Conjugated complement cascade inhibitors
First Claim
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1. A composition comprising a conjugated complement inhibitor.
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Accused Products
Abstract
The present invention is directed to conjugated complement cascade inhibitors, and a method of treating a patient using a conjugated complement cascade inhibitor.
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Citations
61 Claims
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1. A composition comprising a conjugated complement inhibitor.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)
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2. The composition of claim 1 having a formula (I) or formula (IV):
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(D-L)n-P
(I)
D-Ln-Pn′
(IV)wherein;
D is independently selected at each occurrence from compounds which are complement cascade inhibitors;
L is an optional (at each occurrence) linking group independently selected at each occurrence;
n is 1, 2, 3, 4, 5, or 6;
n′
is 1, 2, 3, or 4; and
P is independently selected at each occurrence from compounds which enhance the pharmacokinetic properties of D.
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3. The composition of claim 2, wherein the composition has formula (I) and n is 1, 2, 4, or 6.
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4. The composition of claim 2, wherein the bond that connects D to P is substantially non-hydrolyzable under physiological conditions.
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5. The composition of claim 2, wherein D binds to the C1s subcomponent, the C1r subcomponent, MASP-2 subcomponent, or is a C5a receptor antagonist.
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6. The composition of claim 2, wherein D binds to at least one of the C1s subcomponent or the MASP-2 subcomponent.
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7. The composition of claim 2, wherein D is an aromatic compound.
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8. The composition of claim 2, wherein D is a non-peptide.
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9. The composition of claim 2, wherein D is a small molecule having a molecular weight in a range from about 100 molecular weight units to about 2000 molecular weight units.
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10. The composition of claim 2, wherein D is a small molecule having a molecular weight in a range from about 400 molecular weight units to about 1200 molecular weight units.
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11. The composition of claim 2, wherein D is a small molecule having a molecular weight in a range from about 400 molecular weight units to about 2000 molecular weight units.
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12. The composition of claim 2, wherein D is a non-aromatic compound.
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13. The composition of claim 2, wherein D is an aromatic guanidine.
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14. The composition of claim 2, wherein D is an aromatic or heteroaromatic amidine.
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15. The composition of claim 2, wherein D is a compound of the formula (II):
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16. The composition of claim 2, wherein D is:
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17. The composition of claim 2, wherein D is:
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18. The composition of claim 2, wherein D is:
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19. The composition of claim 2, wherein D is a compound of the formula (V):
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20. The composition of claim 19, wherein D is selected from the group:
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21. The composition of claim 19, wherein D is:
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22. The composition of claim 19, wherein D is:
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23. The composition of claim 19, wherein D is:
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24. The composition of claim 2, wherein L is selected from the group:
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25. The composition of claim 2, wherein P is a polymer selected from the group consisting of polyalkylene oxides, dextrans, polyvinyl pyrrolidones, polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers, and activated polymers.
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26. The composition of claim 25, wherein P is a monomethyl-terminated polyethylene glycol having a molecular weight from about 750 formula weight units to about 60,000 formula weight units.
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27. The composition of claim 25, wherein P is a monomethyl-terminated polyethylene glycol having a molecular weight of about 750 formula weight units.
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28. The composition of claim 25, wherein P is a monomethyl-terminated polyethylene glycol having a molecular weight of about 10,000 formula weight units.
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29. The composition of claim 25, wherein P is a monomethyl-terminated polyethylene glycol having a molecular weight of about 20,000 formula weight units.
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30. The composition of claim 25, wherein P is a monomethyl-terminated polyethylene glycol having a molecular weight of about 40,000 formula weight units.
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31. The composition of claim 25, wherein P is a monomethyl-terminated polyethylene glycol having a molecular weight of about 60,000 formula weight units.
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32. The composition of claim 25, wherein P is an activated polymer having a formula (III):
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33. The composition of claim 2, wherein:
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D is a compound of the formula (II) or formula (V);
wherein;
R1, R2, and R3 are independently selected from H, C1-4 alkyl, amino, C1-4 alkoxy, or hydroxy;
U is thiophenyl-R5, benzylene, phenylene, NH or a bond;
R5 is SO2, NH, or a bond;
Z is arylene, heteroarylene, aralkylene, cycloalkylene, cycloheteroene;
W is C(═
O)—
O, HC(CH3)—
NH—
C(═
O), O, NH, S, CH2, C(═
O), or a bond;
T is arylene, heteroarylene, aralkylene, cycloalkylene, cycloheteroene, C1-4 alkyl, O, S, C1-4 alkoxy, C1-4 alkenyloxy, phenoxy, benzyloxy, halo, amino, or nitro;
X is amino, carboxy, hydroxyl, thiol, halogen, olefin, hydrazine, hydroxyl amine, aminoalkyl, carboxyalkyl, haloalkyl, hydroxyalkyl, mercaptoalkyl, or a bond to L or P;
when present, Y is amino, carboxy, hydroxyl, thiol, halogen, olefin, hydrazine, hydroxyl amine, aminoalkyl, carboxyalkyl, haloalkyl, hydroxyalkyl, mercaptoalkyl, urea, guanidinyl, or a bond to L or P; and
V is methyl, ethyl, or Cl; and
R4 is H, C1-4 alkyl, C1-4 alkoxy, amidinyl, aminomethyl, NH2, urea, or guanidinyl;
L is an optional (at each occurrence) linking group independently selected from the group;
wherein AA is an amino acid, and m is 1-12, wherein AA is an amino acid, and m is 1-12, and P is an activated polymer having a formula (III);
wherein;
M is CH3, HC═
CH—
C(═
O), O═
CH—
CH2, H2N—
CH2—
CH2, Cl−
H3N+—
HN—
C(═
O)—
CH2, O═
C═
N—
CH2CH2, HS—
CH2CH2, H2C═
CH—
S(═
O)2—
CH2CH2,j is from 17 to 1400; and
A is O—
CH2—
CH(═
O), O—
C (═
O)—
CH2═
CH2, O—
CH2—
CH2—
NH2, NH2, O—
CH2—
C(═
O)—
NH—
NH3+Cl−
, SH, N═
C═
O, S(═
O)2—
CH═
CH2,
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34. A method of treating a patient to suppress activation of the complement cascade, comprising administering a conjugated complement inhibitor of claim 2 to the patient.
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35. The method of claim 34, wherein the patient has a disorder selected from the group consisting of hereditary angioedema, septic shock, post pump syndrome in cardiopulmonary bypass, paroxysmal nocturnal hemoglobinurea, organ rejection, wounds, brain trauma, asthma, Hashimoto'"'"'s thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture'"'"'s syndrome, Graves'"'"' disease, myasthenia gravis, insulin resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic purpura, rheumatoid arthritis, multiple sclerosis, the neuropathies Guillain-Barre syndrome, Miller-Fisher syndrome, and Alzheimer'"'"'s disease.
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36. A method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway or the MBL pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a conjugated complement inhibitor of claim 2.
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37. The method of claim 36, wherein said acute or chronic disorder is inflammation, tissue damage, or an autoimmune disease.
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38. The method of claim 36, wherein said compound is administered to a mammal in need of treatment of complement-mediated disease selected from the group consisting of inflammation, tissue damage and a combination thereof.
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39. The method of claim 38, wherein said inflammation or tissue damage arises following stroke, myocardial infarction, hemorrhagic shock or surgery, or a combination thereof.
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40. The method of claim 36, wherein said compound is administered to a mammal in need of treatment of intestinal inflammation of Crohn'"'"'s disease, restenosis or psoriasis.
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41. The method of claim 36, wherein said compound is administered to a mammal before, during or after the transplant of an organ or a graft to ameliorate the rejection of such organ or graft by the mammal.
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42. The method of claim 41, wherein the transplant is within an individual, between individuals of the same species, or between individuals of different species.
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43. The method of claim 41, wherein the organ is selected from the group consisting of kidney, heart, lung, and liver.
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44. The method of claim 36, wherein said compound is administered to a mammal before, during or after (1) treatment of said mammal with IL-2, bone marrow transplantation in said mammal or (3) onset of pancreatitis in said mammal, in an amount effective to reduce the toxicity and side-effects of the IL-2 treatment, bone marrow transplantation or pancreatitis.
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45. The method of claim 36, wherein said compound is administered to a mammal that has been diagnosed with an autoimmune disease.
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46. The method of claim 36, wherein said compound is administered to a mammal that has been diagnosed with Addison'"'"'s disease, Type I diabetes mellitus, Hashimoto'"'"'s thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture'"'"'s syndrome, Graves'"'"' disease, myasthenia gravis, insulin resistance, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, immune-complex-induced vasculitis glomerulonephritis, type II collagen-induced arthritis, rheumatoid arthritis or allergic neuritis.
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47. The method of claim 36, wherein said compound is administered to a mammal that has been diagnosed with myasthenia gravis (MG), rheumatoid arthritis, or systemic lupus erythematosus.
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48. The method of claim 36, wherein said compound is administered to a mammal that has been diagnosed with a neurodegenerative disease.
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49. The method of claim 48, wherein said neurodegenerative disease is multiple sclerosis (MS), Guillain-Barré
- syndrome (GBS), Miller-Fisher syndrome (MFS), Alzheimer'"'"'s disease (AD) or variant Creutzfeldt-Jakob disease (vCJD).
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50. The method of claim 36, wherein said compound is administered to a mammal suffering from the symptoms of adult respiratory distress syndrome.
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51. The method of claim 36, wherein said compound is administered to a mammal in septic shock.
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52. The method of claim 36, wherein said compound is administered to a mammal in need of treatment of hereditary angioedema, paroxysmal nocturnal hemoglobinuria, wound healing, brain trauma, asthma, hemodialysis, infection, dermatosis, inflammatory bowel disease, osteoporosis, osteoarthritis, thermal injury (burns and frostbite), hemolytic anemia or post pump syndrome in cardiopulmonary bypass.
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53. A method of ameliorating rejection of a cell transplantation or a graft in an individual, comprising suppressing activation of the complement cascade by administering a conjugated complement inhibitor of claim 2 to the individual.
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54. The method of claim 53, wherein the individual has a condition selected from the group consisting of heart failure, diabetes, stroke, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, dementia, liver disease, kidney disease, bums, and wounds.
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55. The method of claim 53, wherein the graft is a transference of tissue within an individual, between individuals of the same species, or between individuals of different species.
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56. The method of claim 53, wherein the cell transplantation is within an individual, between individuals of the same species, or between individuals of different species.
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57. The method of claim 53, wherein the cells of the cell transplantation are stem cells, primary cells, cells derived from tissue culture, pancreatic islet cells, cells expressing insulin, cells expressing glucose-modulating hormones, or cells expressing factors useful for the treatment of diabetes.
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58. The method of claim 53, wherein the individual is a mammal.
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59. A method for preventing complement activation in an organ in an organ preservation solution, comprising contacting the organ with a conjugated complement inhibitor of claim 2.
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60. A method for preventing complement activation in response to insertion of a foreign object into an individual, comprising contacting the object with a conjugated complement inhibitor of claim 2.
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61. The method of claim 60, wherein the object is a surgical implant, an artificial organ, or an artificial joint.
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2. The composition of claim 1 having a formula (I) or formula (IV):
Specification
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Current Assignee3-Dimensional Pharmaceuticals, Inc. (Johnson & Johnson)
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Original Assignee3-Dimensional Pharmaceuticals, Inc. (Johnson & Johnson)
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InventorsBallentine, Shelley, Travins, Jeremy M., Ali, Farah, Leonard, Kristi A., Hufnagel, Heather Rae, Khalil, Ehab, Bone, Roger F., Subasinghe, Nalin
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/445
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CPC Class CodesA61K 47/60 the organic macromolecular ...A61P 1/00 Drugs for disorders of the ...A61P 1/16 for liver or gallbladder di...A61P 11/06 AntiasthmaticsA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 25/02 for peripheral neuropathiesA61P 25/16 Anti-Parkinson drugsA61P 25/28 for treating neurodegenerat...A61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 31/04 Antibacterial agentsA61P 37/06 Immunosuppressants, e.g. dr...A61P 41/00 Drugs used in surgical meth...A61P 43/00 Drugs for specific purposes...A61P 5/00 : Drugs for disorders of the ...A61P 5/16 : for decreasing, blocking or...A61P 7/00 : Drugs for disorders of the ...A61P 7/06 : AntianaemicsA61P 7/10 : Antioedematous agents; Diur...A61P 9/00 : Drugs for disorders of the ...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...