertonicity-induced increase in proinflammatory cytokine release. Methods: SV-40 immortalized HCEC were maintained in DMEM/FI 2 medium 5 supplemented with 10% FBS and 5 ng/ml epidermal growth factor (EGF). The extracellular medium tonicity was varied from 300 mOsm (isotonic control) to 600 mOsm by adding NaCl. Initial experiments indicated 450 mOsm was an optimal stress level with reproducible increases in cytokine levels and without causing cell detachment, and was the level selected for investigating effects of compounds X and 10 Z. The HCEC were exposed to hypertonicity for 20 hours in the absence or presence of compound X and Z in concentrations between 10'"1 and 10 7 M. The compounds were added 30 minutes prior to starting the hyperosmolar exposure. Q-Plux human inflammatory cytokine arrays were used to screen for select hypertonicity-induced cytokines, which were later quantitatively determined using ELISA. 15 Results: Exposure to a hyperosmolar environment of 450 mOsm caused an increase in IL-6 levels from a basal level of approximately 2000 pg/mL to 4000 pg/mL, and for IL-8 the increase was from 3,700 pg/mL to 9000 pg/mL. Both compound X (Figure 1) and compound Z (Figure 2) in a concentration dependent manner prevented the 20 release of both IL-6 and IL-8. At 10 7 M compound X reduced IL-6 release by 75% (Figure 1a) and IL-8 release by 70% (Figure Ib), while the corresponding decreases seen with compound Z were 70% (Figure 2a) and 65% (Figure 2b) , respectively. There was no effect on I L-6 or IL-8 release by either compound at a concentration of 10" M. 25 Conclusions: Figures 1 and 2 show that both compound X and its analog, compound Z, in a concentration-dependent manner suppress hypertonicity-induced release of the inflammatory mediators IL-6 (Figures Ia and 2a) and IL-8 (Figures lb and 2b) from HCEC. The results indicate that the compounds of this class may have therapeutic 30 value in the treatment of dry eye. - 91 - Example 2: Compounds V and W Protect Against Goblet Cell Loss and Reduce Corneal Epithelial Barrier Disruption in a Murine Model of KCS The purpose of this study was to evaluate the potential of compound V, OH OH 0 v ,3 and compound W, OH OH0 w 5 OH ,in reducing inflammation and signs of disease in a murine model of dry eye. Methods: Experimental dry eye was created in C57BL/6 mice by subcutaneous scopolamine injection and exposure to an air draft for 5 days, with or without topical 10 therapy, 300 pg/mL of compound W, 300 pg/mL of compound V and polysorbate vehicle control, delivered 4 times per day as 1 pL drops. Untreated mice were used as controls. Corneal permeability was assessed using Oregon Green Dextran (OGD) staining. Goblet cell density was evaluated by PAS staining. Results: 15 Figures 3 and 4, respectively, show that desiccating stress caused a significant goblet cell loss (4.97 ± 0.88 vs. 6.18 + 0.86 cells/I 00 pm, P<0.05, respectively) and a marked increase in corneal epithelial permeability to OGD compared to untreated controls ([mean ± SD] 146.50 25.32 vs. 119.3 ±9.71 gray levels, P<0.05, respectively). Figure 4 shows that topical treatment of eyes with compound W 20 significantly reduced OGD staining compared to vehicle control treated group (122.2 ± 5.9 vs. 135.1 ± 17.04 gray levels, P<0.0005, respectively). In addition, Figure 4 shows that topical treatment of eyes with compound V showed a decrease in OGD staining (128.5 ± 17.70 gray levels; P<O.1). Figure 3 shows that topical treatment of eyes with compound V showed a significant preservation in goblet cell density 25 compared to vehicle group (5.72 ± 0.5, P<0.0001). In addition, Figure 3 shows that - 92 topical treatment of eyes with compound W significantly maintained goblet cell density compared to vehicle control treated group (6.29 ± 0.47 vs. 5.10 ± 0.55 cells/100 pm, P<0.0001, respectively). Conclusions: 5 These results show that compounds V and W protected against goblet cell loss and also improved corneal barrier function in mice exposed to desiccating stress. Example 3: Compounds V and W Block the Over-Expression of Arginase and COX 2 in a Mouse Dry Eye Model Dry eye (DE) is a common ocular surface disease, particularly among women 10 and elderly population, which can cause eye irritation and blurred vision. Several studies have shown that there is an inflammatory component in DE, although the pathogenesis is not thoroughly understood. Compounds V and W were investigated in a mouse DE model. Methods: 15 13 to 14-week-old female BALB/C mice were exposed to desiccating conditions, and 5 pl of 1% atropine was applied topically every other day. One week after DE exposure, the animals were treated with 5 pl of 0.01 % compound V (100 pg/mL), 0.01 % compound W (100 gg/mL) or vehicle topically 4 times per day for an additional week. Normal controls (NC) were animals in a normal environment 20 without treatment. Corneas were processed for western blot analysis and immunofluorescence examination. Results: Figure 5 shows results obtained by western blot analysis indicating that Arginase I (Figure 5a) and COX-2 (Figure 5b) were strongly upregulated after DE 25 and decreased with both compounds. Immunofluorescence showed strong positive staining in stroma and/or in epithelium after DE and decrease with treatment. Conclusions: Compounds V and W blocked the over-expression of Arginase I and COX-2, two key pro-inflammatory enzymes. The results suggest that this class of compounds 30 has therapeutic potential in the treatment of DE. - 93 - Example 4: Oxidative Stress-induced Apoptosis is Down-Regulated By Compounds X and Z In Retinal Pigment-Epithelial (arpe-19) Cells The effect of compounds X and Z on apoptotic cell death induced by oxidative stress in ARPE- 19 cells was investigated. The preservation of retinal pigment 5 epithelial cells is critically important in wet and dry age-related macular degeneration, diabetic retinopathy, neonatal retinopathy, and retinitis pigmentosa. Methods: 72h-grown cells in 6 well plates were serum starved for 8 h, and then oxidative stress was induced with TNF-a/H 2 0 2 (600 piM) for 16 h. Cells were 10 incubated with different concentrations of compounds X and Z. Apoptotic cell death was scored by Hoechst positive cells. Results: Figure 6 shows that compounds X and Z inhibit oxidative stress-induced apoptosis in a concentration-dependent manner. Of the three concentrations of 15 compounds used (10, 30, and 50 nM), highest inhibition was achieved at 50 nM (40 46%), lowest at 10 nM (1.5-2%), and intermediate at 30 nM (28-32%). The inhibition of pro-inflammatory IL-10 induced COX-2 expression by compound 48a can also be measured using this model, as was demonstrated in Mukherjee, P. K., et al. (2004) Proc. Natl. Acad. Sci. 101 (22), 3491-8496. 20 Mukherjee et al. also demonstrated the up-regulation of antiapoptotic proteins and down-regulation of proapoptotic protein expression by compound 48a. Conclusions: The inhibitory effect of compounds X and Z on oxidative stress-induced apoptosis demonstrates strong anti-inflammatory bioactivity of these compounds in an 25 oxidative-stress environment. The data suggest that these compounds target signaling mechanisms critical for cell survival, and further suggest their potential as therapeutic intervention in diseases where protecting the integrity of the pigmented retinal epithelium is supported. -94- Example 5: Compounds X. Z, and 48a Inhibit Vascular Leakage and Reduce Choroidal Lesion Size in Experimental Choroidal Neovascularization (CNV) Macular degeneration involves immune inflammatory responses that, in the case of the wet form, results in CNV. Choroidal vascular leakage is a key component 5 of wet age-related macular degeneration. Since compounds of formula A, compounds of any one of formulae 1-49, lipoxin compounds, oxylipin compounds, and the combination of aspirin and an omega-3 fatty acid promote resolution of inflammation leading to tissue repair, we tested compounds X, Z, and 48a as potential down regulators of CNV. 10 Methods: Laser-induced CNV in mice was generated by dilating anesthetized mouse eyes and making 4 lesions positioned at 3, 6, 9, and 12 o'clock around the optic nerve. Laser pulses delivered by a green diode Lumenis Novus-Spectra laser mounted on a Topcon slit lamp (SL- D7), with 200 mW of energy, and 100 mS duration, made a 50 15 pm diameter bum that produced a retinal bubble as Bruch's membrane was breached. Compounds X (18.7 pg/kg), Z (14.3 pg/kg), 48a (19.0 pg/kg), or vehicle (saline/ethanol) were delivered IP (50 nM stock) on days 1, 2, 4, 6, and 8. At days 7 and 14, images of FITC leakage were obtained from lesions 5 min after IP delivery of FITC. These images were captured and viewed with the Topcon IMAGEnet 2000 20 LITE digital imaging system, and ranked as grade 3 (strong; FITC cloud expands and becomes larger than original; clinically significant), grade 2 (moderate; FITC cloud remains the same size as original), grade I (slight; FITC cloud remains small and detail of the lesion site can be seen through it), or grade 0 (none; no evidence of leakage) by an ophthalmologist. Grade 3 would be considered clinically relevant in 25 humans. Eyes were collected I day later and fixed, and retinas removed, leaving a flat-mounted choroid which was labeled with FITC-conjugated Isolectin B4 (specific for endothelial cells). Diameters of choroidal lesions (laser + 15 days) were then plotted to determine the degree of neovascularization. Results: 30 Figure 7 shows that in controls 75% of the lesions displayed leakage at 7 days, and 56% at day 14. However, compounds X and Z showed 7% and 26% leakage, - 95 respectively at day 7, and 4% and 6% leakage for these treatments at day 14. By day 7, compound 48a led to reduced leakage to 13% compared to 75% in controls, and by day 14, leakage had been further reduced to 5%, or a protection level of about 90%. Figures 8 and 9 show the ranking of choroidal vascular leakage at days 7 and 5 14, respectively. Figure 9 shows that the number of "none" leakage was 86% for compound X and 72% for compound Z, as compared to 15% in controls at day 14. Figure 10 shows that the "none" leakage sites for compound 48a had increased to 68% (15% in controls) by day 14. Figure I I shows the reduction in choroidal lesion area at day 14 with 10 compounds X, Z, and 48a. Endothelial cell labeling indicated that choroid lesions were 14 pm and 43 pm in diameter in compound X and compound Z, respectively, as compared to 105 pm in controls. Lesion sites upon treatment with compound 48a decreased from 50 pm to about 18 pm at day 14. Conclusions: 15 Reduction in leakage the first week suggests that compound X protected by acting on early events, and while compound Z reduced leakage, it was not as efficient by day 7. However, by 14 days, when injury-mediated changes are not involved, the effect of compound Z approached that of compound X. The lesion was reduced 70% with compound X, but remained unchanged with compound Z, while lesions of the 20 controls increased, suggesting that compound X may be more efficient than compound Z in reducing CNV. Thus, compound X may be an early counter regulator of signaling that promotes pathogenic angiogenesis in AMD. Rapid reduction in leakage from the lesion sites within the first week of treatment with compound 48a suggest that systemic 48a protects by acting on 25 pathophysiological events during the development of choroidal neovascularization. This is supported by the rapid reduction in lesion site diameter. Thus, compounds of this class may be of therapeutic value for AMD. Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by 30 reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In particular, compounds - 96 of formula A or formulae 1-49 disclosed in WO 2005/105025, WO 2006/078457, WO 2007/041440, US 2003/0191184, WO 2004/014835, WO 2004/078143, US 6670396, US 2003/0236423, and US 2005/0228047, lipoxin compounds disclosed in US 2002/0107289, US 2004/0019110, US 2006/0009521, US 2005/0203184, and US 5 2005/0113443, oxylipin compounds disclosed in W02006/055965, WO 2007/090162, and WO 2008/103753, derivatives and/or analogs of eicosapentaenoic acid or docosahexaenoic acid disclosed in WO 2005/089744, US 2004/0044050, US 2004/01 16408 and US 2005/0261255, and aspirin-triggered lipid mediators disclosed in US 7053230 are incorporated by reference as suitable for use in compositions and 10 methods of the present invention. In case of conflict of structures or naming of compounds between the present application and the referenced patent publications listed above, the present application, including any definitions herein, will control. EQuivalents While specific embodiments of the subject invention have been discussed, the 15 above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. - 97 -

Claims (12)

1. A method of treating the ophthalmic condition post-operative inflammation in a subject, said method comprising administering to said patient a compound of formula 5 43, having the structure: R , Ri ORf OR O O R4 R5 E 43 wherein: Re, Rf, Ri, R 8 and R 9 are each hydrogen; E is hydroxyl or alkoxyl; and 10 R 5 is CH 2 CH 2 CH 2 , or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein said post-operative inflammation is post-LASIK inflammation of the cornea. 15

3. The method of claim 1 wherein said post-operative inflammation is inflammation after cataract surgery.

4. The method of any one of claims 1 to 3 wherein said compound is formula 39, 20 having the structure: ORf ORe O E 39 wherein: Re and Rf are each hydrogen; and E is hydroxyl or alkoxyl, 25 or a pharmaceutically acceptable salt thereof.

5. Use of a compound of formula 43, having the structure: -99 Re Ri ORf ORe O 43 wherein: Re, Rf, Ri, R 8 and R 9 are each hydrogen; E is hydroxyl or alkoxyl; and 5 R 5 is CH 2 CH 2 CH 2 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating the ophthalmic condition post-operative inflammation in a patient. 10

6. The use of claim 5 wherein said post-operative inflammation is post-LASIK inflammation of the cornea.

7. The use of claim 5 wherein said post-operative inflammation is inflammation after cataract surgery. 15

8. The use of any one of claims 5 to 7 wherein said compound is formula 39, having the structure: ORf ORO O E 39 wherein: 20 Re and Rf are each hydrogen; and E is hydroxyl or alkoxyl, or a pharmaceutically acceptable salt thereof.

9. A compound when used in the treatment of the ophthalmic condition post 25 operative inflammation in a patient, wherein said compound is formula 43, having the structure: -100 Re Ri ORf ORe O 43 wherein: Re, Rf, Ri, R 8 and R 9 are each hydrogen; E is hydroxyl or alkoxyl; and 5 R 5 is CH 2 CH 2 CH 2 , or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 wherein said post-operative inflammation is post LASIK inflammation of the cornea. 10

11. The compound of claim 9 wherein said post-operative inflammation is inflammation after cataract surgery.

12. The compound of any one of claims 9 to 11 wherein said compound is formula 15 39, having the structure: ORf ORe O E 39 wherein: Re and Rf are each hydrogen; and E is hydroxyl or alkoxyl, 20 or a pharmaceutically acceptable salt thereof.