Hydroxylamines and derivatives for the inhibition of complement activation
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.
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:
R 1 and R 2 are, independently, H or C 1 to C 3 alkyl;
R 3 and R 4 are, independently C 1 to C 3 alkyl, or wherein R 1 and R 2 , taken together, or R 3 and R 4 , taken together, or R 1 and R 2 , taken together and R 3 and R 4 taken together, are each cycloalkyl;
R 5 is H, OH, or C 1 to C 6 alkyl;
R 6 is or C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
R 7 is C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl; or R 6 and R 7 taken together, or R 5 , R 6 , and R 7 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.
2 . The method of claim 1 , wherein the hydroxylamine compound has the structure:
3 . The method of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each independently C 1 -C 3 alkyl.
4 . The method of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are ethyl.
5 . The method of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are methyl.
6 . The method of claim 5 , wherein R 5 is H or methyl, R 6 is methyl substituted with benzyloxy or C 1 -C 6 alkoxy, and R 7 is methyl.
7 . The method of claim 5 ,wherein R 5 is H or methyl, and R 6 and R 7 , taken together, form a cyclopropyl group.
8 . The method of claim 5 , wherein R 5 , R 6 , and R 7 , taken together, form a furanyl group.
9 . The method of claim 5 , wherein R 5 is H, and R 6 and R 7 , taken together, form a tetrahydrofuranyl group.
10 . The method of claim 5 , wherein R 5 is H, and R 6 and R 7 , taken together, form a cyclopropyl group.
11 . The method of claim 1 , wherein the subject is a mammal.
12 . The method of claim 11 , wherein the mammal is a human.
13 . The method of claim 1 , wherein the hydroxylamine compound or ester derivative thereof inhibits the formation of C3a anaphylatoxin.
14 . The method of claim 1 , wherein the hydroxylamine compound or ester derivative thereof inhibits the formation of C5a anaphylatoxin.
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:
R 1 and R 2 are, independently, H or C 1 to C 3 alkyl;
R 3 and R 4 are, independently C 1 to C 3 alkyl, or wherein R 1 and R 2 , taken together, or R 3 and R 4 , taken together, or R 1 and R 2 , taken together and R 3 and R 4 taken together, are each cycloalkyl;
R 5 is H, OH, or C 1 to C 6 alkyl;
R 6 is or C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
R 7 is C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl; or R 6 and R 7 taken together, or R 5 , R 6 , and R 7 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.
16 . The method of claim 15 , wherein the hydroxylamine compound has the structure:
17 . The method of claim 15 , wherein R 1 , R 2 , R 3 , and R 4 are each independently C 1 -C 3 alkyl.
18 . The method of claim 15 , wherein R 1 , R 2 , R 3 , and R 4 are ethyl.
19 . The method of claim 15 , wherein R 1 , R 2 , R 3 , and R 4 are methyl.
20 . The method of claim 19 , wherein R 5 is H or methyl, R 6 is methyl substituted with benzyloxy or C 1 -C 6 alkoxy, and R 7 is methyl.
21 . The method of claim 19 , wherein R 5 is H or methyl, and R 6 and R 7 , taken together, form a cyclopropyl group.
22 . The method of claim 19 , wherein R 5 , R 6 , and R 7 , taken together, form a furanyl group.
23 . The method of claim 19 , wherein R 5 is H, and R 6 and R 7 , taken together, form a tetrahydrofuranyl group.
24 . The method of claim 19 , wherein R 5 is H, and R 6 and R 7 , taken together, form a cyclopropyl group.
25 . The method of claim 15 , wherein the subject is a mammal.
26 . The method of claim 25 , wherein the mammal is a human.
27 . The method of claim 15 , wherein the composition is administered to the eye of the subject.
28 . The method of claim 27 , wherein the composition is administered to the macula of the eye.
29 . The method of claim 27 , wherein the composition is administered to the retina of the eye.
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 μM to about 10 mM.
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 μM to about 5 mM.
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 μM to about 2.5 mM.
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 μM to about 1 mM.
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 μM to about 100 μM.
35 . The method of claim 27 , wherein the pathology is drusen formation.
36 . The method of claim 27 , wherein the pathology is macular degeneration.
37 . The method of claim 36 , wherein the macular degeneration is age-related macular degeneration.
38 . The method of claim 15 , wherein the hydroxylamine compound or ester derivative thereof inhibits the formation of C3a anaphylatoxin.
39 . The method of claim 15 , wherein the hydroxylamine compound or ester derivative thereof inhibits the formation of C5a anaphylatoxin.
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:
R 1 and R 2 are, independently, H or C 1 to C 3 alkyl;
R 3 and R 4 are, independently C 1 to C 3 alkyl, or wherein R 1 and R 2 , taken together, or R 3 and R 4 , taken together, or R 1 and R 2 , taken together and R 3 and R 4 taken together, are each cycloalkyl;
R 5 is H, OH, or C 1 to C 6 alkyl;
R 6 is or C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
R 7 is C 1 to C 6 alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl; or R 6 and R 7 taken together, or R 5 , R 6 , and R 7 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.
41 . The method of claim 40 , wherein the hydroxylamine compound has the structure:
42 . The method of claim 40 , wherein R 1 , R 2 , R 3 , and R 4 are each independently C 1 -C 3 alkyl.
43 . The method of claim 40 , wherein R 1 , R 2 , R 3 , and R 4 are ethyl.
44 . The method of claim 40 , wherein R 1 , R 2 , R 3 , and R 4 are methyl.
45 . The method of claim 44 , wherein R 5 is H or methyl, R 6 is methyl substituted with benzyloxy or C 1 -C 6 alkoxy, and R 7 is methyl.
46 . The method of claim 44 , wherein R 5 is H or methyl, and R 6 and R 7 , taken together, form a cyclopropyl group.
47 . The method of claim 44 , wherein R 5 , R 6 , and R 7 , taken together, form a furanyl group.
48 . The method of claim 44 , wherein R 5 is H, and R 6 and R 7 , taken together, form a tetrahydrofuranyl group.
49 . The method of claim 44 , wherein R 5 is H, and R 6 and R 7 , taken together, form a cyclopropyl group.
50 . The method of claim 40 , wherein the subject is a mammal.
51 . The method of claim 40 , wherein the mammal is a human.