Hydroxylamines and derivatives for the inhibition of complement activation
First Claim
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1. A method for inhibiting complement activation in a subject, comprising administering to the subject a hydroxylamine compound or an ester derivative thereof in an amount effective to inhibit complement activation in the subject, wherein the ester derivative of hydroxylamine compound has the formula:
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wherein;
R1 and R2 are, independently, H or C1 to C3alkyl;
R3 and R4 are, independently C1 to C3alkyl, or wherein R1 and R2, taken together, or R3 and R4, taken together, or R1 and R2, taken together and R3 and R4 taken together, are each cycloalkyl;
R5 is H, OH, or C1 to C6alkyl;
R6 is or C1 to C6alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
R7 is C1 to C6alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
or R6 and R7 taken together, or R5, R6, and R7 taken together, form a carbocycle having from 3 to 7 atoms in the ring or form a heterocycle having from 3 to 7 atoms in the ring.
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Abstract
Methods for the inhibition of complement activation, for the treatment of complement-mediated pathologies, and for the treatment of drusen-mediated pathologies are disclosed. The methods utilize hydroxylamine compounds and ester derivatives thereof, administered to subjects in effective amounts.
35 Citations
51 Claims
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1. A method for inhibiting complement activation in a subject, comprising administering to the subject a hydroxylamine compound or an ester derivative thereof in an amount effective to inhibit complement activation in the subject, wherein the ester derivative of hydroxylamine compound has the formula:
-
wherein;
R1 and R2 are, independently, H or C1 to C3alkyl;
R3 and R4 are, independently C1 to C3alkyl, or wherein R1 and R2, taken together, or R3 and R4, taken together, or R1 and R2, taken together and R3 and R4 taken together, are each cycloalkyl;
R5 is H, OH, or C1 to C6alkyl;
R6 is or C1 to C6alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
R7 is C1 to C6alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
or R6 and R7 taken together, or R5, R6, and R7 taken together, form a carbocycle having from 3 to 7 atoms in the ring or form a heterocycle having from 3 to 7 atoms in the ring.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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3. The method of claim 1, wherein R1, R2, R3, and R4 are each independently C1-C3alkyl.
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4. The method of claim 1, wherein R1, R2, R3, and R4 are ethyl.
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5. The method of claim 1, wherein R1, R2, R3, and R4 are methyl.
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6. The method of claim 5, wherein R5 is H or methyl, R6 is methyl substituted with benzyloxy or C1-C6alkoxy, and R7 is methyl.
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7. The method of claim 5,wherein R5 is H or methyl, and R6 and R7, taken together, form a cyclopropyl group.
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8. The method of claim 5, wherein R5, R6, and R7, taken together, form a furanyl group.
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9. The method of claim 5, wherein R5 is H, and R6 and R7, taken together, form a tetrahydrofuranyl group.
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10. The method of claim 5, wherein R5 is H, and R6 and R7, taken together, form a cyclopropyl group.
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11. The method of claim 1, wherein the subject is a mammal.
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12. The method of claim 11, wherein the mammal is a human.
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13. The method of claim 1, wherein the hydroxylamine compound or ester derivative thereof inhibits the formation of C3a anaphylatoxin.
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14. The method of claim 1, wherein the hydroxylamine compound or ester derivative thereof inhibits the formation of C5a anaphylatoxin.
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15. A method for treating a subject having a pathology mediated by complement activation comprising administering to the subject a composition comprising a pharmaceutically acceptable carrier and at least one hydroxylamine compound or an ester derivative thereof in an amount effective to inhibit complement activation in the subject, wherein the ester derivative of the hydroxylamine compound has the formula:
-
wherein;
R1 and R2 are, independently, H or C1 to C3alkyl;
R3 and R4 are, independently C1 to C3alkyl, or wherein R1 and R2, taken together, or R3 and R4, taken together, or R1 and R2, taken together and R3 and R4 taken together, are each cycloalkyl;
R5 is H, OH, or C1 to C6alkyl;
R6 is or C1 to C6alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
R7 is C1 to C6alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
or R6 and R7 taken together, or R5, R6, and R7 taken together, form a carbocycle having from 3 to 7 atoms in the ring or form a heterocycle having from 3 to 7 atoms in the ring.- View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)
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17. The method of claim 15, wherein R1, R2, R3, and R4 are each independently C1-C3alkyl.
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18. The method of claim 15, wherein R1, R2, R3, and R4 are ethyl.
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19. The method of claim 15, wherein R1, R2, R3, and R4 are methyl.
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20. The method of claim 19, wherein R5 is H or methyl, R6 is methyl substituted with benzyloxy or C1-C6alkoxy, and R7 is methyl.
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21. The method of claim 19, wherein R5 is H or methyl, and R6 and R7, taken together, form a cyclopropyl group.
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22. The method of claim 19, wherein R5, R6, and R7, taken together, form a furanyl group.
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23. The method of claim 19, wherein R5 is H, and R6 and R7, taken together, form a tetrahydrofuranyl group.
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24. The method of claim 19, wherein R5 is H, and R6 and R7, taken together, form a cyclopropyl group.
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25. The method of claim 15, wherein the subject is a mammal.
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26. The method of claim 25, wherein the mammal is a human.
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27. The method of claim 15, wherein the composition is administered to the eye of the subject.
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28. The method of claim 27, wherein the composition is administered to the macula of the eye.
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29. The method of claim 27, wherein the composition is administered to the retina of the eye.
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30. The method of claim 27, wherein the composition is administered to achieve in the eye of the subject a hydroxylamine concentration of about 0.1 μ
- M to about 10 mM.
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31. The method of claim 27, wherein the composition is administered to achieve in the eye of the subject a hydroxylamine concentration of about 1 μ
- M to about 5 mM.
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32. The method of claim 27, wherein the composition is administered to achieve in the eye of the subject a hydroxylamine concentration of about 10 μ
- M to about 2.5 mM.
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33. The method of claim 27, wherein the composition is administered to achieve in the eye of the subject a hydroxylamine concentration of about 50 μ
- M to about 1 mM.
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34. The method of claim 27, wherein the composition is administered to achieve in the eye of the subject a hydroxylamine concentration of about 1 μ
- M to about 100 μ
M.
- M to about 100 μ
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35. The method of claim 27, wherein the pathology is drusen formation.
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36. The method of claim 27, wherein the pathology is macular degeneration.
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37. The method of claim 36, wherein the macular degeneration is age-related macular degeneration.
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38. The method of claim 15, wherein the hydroxylamine compound or ester derivative thereof inhibits the formation of C3a anaphylatoxin.
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39. The method of claim 15, wherein the hydroxylamine compound or ester derivative thereof inhibits the formation of C5a anaphylatoxin.
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40. A method to inhibit drusen formation in a subject comprising administering to the subject a hydroxylamine compound or ester derivative thereof in an amount effect to inhibit drusen formation in the subject, wherein the ester derivative of the hydroxylamine compound has the formula:
-
wherein;
R1 and R2 are, independently, H or C1 to C3alkyl;
R3 and R4 are, independently C1 to C3alkyl, or wherein R1 and R2, taken together, or R3 and R4, taken together, or R1 and R2, taken together and R3 and R4 taken together, are each cycloalkyl;
R5 is H, OH, or C1 to C6alkyl;
R6 is or C1 to C6alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
R7 is C1 to C6alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
or R6 and R7 taken together, or R5, R6, and R7 taken together, form a carbocycle having from 3 to 7 atoms in the ring or form a heterocycle having from 3 to 7 atoms in the ring.- View Dependent Claims (41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51)
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42. The method of claim 40, wherein R1, R2, R3, and R4 are each independently C1-C3alkyl.
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43. The method of claim 40, wherein R1, R2, R3, and R4 are ethyl.
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44. The method of claim 40, wherein R1, R2, R3, and R4 are methyl.
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45. The method of claim 44, wherein R5 is H or methyl, R6 is methyl substituted with benzyloxy or C1-C6alkoxy, and R7 is methyl.
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46. The method of claim 44, wherein R5 is H or methyl, and R6 and R7, taken together, form a cyclopropyl group.
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47. The method of claim 44, wherein R5, R6, and R7, taken together, form a furanyl group.
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48. The method of claim 44, wherein R5 is H, and R6 and R7, taken together, form a tetrahydrofuranyl group.
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49. The method of claim 44, wherein R5 is H, and R6 and R7, taken together, form a cyclopropyl group.
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50. The method of claim 40, wherein the subject is a mammal.
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51. The method of claim 40, wherein the mammal is a human.
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Current AssigneeColby Pharmaceutical Company
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Original AssigneeColby Pharmaceutical Company
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InventorsPatil, Ghanshyam, Matier, William
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Application NumberUS11/677,462Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/327CPC Class CodesA61K 31/421 1,3-Oxazoles, e.g. pemoline...A61K 31/445 Non condensed piperidines, ...
