Compounds and Methods for Inhibition of Bone Loss Related Applications

This application claims the benefit of priority to U.S. Provisional Patent Application No. 60/854,463, filed October 26, 2006, which application is hereby incorporated by reference in its entirety.

Background

A variety of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontitis, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. One of the most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population. As many as 50% of women and a third of men will experience an osteoporotic fracture. A large segment of the older population already has low bone density and a high risk of fractures. There is a significant need to both prevent and treat osteoporosis and other conditions associated with bone resorption.

Osteoporosis is characterized by progressive loss of bone architecture and mineralization leading to the loss in bone strength and an increased fracture rate. The skeleton is constantly being remodeled by a balance between osteoblasts that lay down new bone and osteoclasts that break down, or resorb, bone. In some disease conditions and advancing age, the balance between bone formation and resorption is disrupted; bone is removed at a faster rate. A prolonged imbalance of resorption over foπnation leads to weaker bone structure and a higher risk of fractures.

One of the most common types of osteoporosis is found in post-menopausal women, affecting an estimated 20 to 25 million women in the United States alone. A significant feature of post-menopausal osteoporosis is the large and rapid loss of bone mass due to the cessation of estrogen production by the ovaries. Indeed, data clearly support the ability of estrogens to limit the progression of osteoporotic bone loss, and estrogen replacement is a recognized treatment for post-menopausal osteoporosis in the United States and many other countries. However, although estrogens have beneficial effects on bone, given even at very low levels, long-term estrogen therapy has been implicated in a variety of disorders, including an increase in the risk of uterine and breast cancer, causing many women to avoid this treatment. Recently suggested therapeutic regimens, which seek to lessen the cancer risk, such as administering combinations of progestogen and estrogen, cause the patient to experience regular withdrawal bleeding, which is unacceptable to most older women. Concerns over the significant undesirable effects associated with estrogen therapy, and the limited ability of estrogens to reverse existing bone loss, support the need to develop alternative therapy for bone loss that generates the desirable effects on bone but does not cause undesirable effects.

Attempts to fill this need by the use of compounds commonly known as antiestrogens, which interact with the estrogen receptor, have had limited success, perhaps due to the fact that these compounds generally display a mixed agonist/antagonist effect. That is, although these compounds can antagonize estrogen interaction with the receptor, the compounds themselves may cause estrogenic responses in those tissues having estrogen receptors. Therefore, some antiestrogens are subject to the same adverse effects associated with estrogen therapy. Bisphosphonates are also used for the treatment of bone loss. These compounds, however, also possess significant and undesired side effects.

Metastatic bone disease involves tumor-induced skeletal metastases, which commonly result from breast cancer, prostate cancer, lung cancer, renal cancer, thyroid cancer, and multiple myeloma. The prevalence of bone-metastases in patients with these cancers may be as high as 60-85%. Patients with these diseases that have bone dominant or bone-only metastases frequently have prolonged survival usually associated with clinical morbidity. The most frequent clinical manifestations of bone metastases are pain,

pathological fracture, immobility, nerve root or spinal cord compression, hypercalcemia, and compromised hematopoiesis. The scope of metastatic bone disease is highlighted by the fact that on any given day, approximately 4 million people worldwide suffer from cancer pain and that at least 40-50% of all cancer pain is due to skeletal metastases. Current therapy for treating metastatic bone disease has limited efficacy with only a modest reduction in skeletal events associated with the disorder. Furthermore, many agents have undesirable side effects. There remains a need for therapeutic options with improved efficacy and reduced adverse events.

Summary of Invention

The present invention provides methods of treating or preventing bone loss comprising administering a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid. In certain embodiments, the bone loss is associated with ankylosing spondylitis, renal osteodystrophy (e.g., in patients undergoing dialysis), osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontitis, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, bone loss associated with microgravity, Langerhan's Cell Histiocytosis (LHC), bone loss associated with renal tubular disorders, or bone loss associated with bed-ridden conditions. In certain embodiments, the bone loss is associated with ankylosing spondylitis, renal osteodystrophy (e.g., in patients undergoing dialysis), osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, bone fractures, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, bone loss associated with microgravity, Langerhan's Cell Histiocytosis (LHC), bone loss associated with renal tubular disorders, or bone loss associated with bed-ridden conditions.

Detailed Description of the Drawings

Figure 1 shows the effects of Compound X on bone damage as was determined by histologic scoring in joints of mice with established Type II collagen arthritis.

Figure 2 shows the effects of Compound X on a) arthritis and b) pannus formation and bone loss in mice with established Type II collagen arthritis.

Figure 3 shows that therapeutic dosing of Compound X significantly reduced knee histopathology scores in rats with CIA.

Figure 4 shows that therapeutic dosing of Compound X protected bone resorption and joint damage in rats with CIA.

Detailed Description of the Invention

The present invention provides methods of treating or preventing bone loss in a patient comprising administering a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid. In certain embodiments, the bone loss is associated with ankylosing spondylitis, renal osteodystrophy (e.g., in patients undergoing dialysis), osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontitis, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, bone loss associated with microgravity, Langerhan's Cell Histiocytosis (LHC), bone loss associated with renal tubular disorders, or bone loss associated with bed-ridden conditions. In certain embodiments, the bone loss is associated with ankylosing spondylitis, renal osteodystrophy (e.g., in patients undergoing dialysis), osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, bone fractures, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, bone loss associated with microgravity, Langerhan's Cell Histiocytosis (LHC),

bone loss associated with renal tubular disorders, or bone loss associated with bed-ridden conditions. In certain embodiments, the bone loss is associated with ankylosing spondylitis, renal osteodystrophy (e.g., in patients undergoing dialysis), osteoporosis, glucocorticoid-induced osteoporosis, abnormally increased bone turnover, periodontitis, bone fractures, periprosthetic osteolysis, osteogenesis imperfecta, hypercalcemia of malignancy, multiple myeloma, bone loss associated with microgravity, Langerhan's Cell Histiocytosis (LHC), bone loss associated with renal tubular disorders, or bone loss associated with bed-ridden conditions. In certain embodiments, the bone loss is associated with osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontitis, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, bone loss associated with microgravity, Langerhan's Cell Histiocytosis (LHC), bone loss associated with renal tubular disorders, or bone loss associated with bed-ridden conditions. In certain embodiments, the bone loss is associated with osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, bone fractures, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, bone loss associated with microgravity, Langerhan's Cell Histiocytosis (LHC), bone loss associated with renal tubular disorders, or bone loss associated with bed-ridden conditions. In certain embodiments, the bone loss is associated with osteoporosis, glucocorticoid-induced osteoporosis, abnormally increased bone turnover, periodontitis, bone fractures, periprosthetic osteolysis, osteogenesis imperfecta, hypercalcemia of malignancy, multiple myeloma, bone loss associated with microgravity, Langerhan's Cell Histiocytosis (LHC), bone loss associated with renal tubular disorders, or bone loss associated with bed-ridden conditions.

The present invention provides a method of treating or preventing osteoporosis in a patient comprising administering a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid. In certain embodiments, the osteoporosis is medicine- induced osteoporosis. In certain embodiments, the medicine-induced osteoporosis is glucocorticoid-induced osteoporosis.

The present invention provides a method of treating or preventing metastatic bone disease in a patient comprising administering a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid. The present invention provides a method of decreasing the incidence of bone metastasis in a patient comprising administering a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid. The present invention further provides a method of delaying the onset of bone metastasis in a patient comprising administering a compound of formula A, a compound of any one of formulae 1 -49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid. In certain embodiments, a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid is administered conjointly with chemotherapy or radiation therapy.

The present invention provides a method of treating or preventing periodontitis in a patient comprising administering a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid.

The present invention provides a method of treating or preventing ankylosing spondylitis in a patient comprising administering a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid.

The present invention provides a method of treating or preventing renal osteodystrophy (e.g., in patients undergoing dialysis) in a patient comprising administering a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid.

TNFalpha and RANKL (receptor activator of nuclear factor-κB ligand) are proteins involved in the formation of osteoclasts, the cells utlimately responsible for bone

breakdown. Signalling from these proteins must be strictly kept in control in order to maintain normal bone homeostasis and prevent pathological bone breakdown. Without wishing to be restricted by the proposal, it is regulation of members of the TNFalpha superfamily (such as RANKL or TNFalpha) or their downsteam signalling effects by the compounds of formula A, compounds of any one of formulae 1-49, lipoxin compounds, or oxylipin compounds that may mediate the utility of these compounds for the treatment or prevention of disorders associated with bone loss.

Compounds suitable for use in methods of the invention include those of Formula A,

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 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, 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 i is ^{λ f} ,Y' is connected to Vi via a carbon atom;

V i is selected from

wherein when q ¹ is 0 and V ₃ is a bond, n' is 0 or 1 ; otherwise n' is 1 ;

V ₂ is selected from a bond,

wherein:

L' is selected from -C(R ¹⁰⁰³ )(R ¹⁰⁰⁴ )-, wherein each of R ¹⁰⁰³ and R ¹⁰⁰⁴ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or heteroaryl, or R ¹⁰⁰³ and R ¹⁰⁰⁴ are connected together to form a

carbocyclic or heterocyclic ring; when V ₃ is , L' is additionally selected from W; and n' is 0 or 1 ;

V ₃ is selected from a bond or wherein: each R ^l00l and R ¹⁰⁰² 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 ^a and R ^b is independently for each occurrence selected from - OR' or-N(R') ₂ , or adjacent R ^a and R ^b 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;

or when V| is and R ^b are both hydrogen;

X ¹ 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 ¹ , -S(O) ₂ -R", S(0) ₂ N(R")(R"), -P(O) ₂ -A', -P0(0R")-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, 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 ¹ 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 selected substituents; o' is O, 1, 2, 3, 4, or 5; p ¹ is O, 1 , 2, 3, 4, or 5; q' is O, 1, or 2; and o' + p' + q' is 1, 2, 3, 4, 5 or 6; wherein: if V ₂ is a bond, then q' is O, and V ₃ is a bond;

IfV ₃ is , then o' is 0, Vi is p' is 1 and V ₂ is

any acyclic double bond may be in a cis or a trans configuration or is optionally replaced by a triple bond; and

portion of the compound, if present,

is portion

of the compound, if present, is optionally 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, aryloxycarbonyloxy or aminocarbonyl.

In certain embodiments, Vi is selected from

10

In certain embodiments, V ₂ is selected from a bond,

In certain embodiments, when q' is O and V ₃ is a bond, n' is O or 1 ; otherwise n' is 1.

In certain embodiments, p' is O, 1 , 2, 3, or 5. In certain embodiments, q' is 0 or 1.

In certain embodiments, if Vi is

p' is 1 or 2, o' + p' is 1 or 2, V ₂ is and V ₃ is a bond.

In certain embodiments, if V i is , then o' is 3, 4 or 5, p' is 0, 1 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 ¹ is 4 or 5, q' is 0, and V ₃ is a bond.

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 of Formula A, the compound is other than Compound X.

In certain embodiments of Formula A, when o' is 0, Vi is y

is 2, V ₂ is at least one occurrence of R ¹⁰⁰¹ is other than hydrogen.

In certain embodiments of Formula A, when o' is 0, Vi is other

Compounds suitable for use in methods of the invention include those of Formula

wherein

Carbons a ¹ and b' are connected by a double bond (e.g., a cis or trans double bond) or a triple bond;

Carbons c ¹ and d' are connected by a double bond (e.g., a cis or trans 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, alkoxycarbonyl, or silyl;

RJi, Ri and Rj are independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl;

1 is selected from -C(O)-E, -SO ₂ -E, -PO(OR)-E, where E is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or arylamino; and R is hydrogen or alkyl;

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, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxarηido, 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 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.

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 of Formula 1, the compound is other than Compound X.

In certain embodiments of Formula 1, at least one of Rh, Ri and Rj is other than hydrogen.

In certain embodiments, a compound of formula 1 is represented by formula 2,

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.

Exemplary compounds of formula 2 include:

In certain embodiments of Formula 2, the compound is other than Compound X.

In certain embodiments, compounds suitable for use in methods of the invention are other than those represented by Formula 2.

In certain embodiments, a compound of formula 1 is represented by formula 3,

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.

Exemplary compounds of formula 3 include:

Further exemplary compounds of formula 1 include Compound X,

Other compounds suitable for use in methods of the invention include those of Formula 4,

wherein

A is H or -OP ₄ ;

Pi ₁ P ₂ and P ₄ each individually is a protecting group or hydrogen atom;

Ri 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(0)0R ^d , -C(O)NR ^C R ^C , -C(O)H, -C(NH)NR ^C R ^C , -C(S)H, -C(S)OR ^d , -C(S)NR ^C R ^C , -CN, preferably a carboxylic acid, ester, amide, thioester, thiocarboxamide or a nitrile; each R ^a , if present, is independently selected from hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, moφholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-1 1 membered heterocyclylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl; each R ^b , if present, is a suitable group independently selected from =0, -0R ^d , (C1-C3) haloalkyloxy, -OCF ₃ , =S, -SR ^d , =NR ^d , =N0R ^d , -NR ^C R ^C , halogen, -CF ₃ , -CN, -NC, -OCN, -SCN, -NO, -NO ₂ , =N ₂ , -N ₃ , -S(O)R ^d , -S(O) ₂ R ^d , -S(O) ₂ OR", -S(O)NR ^C R ^C , -S(O) ₂ NR ^C R ^C , -OS(O)R ^d , -OS(O) ₂ R ^d , -OS(O) ₂ OR ^d , -OS(O) ₂ NR ^C R ^C , -C(O)R ^d , -C(O)OR ^d , -C(O)NR ^C R ^C , -C(NH)NR ^C R ^C , -C(NR ^a )NR ^c R ^c , -C(N0H)R ^a , -C(NOH)NR ^C R ^C , -0C(0)R ^d , -0C(0)0R ^d , -0C(0)NR ^c R ^c , -OC(NH)NR ^C R ^C , -0C(NR ^a )NR ^c R ^c , -[NHC(0)] _n R ^d , -[NR ^a C(0)] _n R ^d , -[NHC(0)] _n 0R ^d ,

-[NR ^a C(O)] _n OR ^d , [NHC(O)] _n NR ^c R ^c , -[NR ^a C(O)] _n NR ^c R ^c , -[NHC(NH)] _n NR ^c R ^c and -[NR ^a C(NR ^a )] _n NR ^c R ^c ; each R ^c , if present, is independently a protecting group or R ^a , or, alternatively, two R ^c 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 same or different R ^a or suitable R ^b groups; each n independently is an integer from 0 to 3; each R >d : independently is a protecting group or R ;

or pharmaceutically acceptable salts thereof.

Other compounds suitable for use in methods of the invention include those of Formula 5,

or pharmaceutically acceptable salts thereof, wherein

P ₃ is a protecting group or hydrogen atom; and P i, P ₂ , Ri and Z are as defined above in formula 4.

Other compounds suitable for use in methods of the invention include those of Formula 6,

or pharmaceutically acceptable salts thereof, wherein

each X represents hydrogen or taken together both X groups represent one substituted or unsubstituted methylene, an oxygen atom, a substituted or unsubstituted N atom, or a sulfur atom such that a three-membered ring is formed; and

Pι _> P2, P3, Ri and Z are as defined above.

In certain embodiments, X represents hydrogen or taken together both X groups represent one substituted or unsubstituted methylene.

Other compounds suitable for use in methods of the invention include those of Formula 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' 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 ¹ through a double bond the stereochemistry is cis or trans;

m is 0 or 1 ;

T' is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C5-C14) aryl, (C6- C 16) arylalkyl, 5-14 membered heteroaryl, 6-16 membered heteroaryl alkyl, or -CH=CHCH ₂ CH ₃ ;

T is -(CH ₂ )^- or -(CH ₂ )^-O-, where q is an integer from 0 to 6;

Z' is (C1-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 -(CH ₂ ) _OT -S-CH ₂ -, where p is an integer from 0 to 4;

Ri i, Ri ₂ and R1 ₃ each individually is substituted or unsubstituted, branched or unbranched alkyl, alkenyl, or alkynyl group, substituted or unsubstituted aryl group, substituted or unsubstituted, branched or unbranched alkylaryl group, Ci _-4 alkoxy, halogen atom, -CH ₂ Ri ₄ , -CHR ₎₄ Ri ₄ , -CR _I4 R _I4 R _I4, or a hydrogen atom;

Ri ₄ is independently for each occurrence selected from -CN, -NO ₂ or halogen;

Pi, P2, P3, and Z are as defined above.

In certain embodiments Of Formula 7, the compound is other than Compound X.

In certain embodiments of Formula 7, at least one of Ri ₁ , Rj ₂ and R ₁₃ is other than hydrogen.

Other compounds suitable for use in methods of the invention include those of Formula 8,

or pharmaceutically acceptable salts thereof, wherein

the stereochemistry of the carbon i' to carbon j' bond is cis or trans;

m is O or

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, aryloxycarbonyl, alkoxycarbonyloxy, and aryloxycarbonyloxy group;

A is H or -OP ₄ ;

Pi, P2, P4, Ri, R2 and Z are as defined above.

Other compounds suitable for use in methods of the invention include those of Formula 9,

or pharmaceutically acceptable salts thereof, wherein

Carbons k ¹ and 1' are connected by a double bond or a triple bond;

the stereochemistry of the carbon m' to carbon n' double bond is cis or trans;

m is 0 or 1 ;

D is -CH ₃ or -CH=CHCH ₂ CH ₃ ;

P 1, P ₂ , P ₃ , R|, X, and Z are as defined above.

Other compounds suitable for use in methods of the invention include those of Formula 10,

or pharmaceutically acceptable salts thereof, wherein

Pi, P ₂ , P ₃ , Ri 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, alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl group.

Other compounds suitable for use in methods of the invention include those of Formula 11,

or pharmaceutically acceptable salts thereof, wherein

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,

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 Formula 13,

13

or pharmaceutically acceptable salts thereof, wherein

P 1, P ₂ , Ri, R ₂ , U, and Z are as defined above.

Other compounds suitable for use in methods of the invention include those of Formula 14,

or pharmaceutically acceptable salts thereof, wherein

Pi, P2, Ri, R2, Q, and Z are as defined above.

Other compounds suitable for use in methods of the invention include those of Formula 15,

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,

16

or pharmaceutically acceptable salts thereof, wherein

Pi and Z are as defined above.

Other compounds suitable for use in methods of the invention include those of Formula 17,

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

P i, P ₂ , and Z are as defined above.

In certain embodiments, carbons o' and p' are connected by a double bond (e.g., a cis or trans double bond). In certain embodiments, carbons q' and r' are connected by a double bond (e.g., a cis or trans double bond).

Other compounds suitable for use in methods of the invention include those of Formula 18,

or pharmaceutically acceptable salts thereof, wherein

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

Pi, P ₂ , R i, R ₂ , and Z are as defined above.

Other compounds suitable for use in methods of the invention include those of Formula 19,

or pharmaceutically acceptable salts thereof, wherein

Carbons w' and x' are connected by a single or a double bond;

Carbons y' and z' are connected by a single or a double bond; and

P i, P ₂ , and Z are as defined above.

In certain embodiments of formulae 4 to 19, each R ^b , if present, is a suitable group independently selected from =0, -OR ^d , (C1-C3) haloalkyloxy, -OCF ₃ , =S, -SR ^d , =NR ^d , =N0R ^d , -NR ^C R ^C , halogen, -CF ₃ , -CN, -NC, -OCN, -SCN, -NO, -NO ₂ , =N ₂ , -N ₃ , -S(O)R ^d , -S(O) ₂ R ^d , -S(O) ₂ OR", -S(O)NR ^C R ^C , -S(O) ₂ NR ^C R ^C , -OS(O)R ^d , -OS(O) ₂ R", -OS(O) ₂ OR ^d , -OS(O) ₂ NR ^C R ^C , -C(O)R", -C(O)OR", -C(O)NR ^C R ^C , -C(NH)NR ^C R ^C , -C(NR ^a )NR ^c R ^c , -C(NOH)R ³ , -C(N0H)NR ^c R ^c , -OC(O)R", -OC(O)OR", -0C(0)NR ^c R ^c , -OC(NH)NR ^C R ^C , -0C(NR ^a )NR ^c R ^c , -[NHC(O)J _n R", -[NR ^a C(O)] _n R ^d , -[NHC(0)] _n 0R ^d , [NHC(0)] _n NR ^c R ^c , -[NR ^a C(0)] _n NR ^c R ^c , -[NHC(NH)] _n NR ^c R ^c and -[NR ^a C(NR ^a )] _n NR ^c R ^c .

Other compounds suitable for use in methods of the invention include those of Formula 20,

Foπnula 21

21

Formula 22,

Formula 23,

Foπnula 24,

Foπnula 25,

Formula 26,

Foπnula 27,

or Formula 28,

, 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, C|. ₆ alkyl (e.g., methyl, ethyl, glycerol), C _2-6 alkenyl or C ₂ - ₆ alkynyl.

Other compounds suitable for use in methods of the invention include those of Formula 29,

29

and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein:

D i -E i and Fi-Gi are independently are cis or trans -C=C- or -C≡C-;

Rioi, Ri ₀₂ and Ri ₀₃ are independently selected from hydrogen, (C1-C4) straight-chained or branched alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) alkoxy, -CH ₂ R ₁₀₄ , -CHRIO ₄ RI ₀₄ and -CRiO ₄ R I ₀₄ Ri ₀₄ ;

each Ri _O4 is independently selected from CN, -NO ₂ and halogen;

W| is selected from -Ri ₀₅ , -ORi ₀₅ , -SRi ₀₅ and -NRio ₅ Rio ₅ ;

each Rio ₅ is independently selected from hydrogen, (Cl -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 of the same or different R groups, (C6-C16) 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;

Ai is selected from (C1-C6) alkylene optionally substituted with 1, 2, 3, 4, 5 or 6 of the same or different halogen atoms, -(CH ₂ ) _m -O-CH ₂ - and -(CH ₂ ) _m -S-CH ₂ -, where m is an integer from 0 to 4;

Xi is selected from -(CH ₂ ),,- and -(CH ₂ ) _n -O-, where n is an integer from 0 to 6;

Yi is selected from hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl, optionally substituted with one or more of the same or different Rioo groups, (C5-C14) aryl optionally substituted with one or more of the same or different Rioo groups, phenyl, optionally substituted with one or more of the same or different Ri ₀₀ groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different Rioo groups, 5-14 membered heteroaryl optionally substituted with one or more of the same or different Rioo groups, 6-16 membered

heteroarylalkyl optionally substituted with one or more of the same or different Rιoo groups and a detectable label molecule;

each Rioo is independently selected from an electronegative group, =0, -OR ^al , (C1-C3) haloalkyloxy, =S, -SR ^al , =NR ^{a l} , =NONR ^al , -NR ^cl R ^cl , halogen, ,-CF ₃ , -CN, -NC, -OCN, -SCN, -NO, -NO ₂ , =N ₂ , -N ₃ , -S(O)R ^al , -S(O) ₂ R ³ ', -S(O) ₂ OR ³ ', -S(O) ₂ NR ⁰ 'R ^cl , -OS(O)R ³ ', -OS(O) ₂ R ³ ', -OS(O) ₂ OR ³ ', -0S(0) ₂ NR ^C1 R ^{C 1} , -C(O)R ³ ', -C(O)OR ³ ', -C(O)NR ^C| R ^C| , -C(NH)NR ^cl R ^cl , -OC(O)R ³ ', -OC(O)OR ³ ', -0C(0)NR ^cl R ^{c l} , -OC(NH)NR ^cl R ^cl , -NHC(O)R ³ ', -NHC(O)OR ³ ', -NHC(0)NR ^cl R ^cl and -NHC(NH)NR ⁰ 'R ^cl ;

each R ³ ' is independently selected from hydrogen, (C1-C4) alkyl, (C2-C4) alkenyl or (C2-C4) alkynyl; and

each R ^cl is independently an R ^al or, alternatively, R ^cl R ^cl 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 Rioi, Rio2 or Rio ₃ is other than hydrogen.

In certain embodiments of Formula 29, the compound is other than Compound X.

In certain embodiments, a compound of Formula 29 is represented by Formula 30,

W ₁

30

In certain embodiments of Formula 30, the compound is other than Compound X.

In certain embodiments of Formula 30, at least one of Rioi, R ₁₀₂ or Rio ₃ is other than hydrogen.

Other compounds suitable for use in methods of the invention include those of Formulae 31 to 37

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

Other compounds suitable for use in methods of the invention include those of Formula 38,

wherein

Carbons aa ¹ and bb' are connected by a double bond (e.g., a cis or trans double bond) or a triple bond;

Carbons cc ¹ and dd' are connected by a double bond (e.g., a cis or trans 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, 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, 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 R ₇ )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 foπn a

carbocyclic or heterocyclic ring; iii) CH ₂ OCH ₂ , CH ₂ C(O)CH ₂ , or CH ₂ CH 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;

or pharmaceutically acceptable salts thereof.

In certain embodiments R ₈ 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.

In certain embodiments of Formula 41, the compound is other than Compound X.

In certain embodiments of Formula 41, at least one of Rh, Ri and Rj is other than hydrogen.

Other compounds suitable for use in methods of the invention include those of Formulae 39-44,

and pharmaceutically acceptable salts thereof, wherein

Re, Rf, E, Ri, R ₅ , R ₈ and R ₉ are as defined above.

Exemplary compounds of formulae 39, 41, and 43 include:

Other compounds suitable for use in methods of the invention include those of Formula 46,

Ri 46

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

each independently designates a double or triple bond;

R ¹ , R ² , and R ³ are each independently OR, OX ¹ , 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 Ci _-6 aliphatic, a 3-8 membered saturated, partially unsaturated, 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;

each X ¹ 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 SO ₂ N(R) ₂ .

Other compounds suitable for use in methods of the invention include those of Formula 47:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

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, carboxy, 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;

X ¹ is selected from -CN, -C(NH)N(R")(R"), -C(S)-A ¹ , -C(S)R", -C(O)-A', -C(O)-R", -C(O)-SR", -C(O)-NH-S(O) ₂ -R", -S(O) ₂ -A ¹ , -S(O) ₂ -R", S(O) ₂ N(R ¹¹ XR"), -P(O) ₂ -A", -PO(OR")-A', -tetrazole, alkyltetrazole, or -CH ₂ OH, wherein

A ¹ is selected from -OR", -N(R")(R") or -OM ¹ ;

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

M' is a cation.

In certain embodiments, a compound of formula 47 is represented by formula 48,

In certain embodiments, a compound of formula 47 is represented by formula 49,

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.

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 disease. Examples of such compounds are disclosed in the following patents and applications: US 2003/0191 184, 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.

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 of one of the a compounds of formula A or compounds of any one of formulae 1-49, above with a corresponding end group of any other compound of formula A or compound of any one of formulae 1-49, modification of the orientation of any double bond in a compound of formula A or a compound of any one of formulae 1-49, the replacement of any double bond with a triple bond in any compound of formula A or compound of any one of formulae 1-49,, and the replacement of one or more substituents present in one of the compounds of formula A or compounds of any one of formulae 1-49 above with a corresponding substituent of any other compound of formula A or compound of any one of formulae 1-49.

Lipoxin compounds suitable for use in this invention include those of formula 50:

₅ wherein:

X is R _30I , OR _30I , or SR ₃₀ , ;

(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;

(e) phenyl;

(f) substituted phenyl wherein Z ₁ Z ₁₁ , Z ₁₁₁ , Z _1V and Z _v are each independently selected from -NO ₂ , -CN, -SO ₃ H, a hydrogen atom, halogen, methyl, -OR _x , wherein R _x is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl, wherein when any of Z ₁ Z ₁₁ , Z ₁₁₁ , Z _1V or Z _v is C(=0)-R ₃ oι, said Z ₁ Z ₁₁ , Z ₁₁₁ , Z _1V or Z _v is not substituted with another C(=O)-R ₃₀₁ .

(g) a detectable label molecule; or

(h) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;

=O), SO ₂ or (CN), provided when Qi is CN, then X is absent; Q ₃ and Q ₄ are each independently O, S or NH; one Of R ₃₀₂ and R ₃₀₃ is a hydrogen atom and the other is:

(a) H;

(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a straight 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) R _k Q ₂ Ri wherein Q ₂ is -O- or -S-; wherein R _k is alkylene of O to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein R| is alkyl of O to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R| is O, then R| is a hydrogen atom;

R.304 is

(a) H;

(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;

R305 is , wherein Z; Z ₁₁ , Z _n ;, Z _w and Z _v are defined as above;

R-306 is

(a) H;

(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;

wherein Y ₃₀₁ is -OH, methyl, -SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or (CH) _p (Z) _q , where p+q=3, p=0 to 3, q=0 to 3 and Z is cyano, nitro or a halogen; and

T is O or S, and pharmaceutically acceptable salts thereof.

Lipoxin compounds suitable for use in this invention include those of formulae 51, 52, 53 or 54:

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

R308, R309, R310, R319, and R ₃₂₀ are independently selected from:

(a) hydrogen;

(b) straight, branched, cyclic, saturated, or unsaturated alkyl having from 1 to 20 carbon atoms;

(c) 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, arylamino, hydroxyamino, alkoxyamino, alkylthio, arylthio, carboxy, carboxamido, carboalkoxy, aryl, and heteroaryl;

(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:

Z is selected from a straight, branched, cyclic, saturated, or unsaturated alkyl having from 1 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, alkylamino, dialkylamino, acylamino, arylamino, hydroxyamino, alkoxyamino, alkylthio, arylthio, carboxy, carboxamido, carboalkoxy, aryl, and 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 substituted with one or more substituents selected from alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and carboxamido; and

R _{31 1} to R ₃ | ₈ are independently selected from:

(a) hydrogen;

(b) halo;

(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, 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

R ₃₀₈ to R ₃₂₀ are independently a bond that forms a carbon-carbon double bond, a carbon-carbon triple bond, or a ring with the lipoxin backbone; or any two of R ₃₀₇ to R ₃₂ o are taken together with the atoms to which they are bound and optionally to 1 to 6 oxygen atoms, 1 to 6 nitrogen atoms, or both 1 to 6 oxygen atoms and 1 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 55:

(55) wherein:

R _40I is selected from:

R _4O2 is selected from:

(forms

Xιo is R _{4 H} , OR _4H , or SR _{4 H} ; R _4I i is

(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;

(e) phenyl;

(f) substituted phenyl wherein Z ₁ Z ₁₁ , Z _1n , Z, _v and Z _v are each independently selected from -NO ₂ , -CN, -C(=O)-R ₄ i i, -SO ₃ H, a hydrogen atom, halogen, methyl, -OR _x , wherein R _x is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl; wherein when any of Z ₁ Z _n , Z ₁₁₁ , Z _1V or Z _v is CC=O)-R _{41 1} , said Z ₁ Z ₁₁ , Z ₁₁₁ , Z _1V or Z _v is not substituted with another Q=O)-R _4H .

(g) a detectable label molecule; or

(h) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;

Q ₁ is (C=O), SO ₂ or (CN);

Q ₃ is O, S or NH; one Of R _{4 I2} and R _4I3 is a hydrogen atom and the other is selected from:

(a) H;

(b) an alkyl of 1 to 8 carbon atoms, inclusive, which can be straight 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

(e) R ₄₃ IQ ₂ R ₄₃₂ wherein Q ₂ is -O- or -S-; wherein R ₄₃ ) is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched and wherein R _{43 I} is alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched;

R _{4 I3} ;, and R ₄ I ₃ ), are each independently:

(a) H;

(b) an alkyl of 1 to 8 carbon atoms, inclusive, which can be straight 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

(e) R ₄₃ )Q ₂ R ₄₃₂ wherein R ₄₃ ), Q ₂ , and R ₄₃₂ are as defined above;

R _{4 I4} is

(a) H;

(b) an alkyl of 1 to 6 carbon atoms, inclusive, can be straight chain or branched;

(a) an alkyl of 1 to 9 carbon atoms which can be straight chain or branched;

(b) -(CHa)-R ₁

wherein n=0 to 4 and R, is

(i) a cycloalkyl of 3 to 10 carbon atoms, inclusive; (ii) a phenyl; or

(iii) substituted phenyl , wherein Z ₁ through

Zv are as defined above;

(b) R43iQ ₂ R43 ₂ , wherein R ₄ 3 ₁ , Q ₂ , and R ₄₃₂ are as defined above;

wherein R ₁ ,, and R, _v are each independently:

(i) a hydrogen atom;

(ii) (CH) _p (Z) _q , wherein Z, p, and q are as defined above;

(e) a haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched;

R416 is

(a) H;

(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;

(c) a halogen;

one Of Y _40I or Y _4O2 is -OH, methyl, or -SH, and wherein the other is selected 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 branched; or

(d) an alkoxy of 1 to 4 carbon atoms, inclusive,

or Y _4O i and Y ₄ O ₂ taken together are:

(d) =NH; or

(e) =0;

one of Y ₄₀₃ or Y ₄₀₄ 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 branched; or

(d) an alkoxy of 1 to 4 carbon atoms, inclusive,

or Y ₄₀₁ and Y ₄₀₂ taken together are:

(a) =NH; or

(b) =0;

one OfY ₄₀₅ or Y ₄₀₆ 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 branched; or

(d) an alkoxy of 1 to 4 carbon atoms, inclusive,

or Y ₄ oι and Y ₄₀₂ taken together are:

(a) =NH; or

(b) =0;

R ₄₂ I is

(a) H; or

(b) alkyl of 1 to 8 carbon atoms;

R ₄₂₂ and R ₄₂₃ are each independently:

(a) H;

(b) a hydroxyl, or a thiol;

(c) a methyl or a halomethyl;

(d) a halogen; or

(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;

(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

(a) a substituted phenyl , wherein Z, through Z _v are as defined above;

(b) a substituted phenoxy wherein Z ₁ through Z _v are as defined above; or

(C) wherein Z, through Z _v are as defined above.

Lipoxin compounds suitable for use in this invention include those of formula 56:

(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 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 ₅ oi-R _5O3 are independently selected from hydrogen, alkyl, aryl, acyl or alkoxyacyl; n is O, I or 2; m is I or 2; and

the two substituents on the phenyl ring are ortho, meta, or para.

Lipoxin compounds suitable for use in this invention include those of formula 57:

(57), wherein:

I is selected from: -C(O)-E, -SO ₂ -E, -PO(OR)-E, where E is hydroxy, alcoxy, 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 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, 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;

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, alcoxyacyl and aminoacyl;

R _ό oi, R _ό 0 ₂ and R ₆₀₃ are independently selected from hydrogen, alkyl, aryl and heteroaryl, provided that R ₆₀ ], R ₆₀₂ and R ₆₀₃ can independently be connected to linkers J' or K';

R ₆₀₄ and R _6O5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, fluoro, and provided that R ₆₀₄ and R ₆₀₅ can be joined together to form a

carbocyclic, heterocyclic or aromatic ring, and further provided that R ₆₀₄ and R ₆₀₅ can be replaced by a bond to form a triple bond.

Other compounds suitable for use in methods of the invention are the oxylipins described in international applications WO 2006055965 and WO 2007090162, the compounds in which are incorporated herein by reference. Examples of such compounds are those of formulae 58-132, as shown in Table 1. These compounds include long chain omega-6 fatty acids, docosapentaenoic acid (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 98-1 15, the γ-linolenic acids (GLA) (compounds 116-122), and the stearidonic acids (SDA) (compounds 123-132). Table 1

,8-epoxyDPA(111)

0,11 epoxyDPA(112)

9,20 epoxy DPA (113)

-hydroxyDHA(114)

3,14 epoxy DPA (115)

-hydroxyGLA(116)

0-hydroxyGLA(117)

-hydroxyGLA(118)

2-hydroxyGLA(119)

-hydroxyGLA(120)

3-hydroxyGLA(121)

,13 dihydroxy GLA (122)

-hydroxySDA(123)

0-hydroxy SDA (124)

-hydroxy SDA (125)

2-hydroxySDA(126)

-hydroxySDA(127)

3-hydroxySDA(128)

5-hydroxySDA(129)

6-hydroxySDA(130)

6 13 di hydroxy SDA (131 )

6, 16 dihydroxy SDA (132)

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 triple bonds, those wherein 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 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); monohydroxy, dihydroxy, and trihydroxy derivatives of DPAn-6; isolated 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 "acyl" is art-recognized and refers to a group represented by the general foπnula 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-.

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.

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 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, 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. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C ₃ -C ₃₀ 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 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 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 sulfate, a sulfonate, a sulfamoyl, a sulfonamide, 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, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkyl thios, 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-substituted alkyls, -CF ₃ , -CN, and the like.

The term "C _x . _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 "C _x . _y alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain 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 "C ₂ . _y alkenyl" and "C ₂ . _y alkynyl" refer to substituted or unsubstituted 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.

The teπn "alkylthio", as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general foπnula alkylS-.

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 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, heterocyclyl, or heteroaryl groups is contemplated.

The term "amide", as used herein, refers to a group

wherein each R ¹⁰ independently represent a hydrogen or hydrocarbyl group, or two R ¹⁰ 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.

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

_R 10 _R 10

| — N [ -N ⁺ -R ^{10 X R 10 or X R 10 wherein each R 10 independently represents a hydrogen or a hydrocarbyl group, or two R 10 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.}

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.

The teπn "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 teπn "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 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

wherein each R ¹⁰ independently represent hydrogen or a hydrocarbyl group.

The terms "carbocycle", "carbocyclyl", and "carbocyclic", as used herein, refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring 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 -OCO ₂ -R ¹⁰ , wherein R ¹⁰ represents a hydrocarbyl group.

The term "carboxy", as used herein, refers to a group represented by the formula -CO ₂ H.

The term "ester", as used herein, refers to a group -C(O)OR ¹⁰ wherein R ¹⁰ represents a hydrocarbyl group.

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-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 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 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 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 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 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, 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 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 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.

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. 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 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., 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.

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 "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 peπnissible 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 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 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, 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 pharmaceutically acceptable salt thereof.

The term "sulfonamide" is art-recognized and refers to the group represented by the general formulae

O O

Il _R ¹⁰ I l

0 \ I °

R ¹⁰ or R ¹⁰ wherein each R ¹⁰ independently represents hydrogen or hydrocarbyl.

The teπn "sulfoxide" is art-recognized and refers to the group -S(O)-R ¹⁰ , wherein R ¹⁰ represents a hydrocarbyl.

The term "sulfonate" is art-recognized and refers to the group SO ₃ H, or a pharmaceutically acceptable salt thereof.

The teπn "sulfone" is art-recognized and refers to the group -S(O) ₂ -R ¹⁰ , wherein R ¹⁰ 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 ¹⁰ or -SC(O)R ¹⁰ wherein R ¹⁰ represents a hydrocarbyl.

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

wherein each R ¹⁰ independently represent hydrogen or a hydrocarbyl.

"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 ^rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, VoIs. 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, allyloxycarbonyl, 9- fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxylprotecting 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), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.

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 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.

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.

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 incorporated by reference. The synthesis of lipoxin compounds is set forth in US 2002/0107289, US 2004/00191 10, US 2006/0009521, US 2005/0203184, US 2005/0113443. The preparation of oxylipin compounds is set forth in WO 2006/055965 and WO 2007/090162.

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, a compound of any one of formulae 1-49, a lipoxin, an oxylipin, 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 organic esters. In a preferred embodiment, when such phannaceutical 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 phannaceutical 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 agents that act, for example, to stabilize or to increase the absorption of a compound such as a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or aspirin and/or an omega-3 fatty acid. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, 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 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 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 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, 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) glycols, such as propylene glycol; (1 1) 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) 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, boluses, powders, granules, pastes for application to the tongue); sublingually; anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramusclularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, 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 4,172,896, as well as in patents cited therein. The most preferred route of administration is the oral route.

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 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 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, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or 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 uniformly 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 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 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.

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 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, 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 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.

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 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 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 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 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 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 (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.

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 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 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.

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.

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 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, 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 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 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.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

The phrases "parenteral administration" and "administered parenterally" as 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, 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 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 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 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 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 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 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 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.

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 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.

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 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 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 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. 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, 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 cil. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

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 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.

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, compounds of formula A, compounds of any one of formulae 1-49, lipoxin compounds, oxylipin compounds, or a combination of aspirin and an omega-3 fatty acid may be used alone or conjointly administered with another type of 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 {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 receives such treatment can benefit from a combined effect of different therapeutic compounds.

In one embodiment, the method of treating bone loss may comprise administering a compound of foπnula A, a compound of any one of foπnulae 1-49, a lipoxin

compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid conjointly with an additional agent useful in the treatment of bone loss. In certain embodiments, the 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 may be conjointly administered with a bisphosphonate (e.g., ibandronate, zolendronate, risedronate, etidronate, or alendronate), a selective estrogen receptor modulator (e.g., raloxifene), or hormone treatment (e.g., calcitonin or teriparitide). In certain embodiments, the 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 may be conjointly administered with growth factors or other therapeutic agents that have a positive effect on the growth of bone or connective tissue, such as osteoprotegerin, interleukins, MMP inhibitors, beta glucans, integrin antagonists, calcitonin, proton pump inhibitors, protease inhibitors, insulin-like growth factor-1, platelet-derived growth factor, epidermal growth factor, inhibitors of transforming growth factor-alpha, transforming growth factor-beta, bone morphogenetic protein, parathyroid hormone, osteoprotegerin, a fibroblast growth factor, Vitamin D, vitronectin, plasminogen-activator inhibitor, or a protease inhibitor such as a metalloprotease inhibitor, or compounds known to be beneficial to bone formation, such as calcium, fluoride, magnesium, boron, or a combination thereof.

In one embodiment, the method of treating metastatic bone disease may comprise administering a compound of foπnula A, a compound of any one of formulae 1-49, a lipoxin compound, or an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid conjointly with a chemotherapeutic agent. Chemotherapeutic agents that may be conjointly administered with compounds of formula A, compounds of any one of foπnulae 1-49, lipoxin compounds, oxylipin compounds, or a combination of aspirin and an omega-3 fatty acid include: aminoglutethimide, amsacrine, anastrozole, asparaginase, beg, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil,

fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine.

Many combination therapies have been developed for the treatment of cancer. In certain embodiments, compounds of formula A, compounds of any one of formulae 1-49, lipoxin compounds, oxylipin compounds, or the combination of aspirin and an omega-3 fatty acid may be conjointly administered with a combination therapy. Examples of combination therapies with which compounds of formula A, compounds of any one of formulae 1-49, lipoxin compounds, oxylipin compounds, or the combination of aspirin and an omega-3 fatty acid may be conjointly administered are included in Table 2.

Table 2: Exemplary combinatorial therapies for the treatment of cancer.

In certain embodiments, the present invention provides a kit comprising: a) one or more single dosage forms of a compound of formula A, a compound of any one of formulae 1 -49, a lipoxin compound, or an oxylipin compound; b) one or more single dosage forms of a chemotherapeutic agent as mentioned above; and c) instructions for the administration of the compound of formula A, compound of any one of formulae 1-49, lipoxin compound, or oxylipin compound and the chemotherapeutic agent.

In certain embodiments, a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or combination of aspirin and an omega-3 fatty acid may be conjointly administered with non-chemical methods of cancer treatment. In certain embodiments, a compound of formula A, a compound of any one of formulae 1 -49, a lipoxin compound, an oxylipin compound, or combination of aspirin and an omega-3 fatty acid may be conjointly administered with radiation therapy. In certain embodiments, a compound of formula A, a compound of any one of formulae 1-49, a lipoxin compound, an oxylipin compound, or combination of aspirin and an omega-3 fatty acid may be conjointly administered with surgery, with thermoablation, with focused ultrasound therapy, or with cryotherapy.

In certain embodiments, different compounds of formula A, compounds of any one of formulae 1-49, lipoxin compounds, or oxylipin compounds may be conjointly administered with one another, and such combinations may be conjointly administered with other therapeutics as discussed above. In certain embodiments, different compounds of foπnula A, compounds of any one of formulae 1-49, lipoxin compounds, or oxylipin compounds may be conjointly administered with a combination of aspirin and an omega- 3 fatty acid, and such combinations may be conjointly administered with other therapeutics as discussed 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 foπnulation comprising both components or in separate formulations, 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 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 Cl 8:3, C20:5, or C22:6 fatty acid, particulary 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 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 specificed omega-3 fatty acids. Non-fatty acid components, such as excipients or other materials added during formulation, are not 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 be used in combination with an omega-3 fatty acid for the treatment or prevention of bone loss in any of the various embodiments discussed herein. In certain embodiments, a nonselective NSAID other than aspirin, such as diclofenac, diflunisal, etodolac, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, or tolmetin, may be used in combination with an omega-3 fatty acid for the treatment or prevention of bone loss in any of the various embodiments discussed herein. The combination of different COX-2 inhibitors with an omega-3 fatty acid may result in the production of different subsets or proportions of active omega-3 metabolites.

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 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 crystallization, or adventitious to such solvent.

Wetting agents, emulsifϊers 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.

Examples of pharmaceutically 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 (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:

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 or preventing bone loss.

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 suitable for the treatment of bone loss (e.g., a bisphosphonate) as mentioned above. In certain embodiments, the kit further comprises a second pharmaceutical formulation comprising

an agent suitable for the treatment of bone loss (e.g., a bisphosphonate) as mentioned above.

The present invention provides a kit comprising:

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 or inhibiting the development of osteoporosis, treating or inhibiting the development of periodontitis, treating or inhibiting the development of metastatic bone disease, decreasing the incidence of bone metastasis, or delaying the onset of bone metastasis.

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 a chemotherapeutic agent as mentioned above. In certain embodiments, the kit further comprises a second pharmaceutical formulation comprising a chemotherapeutic agent 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 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 administering the single dosage forms for treating or preventing bone loss.

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

suitable for the treatment of bone loss (e.g., a bisphosphonate) as mentioned above. In certain embodiments, the kit further comprises one or more single dosage forms of an agent suitable for the treatment of bone loss (e.g., a bisphosphonate) 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 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 administering the single dosage forms for treating or inhibiting the development of osteoporosis, treating or inhibiting the development of periodontitis, treating or inhibiting the development of metastatic bone disease, decreasing the incidence of bone metastasis, or delaying the onset of bone metastasis.

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 a chemotherapeutic agent as mentioned above. In certain embodiments, the kit further comprises one or more single dosage forms of a chemotherapeutic agent as mentioned above.

In certain embodiments, the present invention provides a kit comprising:

a) one or more single dosage forms each comprising an agent suitable for the treatment of bone loss (e.g., a bisphosphonate) 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 compound, oxylipin compound, or combination of aspirin and an omega-3 fatty acid for treating or preventing bone loss, treating or inhibiting the development of osteoporosis, treating or inhibiting the development of periodontitis, treating or

inhibiting the development of metastatic bone disease, decreasing the incidence of bone metastasis, or delaying the onset of bone metastasis.

The present invention provides a kit comprising:

a) a first pharmaceutical formulation comprising an agent suitable for the treatment of bone loss (e.g., a bisphosphonate) as mentioned above; and

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 bone loss, treating or inhibiting the development of osteoporosis, treating or inhibiting the development of periodontitis, treating or inhibiting the development of metastatic bone disease, decreasing the incidence of bone metastasis, or delaying the onset of bone metastasis.

In certain embodiments, the present invention provides a kit comprising:

a) one or more single dosage forms each comprising a chemotherapeutic agent as mentioned above; and

b) instructions for the administration of the one or more single dosage foπns with a compound of formula A, compound of any one of foπnulae 1-49, lipoxin compound, oxylipin compound, or combination of aspirin and an omega-3 fatty acid for treating or preventing bone loss, treating or inhibiting the development of osteoporosis, treating or inhibiting the development of periodontitis, treating or inhibiting the development of metastatic bone disease, decreasing the incidence of bone metastasis, or delaying the onset of bone metastasis.

The present invention provides a kit comprising:

a) a first pharmaceutical formulation comprising a chemotherapeutic agent as mentioned above; and

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 bone loss, treating or inhibiting the development of osteoporosis, treating or inhibiting the development of periodontitis, treating or inhibiting the development of metastatic bone disease, decreasing the incidence of bone metastasis, or delaying the onset of bone metastasis.

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 formulation or kit for treating or preventing bone loss, inhibiting the development of metastatic bone disease, treating metastatic bone disease, decreasing the incidence of bone metastasis, delaying the onset of bone metastasis, inhibiting the development of osteoporosis, treating osteoporosis, inhibiting the development of periodontitis, or treating periodontitis.

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 foπnula 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 kit as described herein, and providing instruction material to patients or physicians for using the foπnulation for treating or preventing bone loss, inhibiting the development of metastatic bone disease, treating metastatic bone disease, decreasing the incidence of bone metastasis, delaying the onset of bone metastasis, inhibiting the development of osteoporosis, treating osteoporosis, inhibiting the development of periodontitis, or treating periodontitis.

In certain embodiments, the invention comprises a method for conducting a phaπnaceutical 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 compound,

an oxylipin compound, or a combination of aspirin and an omega-3 fatty acid for treating or preventing bone loss, inhibiting the development of metastatic bone disease, treating metastatic bone disease, decreasing the incidence of bone metastasis, delaying the onset of bone metastasis, inhibiting the development of osteoporosis, treating osteoporosis, inhibiting the development of periodontitis, or treating periodontitis, 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 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 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 bone loss, inhibiting the development of metastatic bone disease, treating metastatic bone disease, decreasing the incidence of bone metastasis, delaying the onset of bone metastasis, inhibiting the development of osteoporosis, treating osteoporosis, inhibiting the development of periodontitis, or treating periodontitis, and licensing, to a third party, the rights for further development and sale of the formulation.

Examples

Example 1 : Effects of Compounds in 1 1 Day Male DBA/1 J Mouse Established Type II Collagen Arthritis

Male DBA/1 J mice (7-9 weeks old on arrival; at least 7 weeks old at time of first immunization) were housed 5 per cage and were acclimated for enough days after arrival such that all animals were at least 7 weeks old at start of study.

Mice were anesthetized with Isoflurane and given intradermal collagen (2 mg/ml) injections at the base of the tail in a volume of 150μl (DO and D21). On days 21-35, onset of arthritis occured and mice were randomized into treatment groups. Randomization into each group was done after swelling was obviously established in at

least one paw, and attempts were made to assure approximately equal mean scores across the groups at time of enrollment. Treatment was initiated after enrollment and continued every day for a total of 10 days as outlined in Table 3. During the ten days of treatment, clinical scores were given for each of the paws (right front, left front, right rear, and left rear) according to the scoring methods provided below.

Clinical Scoring Criteria for Fore and Hind Paws

0 normal

1 1 hind or fore paw joint affected or minimal diffuse erythema and swelling

2 2 hind or fore paw joints affected or mild diffuse erythema and swelling

3 3 hind or fore paw joints affected or moderate diffuse erythema and swelling

4 Marked diffuse erythema and swelling, or 4 digit joints affected

5 Severe diffuse erythema and severe swelling entire paw, unable to flex digits

All dose solutions were prepared to deliver 10 ml/kg (0.3 ml/30 g mouse). On day 1 1 of arthritis, animals were euthanized, and both fore and hind limbs with knees were removed, placed into formalin and then processed for microscopy. Following 1-2 days in fixative and then 4-5 days in decalcifϊer, the joints were processed, embedded, sectioned and stained with toluidine blue. (Only fore and hind paws and knees were initially processed - 6 joints/mouse.)

Histopathologic Scoring Methods for Mouse Joints with Type II Collagen Arthritis

When scoring paws or ankles from mice with lesions of type II collagen arthritis, severity of changes as well as number of individual joints affected must be considered. When only 1-3 joints of the paws or ankles out of a possibility of numerous metacarpal/metatarsal/digit or tarsal/tibiotarsal joints were affected, an arbitrary assignment of a maximum score of 1 , 2 or 3 from the scoring scale below was given

depending on severity of changes. If more than 3 joints were involved, the full scoring scale below was applied only to the most severely affected/majority of joints.

Pannus

0 Normal

1 Minimal infiltration of pannus in cartilage and subchondral bone

2 Mild infiltration with marginal zone destruction of hard tissue in affected joints

3 Moderate infiltration with moderate hard tissue destruction in affected joints

4 Marked infiltration with marked destruction of joint architecture, most joints

5 Severe infiltration associated with total or near total destruction of joint architecture, affects all joints

Bone Resorption Scores

0 Normal

1 Minimal — small areas of resorption, not readily apparent on low magnification, rare osteoclasts in affected joints

2 Mild ~ more numerous areas of resorption, not readily apparent on low magnification, osteoclasts more numerous in affected joints

3 Moderate — obvious resorption of medullary trabecular and cortical bone without full thickness defects in cortex, loss of some medullary trabeculae, lesion apparent on low magnification, osteoclasts more numerous in affected joints

4 Marked — Full thickness defects in cortical bone, often with distortion of profile of remaining cortical surface, marked loss of medullary bone, numerous osteoclasts, affects most joints

5 Severe ~ Full thickness defects in cortical bone and destruction of joint architecture of all joints

Statistical Analysis

Histologic parameters (mean±SE) for each group were analyzed for differences using the Chi Square Test and one way ANOVA. Significance was set at p<0.05.

Table 3

Figure 1 shows the effects of Compound X, °» , on bone damage as was determined by histologic scoring in joints of mice (n=15) with established Type II collagen arthritis. In particular, twice daily dosing of 5 μg/kg showed a significant decrease in the score of bone damage as compared to vehicle control.

Figure 2 shows the effects of Compound X on a) arthritis as was determined by clinical scoring in the paws of mice (n=16) with established Type II collagen arthritis, and b) pannus formation and bone loss as determined by histologic scoring in mice (n=16) with established Type II collagen arthritis. In particular, once daily i.v. dosing of Compound X at both 0.5 and 5.0 μg/kg inhibited clinical symptoms of arthritis as compared to arthritic control. Furthermore, once daily i.v. dosing of Compound X at both 0.5 and 5.0 μg/kg reduced pannus formation and bone loss as compared to vehicle control.

Example 2: Study of the ex vivo activity of Compound X on CIA rat blood and lymph node cells

Female Lewis rats were anesthetized with 3-5% isoflurane and arthritis was induced by intradermal injection of 0.3 mL (100 μL at three different sites) of an emulsion containgin 1.5 mg/mL of type II bovine collagen, CII (Elastin Products Inc., Cat# CM276), in incomplete Freund's adjuvant (IFA) at the base of the tail on day 0 and 6. Control rats were injected with an equal amount of IFA only.

The volume of both hind paws were measured using a water displacement plethysmometer (Ugo Basile, Biological Research Apparatus, Italy), and the onset of arthritis was indicated by increased paw volume, which appeared approximately on day 1 1 post injection. Both paw volumes and body weights were measured throughout the study every 2-3 days. Nineteen to twenty-one days after CII injection, the rats were euthanized with CO ₂ . Blood was collected by cardiac puncture and serum was saved.

The effects of Compound X, , were measured when administered i.v., twice daily, at 0.3 mg/kg from day 8 (when proinflammatory markers are highly up-regulated) to day 16 or 19. Bovine Type II collagen for tissue culture was purchased from Chondrex (Cat# 2022) and was reconstituted according to the manufacturer's instructions. All data were processed and analyzed by t- test using GraphPad Prism software.

After the animals were euthanized, both hind paws and knees were removed, hind paws were weighed, and the paws and knees were placed in formalin. Following 1-2 days in fixative and 4-5 days in decalcifϊer, the ankle joints were cut in half longitudinally, and the knees were cut in half in the frontal plane. The joints were then processed, embedded, sectioned and stained with toluidine blue. Collagen arthritic ankles and knees were given scores of 0-5 for inflammation, pannus formation and bone resorption according to the following criteria:

Knee Inflammation

0 Normal

1 Minimal infiltration of inflammatory cells in periarticular tissue

2 Mild infiltration

3 Moderate infiltration with moderate edema

4 Marked infiltration with marked edema

5 Severe infiltration with severe edema

Knee Pannus

0 Normal

1 Minimal infiltration of pannus in cartilage and subchondral bone

2 Mild infiltration (extends over up to 1/4 of surface or subchondral area of tibia or femur)

3 Moderate infiltration (extends over > 1/4 but < 1/2 of surface or subchondral area of tibia or femur)

4 Marked infiltration (extends over 1/2 to 3/4 of tibial or femoral surface)

5 Severe infiltration (covers > 3/4 of surface)

Cartilage Damage (Knee, emphasis on femoral condyles)

0 Noπnal

1 Minimal: minimal to mild loss of toluidine blue staining with no obvious chondrocyte loss or collagen disruption

2 Mild: mild loss of toluidine blue staining with focal mild (superficial) chondrocyte loss and/or collagen disruption

3 Moderate: moderate loss of toluidine blue staining with multifocal to diffuse moderate (depth to middle zone) chondrocyte loss and/or collagen disruption

4 Marked: marked loss of toluidine blue staining with multifocal to diffuse marked (depth to deep zone) chondrocyte loss and/or collagen disruption

5 Severe: severe diffuse loss of toluidine blue staining with multifocal severe (depth to tide mark) chondrocyte loss and/or collagen disruption on both femur and tibia

Bone Resorption (Knee)

0 Noπnal

1 Minimal: small areas of resorption, not readily apparent on low magnification, rare osteoclasts

2 Mild: more numerous areas of resorption, definite loss of subchondral bone involving 1/4 of tibial or femoral surface (medial or lateral)

3 Moderate: obvious resorption of subchondral bone involving >l/4 but <l/2 of tibial or femoral surface (medial or lateral)

4 Marked: obvious resorption of subchondral bone involving > 1/2 but <3/4 of tibial or femoral surface (medial or lateral)

5 Severe: distortion of entire joint due to destruction involving >3/4 of tibial or femoral surface (medial or lateral)

Figure 3 shows that therapeutic dosing of Compound X significantly reduced knee histopathology scores in rats (n=9 for vehicle or treatment with Compound X; n=4 for non-arthritis control groups) with CIA. Specifically, twice daily i.v. dosing of Compound X at 0.3 mg/kg from days 8 to 19 showed a significant reduction in inflammation, pannus, cartilage damage, and bone resorption as determined by knee histopathology scoring.

Figure 4 shows that therapeutic dosing of Compound X protected bone resorption and joint damage in rats (n=9 for vehicle or treatment with Compound X; n=4 for non- arthritis control groups) with CIA.

Incorporation by Reference

All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents

While specific embodiments of the subject invention have been discussed, the 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.