Compounds and compositions as tlr activity modulators
AssigneeNovartis AG
InventorsManmohan Singh, David Skibinski, Simona Cianetti, Francesco Doro, Siddhartha Jain
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Abstract
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.
Claims63
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:
- R1 is H, C1-C6alkyl, —C(R5)2OH, -L1R5, -L1R6, -L2R5, -L2R6, —OL2R5, or —OL2R6;
- L1 is —C(O)— or —O—;
- L2 is C1-C6alkylene, C2-C6alkenylene, arylene, heteroarylene or —((CR4R4)pO)q(CH2)p—, wherein the C1-C6alkylene and C2-C6alkenylene of L2 are optionally substituted with 1 to 4 fluoro groups;
- each L3 is independently selected from C1-C6alkylene and —((CR4R4)pO)q(CH2)p—, wherein the C1-C6alkylene of L3 is optionally substituted with 1 to 4 fluoro groups;
- L4 is arylene or heteroarylene;
- R2 is H or C1-C6alkyl;
- R3 is selected from C1-C4alkyl, -L3R5, -L1R5, -L3R7, -L3L4L3R7, -L3L4R5, -L3L4L3R5, —OL3R5, —OL3R7, —OL3L4R7, —OL3L4L3R7, —OR8, —OL3L4R5, —OL3L4L3R5 and —C(R5)2OH ;
- each R4 is independently selected from H and fluoro;
- R5 is —P(O)(OR9)2,
- R6 is —CF2P(O)(OR9)2 or —C(O)OR10;
- R7 is —CF2P(O)(OR9)2;
- R8 is H or C1-C4alkyl;
- each R9 is independently selected from H and C1-C6alkyl;
- R10 is H or C1-C4alkyl;
- 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 R3 is C1-C4 alkyl or —OR8, R1 is —C(R5)2OH, -L1R5, -L1R6, -L2R5, -L2R6, —OL2R5, or —OL2R6, wherein R6 is —CF2P(O)(OR9)2.
A method for enhancing the effectiveness of an immunogenic composition, the method comprising adding an effective amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein the immunogenic composition comprises an aluminum-containing adjuvant and an antigen, 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:
- R1 is H, C1-C6alkyl, —C(R5)2OH, -L1R5, -L1R6, -L2R5, -L2R6, —OL2R5, or —OL2R6;
- L1 is —C(O)— or —O—;
- L2 is C1-C6alkylene, C2-C6alkenylene, arylene, heteroarylene or —((CR4R4)pO)q(CH2)p—, wherein the C1-C6alkylene and C2-C6alkenylene of L2 are optionally substituted with 1 to 4 fluoro groups;
- each L3 is independently selected from C1-C6alkylene and —((CR4R4)pO)q(CH2)p—, wherein the C1-C6alkylene of L3 is optionally substituted with 1 to 4 fluoro groups;
- L4 is arylene or heteroarylene;
- R2 is H or C1-C6alkyl;
- R3 is selected from C1-C4alkyl, -L3R5, -L1R5, -L3R7, -L3L4L3R7, -L3L4R5, -L3L4L3R5, —OL3R5, —OL3R7, —OL3L4R7, —OL3L4L3R7, —OR8, —OL3L4R5, —OL3L4L3R5 and —C(R5)2OH ;
- each R4 is independently selected from H and fluoro;
- R5 is —P(O)(OR9)2,
- R6 is —CF2P(O)(OR9)2 or —C(O)OR10;
- R7 is —CF2P(O)(OR9)2;
- R8 is H or C1-C4alkyl;
- each R9 is independently selected from H and C1-C6alkyl;
- R10 is H or C1-C4alkyl;
- 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 R3 is C1-C4 alkyl or —OR8, R1 is —C(R5)2OH, -L1R5, -L1R6, -L2R5, -L2R6, —OL2R5, or —OL2R6, wherein R6 is —CF2P(O)(OR9)2.
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Dependencies are inferred from the claim text.