Alkyl chain modified imidazoquinoline TLR7/8 agonist compounds and uses thereof
Inventors
Chipman, Stewart D. • DeMattei, John • Kiwan, Radwan • KACHURA, Melissa A.
Assignees
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Publication Number
US-10618896-B2
Publication Date
2020-04-14
Expiration Date
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 document discloses alkyl chain-modified 1H-imidazo[4,5-c]quinoline compounds and pharmaceutically acceptable salts thereof. The compounds are defined by a specified core chemical formula with variable substituents including R0 long alkyl/hydrocarbyl, RA cycloalkyl optionally substituted with defined groups, X as —NH—, and further substituent options R1, R2, R3, and R4a/R4b, with discrete constraints on m, z, and q.
The compounds are described as dual TLR7/8 agonists with balanced bioactivity. The disclosure frames the invention to enhance immune responses while improving retention at the injection site and increasing hydrophobicity, with the aim of reducing systemic toxicities compared to previously described soluble imidazoquinoline TLR agonists.
The document discloses pharmaceutical compositions including the compounds, optionally with antigen, and provides example formulations including oil-in-water nanoemulsions based on squalene and liposomal formulations. The disclosed compositions are used for stimulating local or systemic immune responses and therapeutic use for cancer, infectious disease, and IgE-related disorders, including use as part of kits.
Claims Coverage
The claim coverage centers on one structurally defined independent claim for an alkyl chain-modified 1H-imidazo[4,5-c]quinoline compound or salt, with bounded substituent definitions and integer constraints. Dependent claims narrow the structure by selecting specific substituent options, restricting coverage to enumerated compound numbers, and extending the scope to pharmaceutical compositions containing a pharmaceutically acceptable excipient.
Alkyl chain-modified 1H-imidazo[4,5-c]quinoline compound class
A compound of the specified formula, or a salt thereof, with variable substituents R0, RA, X, R1, R2, R3, and R4a/R4b, and discrete constraints on m, z, and q.
Substituent pattern with cycloalkyl RA and amino-linked R2
RA is C3-C8 cycloalkyl optionally substituted by 1 to 4 groups independently selected from C1-C4 alkyl, C1-C4 alkylene, and halogen; R1 is C3-C6 alkyl, —(CH2)pOR1a, —(CH2)pNHR1b, or —(CH2)pR1c; R2 is NHR2a with R2a selected from H, OH, NH2, or methyl.
Additional variable-group definitions and integer limits
Each R3 is independently halogen, C1-C8 alkyl, —(C1-C7 alkylene)-NH2, or —CH2-phenylene-CH2NH2; R4a and R4b are independently H or C1-C8 alkyl; m is 0, 1, 2, or 3; z is 1 or 2; and q is 0, 1, 2, 3, or 4.
Selected enumerated compound members
Coverage includes compounds identified as Compound No. 63-33, 63-35, 63-36, and 63-38 to 63-49.
Pharmaceutical composition with excipient
A pharmaceutical composition containing the defined compound or a salt thereof together with a pharmaceutically acceptable excipient.
The claim set defines a chemically bounded class of alkyl chain-modified 1H-imidazo[4,5-c]quinoline compounds, narrows that class through selected substituent and integer constraints, identifies specific enumerated compounds, and includes pharmaceutical composition coverage with a pharmaceutically acceptable excipient.
Stated Advantages
Improved oil-based, injection-site retention associated with increased hydrophobicity.
Balanced dual TLR7 and TLR8 agonism.
Enhances immune responses.
Reduces systemic toxicities compared to soluble imidazoquinoline TLR agonists.
Immune response stimulation described through cytokine kinetics and immune stimulation endpoints.
Anti-tumor activity described, including tumor growth inhibition in a model described as CT26 colon carcinoma.
Documented Applications
Pharmaceutical compositions for immune stimulation by targeting TLR7/8 agonism.
Optional co-formulation with antigens, including protein antigen and polysaccharide antigen, where the antigen is described as a microbial antigen, allergen, or tumor antigen.
Administration by parenteral and intratumoral delivery.
Anti-tumor use, including tumor growth inhibition using a model described as CT26 colon carcinoma.
Combination with anti-PD-1 checkpoint inhibition for anti-tumor evaluation.
Methods for stimulating local or systemic immune responses.
Therapeutic use for cancer.
Therapeutic use for infectious disease.
Therapeutic use for IgE-related disorders.
Use as part of kits.
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