Compounds and compositions as TLR activity modulators
The invention provides a novel class of compounds, immunogenic compositions and pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with Toll-Like Receptors 7. In one aspect, the compounds are useful as adjuvants for enhancing the effectiveness of a vaccine.
1. An immunogenic composition comprising (i) a compound of Formula (I), or pharmaceutically acceptable salt thereof, (ii) an antigen, and (iii) an aluminum-containing adjuvant; wherein the aluminum-containing adjuvant is selected from aluminum hydroxide, aluminum oxyhydroxide and aluminum hydroxyphosphate; and wherein the compound of Formula (I) is a TLR7 agonist:
wherein:
R 1 is H, C 1 -C 6 alkyl, —C(R 5 ) 2 OH, -L 1 R 5 , -L 1 R 6 , -L 2 R 5 , -L 2 R 6 , —OL 2 R 5 , or —OL 2 R 6 ;
L 1 is —C(O)— or —O—;
L 2 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, arylene, heteroarylene or —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene and C 2 -C 6 alkenylene of L 2 are optionally substituted with 1 to 4 fluoro groups;
L 4 is arylene or heteroarylene;
R 2 is H or C 1 -C 6 alkyl;
R 3 is:
selected from C 1 -C 4 alkyl, -L 3 R 5 , -L 1 R 5 , -L 3 R 7 , -L 3 L 4 L 3 R 7 , -L 3 L 4 R 5 , -L 3 L 4 L 3 R 5 , —OL 3 R 7 , —OL 3 L 4 R 7 , —OL 3 L 4 L 3 R 7 , —OR 8 , —OL 3 L 4 R 5 , —OL 3 L 4 L 3 R 5 and —C(R 5 ) 2 OH, wherein each L 3 is independently selected from C 1 -C 6 alkylene and —((CR 4 R 4 ) p O) q (CH 2 ) p —, wherein the C 1 -C 6 alkylene of L 3 is optionally substituted with 1 to 4 fluoro groups; or
—OL 3 R 5 , wherein L 3 is —((CR 4 R 4 ) p O) q (CH 2 ) p —;
each R 4 is independently selected from H and fluoro;
R 5 is —P(O)(OR 9 ) 2 ;
R 6 is —CF 2 P(O)(OR 9 ) 2 or —C(O)OR 10 ;
R 7 is —CF 2 P(O)(OR 9 ) 2 ;
R 8 is H or C 1 -C 4 alkyl;
each R 9 is H;
R 10 is H or C 1 -C 4 alkyl;
each p is independently selected from 1, 2, 3, 4, 5 and 6, and
q is 1, 2, 3 or 4;
with the proviso that when R 3 is C 1 -C 4 alkyl or —OR 8 , R 1 is —C(R 5 ) 2 OH, -L 1 R 5 , -L 1 R 6 , -L 2 R 5 , —L 2 R 6 , —OL 2 R 5 , or —OL 2 R 6 , wherein R 6 is —CF 2 P(O)(OR 9 ) 2 ;
wherein the compound of Formula (I) is bound to the aluminum containing adjuvant.
2. The immunogenic composition of claim 1 , wherein:
R 1 is C 1 -C 6 alkyl;
R 2 is C 1 -C 6 alkyl;
R 3 is —OL 3 R 7 ;
R 7 is —CF 2 P(O)(OH) 2 , and
L 3 is C 1 -C 6 alkylene.
3. The immunogenic composition of claim 1 , wherein:
R 1 is C 1 -C 6 alkyl;
R 2 is C 1 -C 6 alkyl;
R 3 is —OL 3 R 5 or —OL 3 R 7 ;
R 5 is —P(O)(OH) 2 ;
R 7 is —CF 2 P(O)(OH) 2 ;
L 3 is —((CR 4 R 4 )pO) q (CH 2 )p-;
R 4 is H;
q is 1 or 2, and
p is 2.
4. The immunogenic composition of claim 1 , wherein:
R 1 is -L 2 R 6 ;
R 2 is C 1 -C 6 alkyl;
R 3 is —OL 3 R 7 ;
R 6 is —C(O)OH;
R 7 is —CF 2 P(O)(OH) 2 ;
L 2 is C 1 -C 6 alkylene, and
L 3 is C 1 -C 6 alkylene.
5. The immunogenic composition of claim 1 , wherein:
R 1 is -L 2 R 6 ;
R 2 is C 1 -C 6 alkyl;
R 3 is —OL 3 R 5 or —OL 3 R 7 ;
R 5 is —P(O)(OH) 2 ;
R 6 is —C(O)OH;
R 7 is —CF 2 P(O)(OH) 2 ;
L 2 is C 1 -C 6 alkylene;
L 3 is —((CR 4 R 4 ) p O) q (CH 2 ) p —;
R 4 is H;
q is 1 or 2, and
p is 2.
6. The immunogenic composition of claim 1 , wherein:
R 1 is —C(R 5 ) 2 OH, -L 1 R 5 , -L 2 R 5 or -L 1 R 6 ;
R 2 is C 1 -C 6 alkyl;
R 3 is —OR 8 ;
R 8 is C 1 -C 6 alkyl;
R 5 is —P(O)(OH) 2 ;
R 6 is —CF 2 P(O)(OH) 2 ;
L 1 is —C(O)—, and
L 2 is C 1 -C 6 alkylene or C 2 -C 6 alkenylene, each optionally substituted with 1 to 4 fluoro groups.
7. The immunogenic composition of claim 1 , wherein:
R 1 is C 1 -C 6 alkyl;
R 2 is C 1 -C 6 alkyl;
R 3 is —OL 3 L 4 R 5 , —OL 3 L 4 L 3 R 5 , or —OL 3 L 4 L 3 R 7 ;
R 5 is —P(O)(OH) 2 ;
R 7 is —CF 2 P(O)(OH) 2 ;
each L 3 is independently a C 1 -C 6 alkylene, and
L 4 is phenylene.
8. The immunogenic composition of claim 1 , wherein:
R 1 is C 1 -C 6 alkyl;
R 2 is C 1 -C 6 alkyl;
R 3 is —C(R 5 ) 2 OH or -L 1 R 5 ;
R 5 is —P(O)(OH) 2 , and
L 1 is —C(O)— or —O—.
9. The immunogenic composition of claim 1 , wherein R 8 is methyl.
10. The immunogenic composition of claim 1 , wherein R 1 is methyl.
11. The immunogenic composition of claim 1 , wherein R 2 is methyl.
12. The immunogenic composition of claim 1 , wherein the compound is selected from:
4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutylphosphonic acid;
3-(5-amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid;
3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl) benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid;
4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate;
5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic acid;
3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy) ethoxy)-1,1-difluoropropylphosphonic acid;
2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy) methyl)phenyl)-1,1-difluoroethylphosphonic acid;
2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic acid;
(E)-2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonic acid;
2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic acid;
(E)-2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonic acid;
3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy) methyl)phenylphosphonic acid;
5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonylphosphonic acid;
(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl) (hydroxy)methylenediphosphonic acid;
3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid;
(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)(hydroxy)methylenediphosphonic acid;
3-(5-amino-2-(2-methyl-4-(2-(2-phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7] naphthyridin-8-yl)propanoic acid;
6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexylphosphonic acid;
4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzylphosphonic acid;
2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethylphosphonic acid, and
3-[5-amino-2-(2-{4-[2-(3,3-difluoro-3-phosphonopropoxy)ethoxy]-2-methylphenyl}ethyl)benzo[f]1,7-naphthyridin-8-yl]propanoic acid.
13. The immunogenic composition of claim 1 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
14. The immunogenic composition of claim 1 , wherein the compound is present in an amount effective to enhance an immune response to the antigen in a subject to whom the composition is administered.
15. The immunogenic composition of claim 1 , wherein the antigen is a bacterial antigen.
16. The immunogenic composition of claim 15 , wherein the bacterial antigen is an antigen from Neisseria meningitidis.
17. The immunogenic composition of claim 16 , wherein the antigen is a saccharide.
18. The immunogenic composition of claim 17 , wherein the saccharide is from Neisseria meningitidis serogroup A, W135, Y or C.
19. The immunogenic composition of claim 16 , wherein the antigen is a polypeptide.
20. The immunogenic composition of claim 19 , wherein the polypeptide has at least 85% identity to a sequence selected from the group consisting of SEQ ID NOs: 1-6.
21. The immunogenic composition of claim 1 , wherein the antigen is a viral antigen.
22. The immunogenic composition of claim 21 , wherein the viral antigen is an antigen from respiratory syncytial virus (RSV).
23. The immunogenic composition of claim 22 , wherein the antigen is selected from the group consisting of F, G, M and fusion proteins thereof.
24. The immunogenic composition of claim 1 , further comprising an additional adjuvant.
25. The immunogenic composition of claim 1 , wherein the compound is present in a therapeutically effective amount and is bound to the aluminum-containing adjuvant.
26. The immunogenic composition of claim 1 , wherein the aluminum-containing adjuvant is aluminum oxyhydroxide or aluminum hydroxide.
27. The immunogenic composition of claim 1 , wherein the immunogenic composition is a solid.
28. The immunogenic composition of claim 27 , wherein the immunogenic composition is a lyophilized solid.
29. The immunogenic composition of claim 6 , wherein R 8 is methyl.
30. The immunogenic composition of claim 2 , wherein R 1 is methyl.
31. The immunogenic composition of claim 3 , wherein R 1 is methyl.
32. The immunogenic composition of claim 7 , wherein R 1 is methyl.
33. The immunogenic composition of claim 8 , wherein R 1 is methyl.
34. The immunogenic composition of claim 9 , wherein R 1 is methyl.
35. The immunogenic composition of claim 2 , wherein R 2 is methyl.
36. The immunogenic composition of claim 3 , wherein R 2 is methyl.
37. The immunogenic composition of claim 4 , wherein R 2 is methyl.
38. The immunogenic composition of claim 5 , wherein R 2 is methyl.
39. The immunogenic composition of claim 6 , wherein R 2 is methyl.
40. The immunogenic composition of claim 7 , wherein R 2 is methyl.
41. The immunogenic composition of claim 8 , wherein R 2 is methyl.
42. The immunogenic composition of claim 9 , wherein R 2 is methyl.
43. The immunogenic composition of claim 10 , wherein R 2 is methyl.
44. The immunogenic composition of claim 30 , wherein R 2 is methyl.
45. The immunogenic composition of claim 31 , wherein R 2 is methyl.
46. The immunogenic composition of claim 32 , wherein R 2 is methyl.
47. The immunogenic composition of claim 33 , wherein R 2 is methyl.
48. The immunogenic composition of claim 34 , wherein R 2 is methyl.
49. The immunogenic composition of claim 35 , wherein R 2 is methyl.
50. The immunogenic composition of claim 2 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
51. The immunogenic composition of claim 3 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
52. The immunogenic composition of claim 4 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
53. The immunogenic composition of claim 5 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
54. The immunogenic composition of claim 6 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
55. The immunogenic composition of claim 7 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
56. The immunogenic composition of claim 8 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
57. The immunogenic composition of claim 9 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
58. The immunogenic composition of claim 10 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
59. The immunogenic composition of claim 11 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.
60. The immunogenic composition of claim 12 , wherein the compound is present in an amount sufficient to produce an immunostimulatory effect when administered.