Alkyl chain modified imidazoquinoline TLR7/8 agonist compounds and uses thereof

Inventors

Chipman, Stewart D. • Kiwan, Radwan • KACHURA, Melissa A. • Coffman, Robert

Assignees

Dynavax Technologies Corp

Abstract

Disclosed are alkyl chain modified 1H-imidazoquinoline compounds, derivatives and analogs thereof, as Toll-like receptor-7 and -8 agonists for enhancing immune responses. Also provided are methods of making pharmaceutical compositions containing these compounds. The present disclosure also describes methods of use for the alkyl chain modified 1H-imidazoquinoline compounds, derivatives and analogs thereof, and pharmaceutical compositions containing these compounds for the treatment of disease in a subject.

Core Innovation

The disclosure relates to imidazo[4,5-c]quinoline derivatives, including alkyl chain-modified 1H-imidazo[4,5-c]quinoline compounds and compounds of formula (J), formula (K), and formula (K-2), with structural variation at the benzylamine position and related alkyl-chain modified substituents. The compounds are characterized by a defined 1H-imidazo[4,5-c]quinoline framework with constrained variables, including X being —NH— and specified options for m, z, R0, RA, R1, R2, R3, q, and R4a/R4b, together with representative cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, linear alkyl-chain, and amide derivatives.

The disclosure presents pharmaceutical compositions containing a compound of formula (J), or a salt thereof, together with a pharmaceutically acceptable excipient, and includes optional antigen co-formulation. The compounds are associated with dual TLR7/8 agonist activity and TLR7/8 agonist activity, including balanced dual TLR7/8 agonist activity, cytokine induction, dendritic cell activation, and immune response stimulation.

The compounds and compositions are framed as supporting improved physiochemical properties and increased hydrophobicity, with local retention after injection and oil-based retention at the injection site. The disclosure also links the compounds to antigen-specific antibody response and/or antigen-specific T cell response, serum cytokine kinetics, tumor growth inhibition, and intratumoral administration, and includes preparation methods, scheme references, and structure-and-exclusion frameworks.

Claims Coverage

The independent claims cover administration of a pharmaceutical composition containing a compound of formula (J), or a salt thereof, together with a pharmaceutically acceptable excipient. Across the input items, two independent inventive features are consistently present: stimulating an immune response in a mammalian subject, and inducing an antigen-specific antibody response and/or an antigen-specific T cell response in a mammalian subject, both defined by the formula (J) structural constraints.

The independent claims are directed to administration of a pharmaceutical composition containing a compound of formula (J), or a salt thereof, with a pharmaceutically acceptable excipient, where the structure is defined by constrained substituent variables. The claims differ in the immune outcome endpoint: one is directed to stimulating an immune response, and the other to inducing antigen-specific antibody and/or T cell responses.

Stated Advantages

Documented Applications