Small molecule toll-like receptor (TLR) antagonists
AssigneesColey Pharmaceutical Group, Inc., Coley Pharmaceutical GmbH
InventorsGrayson B. Lipford, Alexandra Forsbach, Charles Zepp
Life of this patent
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Abstract
The invention provides methods and compositions useful for modulating signaling through Toll-like receptors. The methods involve contacting a TLR-expressing cell with a small molecule having a core structure including at least two rings. Certain of the compounds are 4-primary amino quinolines. Many of the compounds and methods are useful specifically for inhibiting immune stimulation involving at least one of TLR9, TLR8, TLR7, and TLR3. The methods may have use in the treatment of autoimmunity, inflammation, allergy, asthma, graft rejection, graft versus host disease, infection, sepsis, cancer, and immunodeficiency.
Claims9
A quinazoline compound having a structural formula
- wherein
- X is an aryl or heterocyclic group, provided that if X is a phenyl group, NR1R2 is part of a heterocycle or is a diamine NR13(CH2)nNR14R15, wherein n is an integer from 2 to 6, inclusive, and R13, R14, and R15 are each independently a hydrogen atom or an alkyl group;
- R1 and R2 are each independently a hydrogen atom or an alkyl, alkenyl, alkylamino, or aryl group, wherein R1 and R2 optionally are combined to form a heterocycle;
- Y is a sulfur atom, CR9R10, or NR11, where R9, R10, and R11 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein any one of R9, R10, and R11 optionally is combined with R3 or R4 to form a heterocycle;
- L is an alkyl or alkenyl group containing from 1 to 10 carbons or is an aryl group;
- R3 and R4 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein R3 and R4 optionally are combined to form a heterocycle;
- and
- R5, R6, R7, and R8 are each independently a hydrogen atom, a halogen atom, or an alkyl, alkenyl, aryl, heterocyclic, nitro, cyano, carboxy, ester, ketone, amino, amido, hydroxy, alkoxy, mercapto, thio, sulfoxide, sulfone, or sulfonamido group, wherein any pair of R5, R6, R7, and R8 which are adjacent one another optionally are combined to form a heterocycle or a carbocycle,
- and pharmaceutically acceptable hydrates and salts thereof.
The quinazoline compound having a structural formula
- wherein
- X is absent;
- NR1R2 is N-phenylpiperazine;
- Y is NH;
- L is —CH2CH2;
- R3 and R4 are each a methyl group;
- R6 and R7 are each a methoxy group;
- and
- R5 and R8 are each a hydrogen atom,
- and pharmaceutically acceptable hydrates and salts thereof.
Dependencies are inferred from the claim text.