Triazine dimers for the treatment of autoimmune diseases
Compounds containing two mono- or disubstituted triazine rings covalently linked by an organic linker, but not linked directly to each other, may be used to treat autoimmune diseases. Autoimmune diseases which are amenable to treatment with compounds of this invention include rheumatoid arthritis, systemic lupus erythematosus (SLE), idiopathic (immune) thrombocytopenia (ITP), glomerulonephritis and vasculitis. The present invention also relates to reducing drug toxicity which often accompanies traditional therapies for autoimmune diseases. The compounds may also be used to bind antibody in vitro or ex vivo.
1. A compound of the following formula:
wherein R 1 , R 2 , and R 3 are independently selected from the group consisting of
C 2-4 aminoalkyl, aminoethyloxyethyl, aminophenethyl, anilino, benzyl, bis(hydroxyethyl), bis(hydroxyethyl)aminoethyl, 1,3-dihydroxy-2-propyl, and C 2-4 hydroxyalkyl.
2. The compound according to claim 1 , wherein:
3. The compound according to claim 2 , wherein:
R 1 and R 2 are selected from the group consisting of aminoethyl, anilino, 1,3-dihydroxy-2-propyl, and hydroxyethyl; and
R 3 is selected from the group consisting of aminoethyloxyethyl, aminophenethyl, anilino, bis(hydroxyethyl), and bis(hydroxyethyl)aminoethyl.
4. The compound according to claim 3 , wherein:
R 1 is 1,3-dihydroxy-2-propyl or hydroxyethyl; and
R 2 is anilino or 1,3-dihydroxy-2-propyl.
5. A compound selected from the group consisting of:
Compound No.
Structure
1
2
3
4
5
6
7
8
9
10
11a 11b
12
13
14
15
16
17
18
19a X = OH 19b X = NH 2
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
and
51
6. The compound according to claim 1 which can noncovalently bind to antibodies.
7. The compound according to claim 1 which can noncovalently bind to antibodies, wherein one, two, three or all of the substituents R 1 , R 2 , R 3 , R 4 is
8. The compound according to claim 6 , wherein the antibodies are at least of the human IgG isotype.
9. A composition comprised of one or more compound(s) according to claim 1 , wherein said compound(s) is combined with a pharmaceutically acceptable carrier.
10. The composition according to claim 9 , wherein said carrier solubilizes said compound in an alcohol or polyol solvent.
11. The composition according to claim 9 further comprised of a recombinant protein which is able to bind to human TNFα.
12. The composition according to claim 11 , wherein said recombinant protein is anti-TNFα antibody or soluble TNFα receptor.
13. The composition according to claim 9 further comprised of methotrexate.
14. The composition according to claim 9 further comprised of an anti-inflammatory corticosteroid.
15. The composition according to claim 9 further comprised of a nonsteroidal anti-inflammatory drug.
16. A method of treating a patient with glomerulonephritis, psoriasis, rheumatoid arthritis, or systemic lupus erythematosus comprising administering a therapeutically effective amount of a compound according to claim 1 to said patient.
17. A method of treating a patient with glomerulonephritis, psoriasis, rheumatoid arthritis, or systemic lupus erythematosus comprising administering a therapeutically effective amount of a composition according to claim 9 to said patient, wherein said composition is further comprised of methotrexate, an anti-inflammatory corticosteroid, or a nonsteroidal anti-inflammatory drug.
18. A method of treating a patient with glomerulonephritis, psoriasis, rheumatoid arthritis, or systemic lupus erythematosus comprising administering a therapeutically effective amount of a composition according to claim 11 to said patient.
19. The method of claim 16 further comprising simultaneously administering a therapeutically effective amount of a recombinant protein which is able to bind to human TNFα, wherein said therapeutically effective amount of recombinant protein is reduced in the presence of said compound.
20. The method of claim 16 further comprising separately administering therapeutically effective amount of a recombinant protein which is able to bind to human TNFα before and/or after administration of said compound, but not simultaneous administration.
21. A method of removal of human antibodies comprised of circulating blood or other physiological fluid through an apheresis column, wherein one or more compounds according to claim 1 are covalently linked either directly or with an organic linker to an insoluble support material which constitutes part of said apheresis column such that at least some free antibodies and/or antibody-antigen immune complexes are bound thereto; and returning at least some said blood or other physiological fluid, wherein at least some human antibodies have been removed therefrom, to a patient from whom said blood or other physiological fluid was obtained.
22. A method of purification of antibodies comprised of binding antibodies with one or more compounds according to claim 1 covalently linked either directly or with an organic linker to an insoluble support material such that at least some antibodies are noncovalently bound to said compounds linked to the insoluble support and purifying said antibodies.
23. A method of binding antibody using one or more compounds according to claim 1 , comprised of incubating said one or more compounds to bind the antibody and then separating bound antibody from free antibody.
24. A compound selected from the group consisting of:
Compound No.
Structure
1
17
19a
35
38
47
50
52
53
54
55
56
57
58
59
60
61
62
63
64