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1. (WO2010075257) C5AR ANTAGONISTS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

WHAT IS CLAIMED IS:

1. A compound having the formula


and pharmaceutically acceptable salts, hydrates and rotomers thereof; wherein C1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R1 substituents; C2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R2 substituents; C3 is selected from the group consisting of Ci_g alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-Ci_4 alkyl, aryl, aryl-Ci_4 alkyl, heteroaryl, heteroaryl-Ci_4 alkyl, heterocycloalkyl or heterocycloalkyl-Ci_4 alkyl, wherein the heterocycloalkyl group or portion has from 1-3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S, and each C3 is optionally substituted with from 1-3 R substituents; each R1 is independently selected from the group consisting of halogen, -CN, -Rc, -CO2R*1, -C0NRaRb, -C(O)Ra, -0C(0)NRaRb, -NRbC(O)Ra, -NRbC(0)2Rc, -NRa-C(0)NRaRb, -NRaC(0)NRaRb, -NRaRb, -ORa, and -S(O)2NRaRb; wherein each Ra and Rb is independently selected from hydrogen, Ci_g alkyl, and Ci_g haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each Rc is independently selected from the group consisting of Ci_8 alkyl, Ci_8 haloalkyl, C3_6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; each R2 is independently selected from the group consisting of halogen, -CN, -Rf, -CO2Rd, -CONRdRe, -C(O)Rd, -OC(O)NRdRe, -NReC(O)Rd, -NReC(O)2Rf, -NRdC(0)NRdRe, -NRdC(O)NRdRe, -NRdRe, -ORd, and -S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci_8 alkyl, and Ci_8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each Rf is independently selected from the group consisting of Ci_8 alkyl, Ci_8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; each R3 is independently selected from the group consisting of halogen, -CN, -R1, -CO2R8, -CONRgRh, -C(O)Rg, -OC(O)NRgRh, -NRhC(O)Rg, -NR11C(O)2R1, -NRgC(0)NRgRh, -NRgRh, -ORg, -S(O)2NRgRh, -X4-RJ, -X4-NRgRh, -X4-CONRgRh, -X4-NRhC(O)Rg, -NHRJ and -NHCH2R1, wherein X4 is a Ci_4 alkylene; each Rg and Rh is independently selected from hydrogen, Ci_8 alkyl, C3-6 cycloalkyl and Ci_8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R1 is independently selected from the group consisting of Ci_s alkyl, Ci_g haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each RJ is selected from the group consisting of C3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of Rg, Rh, R1 and RJ are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, amino, alkylamino and dialkylamino groups; and X is hydrogen or CH3.

2. The compound of claim 1, wherein X is hydrogen.

3. The compound of claim 1, having the formula:


(Ia).

4. The compound of claim 1, having the formula:

5. The compound of claim 1, having the formula:


wherein X1 is selected from the group consisting of N, CH and CR1; the subscript n is an integer of from 0 to 2; X2 is selected from the group consisting of N, CH and CR2; and the subscript m is an integer of from 0 to 2.

6. The compound of claim 1, having the formula:


wherein X1 is selected from the group consisting of N, CH and CR1; the subscript n is an integer of from 0 to 2; X2 is selected from the group consisting of N, CH and CR2; and the subscript m is an integer of from 0 to 2.

7. The compound of claim 1, having the formula:
wherein the subscript p is an integer of from 0 to 3;

X1 is selected from the group consisting of N, CH and CR1; the subscript n is an integer of from 0 to 2;

X2 is selected from the group consisting of N, CH and CR2; and the subscript m is an integer of from 0 to 2.

8. The compound of claim 1, having the formula:


9. The compound of claim 1, having the formula:


10. The compound of claim 1, having the formula:

11. The compound of claim 1, having the formula:


12. The compound of claim 1, having the formula:


13. The compound of claim 1, having the formula:


14. The compound of claim 1, having the formula:
wherein R3 is a member selected from the group consisting of -NRgRh, -NHRJ and

15. The compound of claim 1, having the formula:


wherein R3 is a member selected from the group consisting of -X4-NRgRh, -X4-RJ and -X4-NRhCORg.

16. The compound of claim 1, wherein C1 is selected from the group consisting of phenyl, pyridyl, indolyl and thiazolyl, each of which is optionally substituted with from 1 to 3 R1 substituents.

17. The compound of claim 1, wherein C2 is selected from the group consisting of phenyl, naphthyl, pyridyl and indolyl, each of which is optionally substituted with from 1 to 3 R2 substituents.

18. The compound of claim 1, wherein C3 is selected from the group consisting of C3-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylCi_2alkyl, phenyl, pyridinyl, pyrazolyl, piperidinyl, pyrrolidinyl, piperidinylmethyl and pyrrolidinylmethyl, each of which is optionally substituted with from 1 to 3 R3 substituents.

19. The compound of claim 16, wherein each R1 is independently selected from the group consisting of halogen, -CN, -Rc, -NR aarR>b and -ORa, and wherein each Ra and Rb is independently selected from hydrogen, Ci_g alkyl, and Ci_g haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a pyrrolidine ring; each Rc is independently selected from the group consisting of Ci_g alkyl, Ci_g haloalkyl and C3_6 cycloalkyl, and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring.

20. The compound of claim 17, wherein each R2 is independently selected from the group consisting of halogen, -Rf and -ORd; wherein each Rd is independently selected from hydrogen, Ci_g alkyl, and Ci_g haloalkyl; each Rf is independently selected from the group consisting of Ci_g alkyl, Ci_g haloalkyl, C3-6 cycloalkyl, heterocycloalkyl and heteroaryl, and wherein the aliphatic and cyclic portions of Rd and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups.

21. The compound of claim 18, wherein each R is independently selected from the group consisting of halogen, -R1, -CO2R8, -CONRgRh, -NRhC(O)Rg, -NR11C(O)2R1, -NRgRh, -ORg, -X4-RJ, -X4-NRgRh, -X4-CONRgRh, -X4-NRhC(O)Rg, -NHRJ and -NHCH2R1, wherein X4 is a Ci_3 alkylene; each Rg and Rh is independently selected from hydrogen, Ci_g alkyl, C3-6 cycloalkyl and Ci_g haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 1 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R1 is independently selected from the group consisting of Ci_8 alkyl, Ci_8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each RJ is selected from the group consisting of C3_6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of Rg, Rh, R1 and RJ are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, amino, alkylamino and dialkylamino groups

22. The compound of claim 20, wherein C2 is selected from the group consisting of:


23. The compound of claim 19, wherein C1 is selected from the group consisting of:






24. The compound of claim 1, wherein C is selected from the group consisting of:


25. The compound of claim 1, wherein C3 is selected from the group consisting of:


26. The compound of claim 1, wherein said compound is selected from the group in Table 1.

27. A pharmaceutical composition comprising a compound a pharmaceutically acceptable carrier and a compound having formula


and pharmaceutically acceptable salts, hydrates and rotomers thereof; wherein C1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R1 substituents; C2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R2 substituents; C3 is selected from the group consisting of Ci_8 alkyl, C3_8 cycloalkyl, C3_8 cycloalkyl-Ci_4 alkyl, aryl, aryl-Ci_4 alkyl, heteroaryl, heteroaryl-Ci_4 alkyl, heterocycloalkyl or heterocycloalkyl-Ci_4 alkyl, wherein the heterocycloalkyl group or portion has from 1-3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S, and each C3 is optionally substituted with from 1-3 R3 substituents; each R1 is independently selected from the group consisting of halogen, -CN, -Rc, -CO2R*1, -CONRaRb, -C(O)Ra, -OC(O)NRaRb, -NRbC(O)Ra, -NRbC(O)2Rc, -NRa-C(0)NRaRb, -NRaC(0)NRaRb, -NRaRb, -ORa, and -S(O)2NRaRb; wherein each Ra and Rb is independently selected from hydrogen, Ci_g alkyl, and Ci_g haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each Rc is independently selected from the group consisting of Ci_g alkyl, Ci_g haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; each R2 is independently selected from the group consisting of halogen, -CN, -Rf, -CO2Rd, -CONRdRe, -C(O)Rd, -OC(O)NRdRe, -NReC(O)Rd, -NReC(O)2Rf, -NRdC(O)NRdRe, -NRdC(O)NRdRe, -NRdRe, -ORd, and -S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci_g alkyl, and Ci_g haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each Rf is independently selected from the group consisting of Ci_g alkyl, Ci_g haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups;

each R3 is independently selected from the group consisting of halogen, -CN, -R1, -CO2R8, -CONRgRh, -C(O)Rg, -OC(O)NRgRh, -NRhC(O)Rg, -NR11C(O)2R1, -NRgC(O)NRgRh, -NRgRh, -ORg, -S(O)2NRgRh, -X4-RJ, -X4-NRgRh, -X4-CONRgRh, -X4-NRhC(O)Rg, -NHRJ and -NHCH2R1, wherein X4 is a Ci_4 alkylene; each Rg and Rh is independently selected from hydrogen, Ci_8 alkyl, C3-6 cycloalkyl and Ci_8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R1 is independently selected from the group consisting of Ci_g alkyl, Ci_g haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each RJ is selected from the group consisting of C3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of Rg, Rh, R1 and RJ are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, amino, alkylamino and dialkylamino groups; and X is hydrogen or CH3.

28. A method for treating a mammal suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors, comprising administering to the mammal an effective amount of a compound having


and pharmaceutically acceptable salts, hydrates and rotomers thereof; wherein C1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R1 substituents; C2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R2 substituents; C3 is selected from the group consisting of Ci_g alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-Ci_4 alkyl, aryl, aryl-Ci_4 alkyl, heteroaryl, heteroaryl-Ci_4 alkyl, heterocycloalkyl or heterocycloalkyl-Ci_4 alkyl, wherein the heterocycloalkyl group or portion has from 1-3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S, and each C3 is optionally substituted with from 1-3 R3 substituents; each R1 is independently selected from the group consisting of halogen, -CN, -Rc, -CO2R*1, -CONRaRb, -C(O)Ra, -OC(O)NRaRb, -NRbC(O)Ra, -NRbC(O)2Rc, -NRa-C(0)NRaRb, -NRaC(O)NRaRb, -NRaRb, -ORa, and -S(O)2NRaRb; wherein each Ra and Rb is independently selected from hydrogen, Ci_8 alkyl, and Ci_8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each Rc is independently selected from the group consisting of Ci_g alkyl, Ci_g haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; each R2 is independently selected from the group consisting of halogen, -CN, -Rf, -CO2Rd, -CONRdRe, -C(O)Rd, -OC(O)NRdRe, -NReC(O)Rd, -NReC(O)2Rf, -NRdC(O)NRdRe, -NRdC(O)NRdRe, -NRdRe, -ORd, and -S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci_g alkyl, and Ci_g haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each Rf is independently selected from the group consisting of Ci_8 alkyl, Ci_g haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; each R is independently selected from the group consisting of halogen, -CN, -R1, -CO2Rg, -CONRgRh, -C(O)Rg, -OC(O)NRgRh, -NRhC(O)Rg, -NR11C(O)2R1, -NRgC(O)NRgRh, -NRgRh, -ORg, -S(O)2NRgRh, -X4-RJ, -X4-NRgRh, -X4-CONRgRh, -X4-NRhC(O)Rg, -NHRJ and -NHCH2R1, wherein X4 is a Ci_4 alkylene; each Rg and Rh is independently selected from hydrogen, Ci_g alkyl, C3_6 cycloalkyl and Ci_g haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R1 is independently selected from the group consisting of Ci_g alkyl, Ci_g haloalkyl, C3_6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each RJ is selected from the group consisting of C3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofliranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of Rg, Rh, R1 and RJ are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, amino, alkylamino and dialkylamino groups; and X is hydrogen or CH3.

29. A method of inhibiting C5 a receptor-mediated cellular chemotaxis comprising contacting mammalian white blood cells with a C5a receptor modulatory amount of a compound having formula


and pharmaceutically acceptable salts, hydrates and rotomers thereof; wherein C1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R1 substituents; C2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R2 substituents; C3 is selected from the group consisting of Ci_g alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-Ci_4 alkyl, aryl, aryl-Ci_4 alkyl, heteroaryl, heteroaryl-Ci_4 alkyl, heterocycloalkyl or heterocycloalkyl-Ci_4 alkyl, wherein the heterocycloalkyl group or portion has from 1-3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S, and each C3 is optionally substituted with from 1-3 R substituents; each R1 is independently selected from the group consisting of halogen, -CN, -Rc, -CO2R*1, -CONRaRb, -C(O)Ra, -OC(O)NRaRb, -NRbC(O)Ra, -NRbC(O)2Rc, -NRa-C(0)NRaRb, -NRaC(O)NRaRb, -NRaRb, -ORa, and -S(O)2NRaRb; wherein each Ra and Rb is independently selected from hydrogen, Ci_8 alkyl, and Ci_8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each Rc is independently selected from the group consisting of Ci_8 alkyl, Ci_8 haloalkyl, C3_6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and optionally when two R1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring; each R2 is independently selected from the group consisting of halogen, -CN, -Rf, -CO2R11, -CONRdRe, -C(O)Rd, -OC(O)NRdRe, -NReC(O)Rd, -NReC(O)2Rf, -NRdC(O)NRdRe, -NRdC(O)NRdRe, -NRdRe, -ORd, and -S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci_g alkyl, and Ci_g haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each Rf is independently selected from the group consisting of Ci_g alkyl, Ci_g haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; each R is independently selected from the group consisting of halogen, -CN, -R1, -CO2Rg, -CONRgRh, -C(O)Rg, -OC(O)NRgRh, -NRhC(O)Rg, -NR11C(O)2R1, -NRgC(O)NRgRh, -NRgRh, -ORg, -S(O)2NRgRh, -X4-RJ, -X4-NRgRh, -X4-CONRgRh, -X4-NRhC(O)Rg, -NHRJ and -NHCH2R1, wherein X4 is a Ci_4 alkylene; each Rg and Rh is independently selected from hydrogen, Ci_g alkyl, C3-6 cycloalkyl and Ci_g haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six- membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R1 is independently selected from the group consisting of Ci_g alkyl, Ci_g haloalkyl, C3_6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each RJ is selected from the group consisting of C3_6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of Rg, Rh, R1 and RJ are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, amino, alkylamino and dialkylamino groups; and X is hydrogen or CH3.

30. The method of claim 28, wherein the disease or disorder is an inflammatory disease or disorder.

31. The method of claim 30, wherein the disease or disorder is selected from the group consisting of neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease, chronic obstructive pulmonary disorder, inflammation associated with burns, lung injury, osteoarthritis, atopic dermatitis, chronic urticaria, ischemia-reperfusion injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, tissue graft rejection and hyperacute rejectionof transplanted organs.

32. The method of claim 28, wherein the disease or disorder is a cardiovascular or cerebrovascular disorder.

33. The method of claim 32, wherein the disease or disorder is selected from the group consisting of myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, artherosclerosis, traumatic central nervous system injury and ischemic heart disease.

34. The method of claim 28, wherein the disease or disorder is an autoimmune disorder.

35. The method of claim 34, wherein the disease or disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis, lupus glomerulonephritis, psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, immuno vasculitis, tissue graft rejection and hyperacute rejection of transplanted organs.

36. The method of claim 28, wherein the disease or disorder is a pathologic sequelae associated with the group consisting of insulin-dependent diabetes, mellitus, lupus nephropathy, Heyman nephritis, membranous nephritis, glomerulonephritis, contact sensitivity responses, and inflammation resulting from contact of blood with artificial surfaces.