# US 2025/0367166 A1 · Next generation diprovocims that activate the innate and adaptive immune response > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2025/0367166 A1 - Document ID: US20250367166A1 - Status: Published application - Kind: A1 - Application number: 18/859,673 - Filed: 2023-04-27 - Published: 2025-12-04 - Earliest claimed: 2022-04-29 - Assignees: The Scripps Research Institute; Board of Regents, The University of Texas System - Applicants: The Scripps Research Institute; The Board of Regents of the University of Texas System - Inventors: Dale L. Boger; Bruce Beutler - Web page: https://patentgrep.com/patent/US20250367166A1 ## CPC - A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim - A61P 35/00: Antineoplastic agents - C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract The present invention contemplates new members of the diprovocim family of compounds that exhibit improvements in both potency and efficacy in the murine system, permitting more effective use in vivo in animal models while maintaining the remarkable activity agonist towards human TLR1/TLR2. The prototypical new agonist called diprovocim-X exhibits the same excellent potency and efficacy of diprovocim-1 in human THP-1 cells (EC50 of 140 pM vs 110 pM with efficacy 100% that of diprovocim-1 and Pam3CSK4), and displays a superb EC50 of 750 pM in mouse macrophages with an efficacy 550% that of diprovocim-1. Diprovocim-X served as an adjuvant in vivo in mice when co-administrated with a non-immunogenic antigen (OVA), indicating stimulation of the adaptive immune response. These the new diprovocim family compounds are now functionalized for linkage to antigenic, targeting, or delivery moieties, properties to enable precision activation of coordinated innate and adaptive immune responses in target tissues. ## Claims ### Claim 1 A compound of Formula I, wherein R1, R2 and R3 are the same or different and are a trans-2-phenylcyclopropyl, or a trans-2-(4-fluorophenyl)cyclopropyl group, and R4 is a composite of (a) a hydrocarbyl group bonded to the depicted amido nitrogen atom and (b) a substituent group bonded thereto as discussed below, the hydrocarbyl group has a longest chain of atoms that has a total length that is about that of a saturated chain of about 2 carbon atoms (an ethylene group), and a length that is less than that of a saturated chain of about 20 carbon atoms [an eicosylene group], said hydrocarbyl group including a methylene group (—CH2—) that is 1) bonded directly to or 2) bonded indirectly and distal to the amido nitrogen of the depicted —C(O)NH—R4 group, and said methylene group is also bonded to a substituent group that is one or another of i) a phenyl group that includes a substituent selected from the group consisting of a hydroxyl, amino, carboxy, C1-C6 alkyl carboxylate, sulfo, C1-C6 alkyl sulfonate, fluoro, azido and an ethynyl group, ii) a hydroxyl, a mercaptan, amine, mono- or disubstituted amine, an azido group or iii) to an oxygen, nitrogen or sulfur atom that is part of a substituent group that is selected from the group consisting of an amino acid, ether, ester, carbonate, carbamate, thioether, thioester, thiourea, amido, mono- or disubstituted amide, urea, and a N′-mono or N′,N′-disubstituted urea, wherein said substituent group contains a chain of atoms that include zero to four oxygens, zero to two sulfur atoms, and zero to four nitrogen atoms, with the proviso that the sum of the sulfur, nitrogen and oxygen atoms in the substituent is at least one, and not greater than eight, and the length of said hydrocarbyl group together with the substituent bonded to said methylene of that hydrocarbyl group is less than that of a saturated chain of about 24 carbon atoms [a tetracosylene group]. ### Claim 2 (depends on 1) The compound according to claim 1, wherein each depicted pyrrolidinyldicarboxamido group has the (S,S) configuration. ### Claim 3 (depends on 2) The compound according to claim 2, wherein bonds to the cyclopropyl moiety have a (1S,2R) configuration. ### Claim 4 (depends on 2) The compound according to claim 2, wherein and said compound has the structural Formula Ia, and wherein the R1-4 moieties are as described above ### Claim 5 (depends on 4) The compound according to claim 4 that is a single enantiomer. ### Claim 6 (depends on 1) A pharmaceutical composition comprising a concentration of a compound of claim 1 effective to induce release of TNF-α from one or both of in vitro cultured human PMA differentiated THP-1 cells and or mouse macrophages, said compound being dissolved or dispersed in a physiologically tolerable diluent. ### Claim 7 (depends on 6) The pharmaceutical composition according to claim 6, wherein said compound is a single enantiomer. ### Claim 8 (depends on 1) The compound according to claim 1, wherein said hydrocarbyl group of said composite R4 has a saturated chain length of about 6 to about 16 carbon atoms. ### Claim 9 (depends on 1) The compound according to claim 1, wherein said substituent group bonded to said R4 hydrocarbyl group is bonded to a methylene group that is bonded indirectly and distal to the amido nitrogen of the depicted —C(O)NH—R4 group. ### Claim 10 (depends on 8) The compound according to claim 8, wherein said methylene group is also bonded to a phenyl group that includes a substituent selected from the group consisting of a hydroxyl, amino, carboxy, C1-C6 alkyl carboxylate, sulfo, C1-C6 alkyl sulfonate, fluoro, azido and an ethynyl group. ### Claim 11 (depends on 8) The compound according to claim 8, wherein said methylene group is also bonded to a phenyl group that includes a substituent selected from the group consisting of a hydroxyl, a mercaptan, amine, mono- or disubstituted amine, and an azido group. ### Claim 12 (depends on 8) The compound according to claim 8, wherein said methylene group is also bonded to a to an oxygen, nitrogen or sulfur atom that is part of a substituent group that is selected from the group consisting of an ether, ester, carbonate, carbamate, thioether, thioester, thiourea, amido, mono- or disubstituted amide, urea, and a N′-mono or N′,N′-disubstituted urea, wherein said substituent group contains a chain of atoms that include zero to four oxygens, zero to two sulfur atoms, and zero to four nitrogen atoms, with the proviso that the sum of the sulfur, nitrogen and oxygen atoms in the substituent is at least one, and not greater than eight. ### Claim 13 (depends on 8) The compound according to claim 8, wherein said methylene group is also bonded to an oxygen atom of a carboxylic acid ester. ### Claim 14 (depends on 13) The compound according to claim 13, wherein said carboxylic acid ester is a glycine ester. ### Claim 15 (depends on 14) The compound according to claim 14, wherein said glycine ester is a Boc-protected glycine ester. ### Claim 16 (depends on 15) The compound according to claim 15, wherein said hydrocarbyl group of said composite R4 has a saturated chain length of about 10 to about 14 carbon atoms. ### Claim 17 (depends on 1) A method of enhancing an immunogen-specific IgG humoral immune response titer that comprises contacting immune cells with composition containing an adjuvant-effective amount of a compound of claim 1 and an immunogen to which said response is to be enhanced that are dissolved or dispersed in a physiologically tolerable diluent, wherein the enhancement in IgG titer is about 2 to about 4 times the titer observed due to the same amount of immunogen dissolved or dispersed said a physiologically tolerable diluent in the absence of said compound, and said titers are measured 14 days after said immune cell contact. ### Claim 18 (depends on 17) The method according to claim 17, wherein said cells are contacted in vivo. ### Claim 19 (depends on 18) The method according to claim 18, wherein said compound is a single enantiomer.