# US 12,594,286 B2 · Immunodulating small molecules > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,594,286 B2 - Document ID: US12594286B2 - Status: Granted - Kind: B2 - Application number: 17/824,362 - Filed: 2022-05-25 - Published: 2023-01-05 - Granted: 2026-04-07 - Earliest claimed: 2018-07-02 - Assignees: Ayuvis Research, Inc. - Applicants: AyuVis Research, Inc. - Inventors: Suchismita Acharya; Santosh K. Panda - Web page: https://patentgrep.com/patent/US12594286B2 ## CPC - A61K 31/702: Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages - A61K 9/0043: {Nose} - A61K 9/0073: {Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M)} - A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)} - A61K 31/7034: attached to a carbocyclic compound, e.g. phloridzin - A61K 31/7036: having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins - A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} - A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom - A61P 37/02: Immunomodulators - Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change - 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 - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE ## Abstract The present invention includes novel compositions and methods for treating comprising a compound with the Formula I: wherein n=0, 1, 2, 3, 4, or 5; X=NH or O or S; Y=phenyl, or a phenyl group substituted with at least one methyl, a phenyl group substituted with at least one nitro, a phenyl group substituted with at least one nitrogen, a phenyl group substituted with at least one boron, aryl, substituted aryl, heteroaryl, four to six membered cycloalkyl, four to six membered heterocycloalkyl; R=H, C(O)R2, SO2R2; R1=H, C(O)R2, SO2R2; R2=Ethyl, methyl, isopropyl, n-propyl, t-butyl, n-butyl, NH2, NR3R4; R3, R4=Ethyl, methyl, isopropyl, n-propyl, t-butyl, n-butyl, three to six membered cycloalkyl, and Z=NH, or O, or none, and optionally wherein both X and Z are not both S, and wherein the amount of the compound is selected to either inhibit or activate the immune response. ## Claims ### Claim 1 A composition for modulating an immune response, wherein the composition comprises at least one molecule selected from and a pharmaceutically acceptable carrier, excipient, buffer, salt, or combinations thereof wherein an amount of the compound is selected to either inhibit or activate the immune response depending on the amount provided. ### Claim 2 (depends on 1) The composition of claim 1, wherein the compound inhibits the immune response at a first concentration, and activates the immune response at a second concentration, wherein the compound is formulated into a low or a high dose composition comprising: % inhibition % activation Compound Concentration over control over control Number Structure (μM) TLR4 TLR2 TLR4 TLR2 8 1-10 +++ + 75-100 ++ ++ ### Claim 3 (depends on 1) The composition of claim 1, wherein the compound inhibits the immune response at a first concentration, and activates the immune response at a second concentration, wherein the compound is formulated into a low composition comprising: provided in an amount effective to inhibit activation of TLR4, TLR2, or both, wherein the amount is between 1-50 micromolar. ### Claim 4 (depends on 1) The composition of claim 1, wherein the compound inhibits the immune response at a first concentration, and activates the immune response at a second concentration, wherein the compound is formulated into a high dose composition comprising: provided in an amount effective to activate TLR2, wherein the amount is greater than 50 micromolar. ### Claim 5 (depends on 1) The composition of claim 1, wherein the compound inhibits the immune response at a first concentration, and activates the immune response at a second concentration, wherein the compound is formulated into a low or a high dose composition comprising: % inhibition % activation Compound Concentration over control over control Number Structure (μM) TLR4 TLR2 TLR4 TLR2. 17 1-10 75-100 — — ++ +++ ++ 28 1-10 75-100 + ++ 29 1-10 75-100 + ++ + 30 1-10 75-100 + + 35 1-10 75-100 +++ ++ ### Claim 6 (depends on 1) The composition of claim 1, wherein the compound has the formula and is formulated into a composition at a low concentration of between 0.1-50 milligrams/kg to inhibit an immune response. ### Claim 7 (depends on 1) The composition of claim 1, wherein the compound has the formula: and is formulated into a composition formulated at a high concentration greater than 50 milligrams/kg to activate an immune response. ### Claim 8 (depends on 1) The composition of claim 1, wherein the compound is formulated into a composition to activate the immune response as a vaccine adjuvant, antimicrobial, antibacterial, antiviral or immune stimulator, wherein the compound is selected from: ### Claim 9 (depends on 1) The composition of claim 1, wherein the compound is formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, liposomes, polymers, surfactants, buffers, salts, an aerosol, a nebulizer, or an inhaler. ### Claim 10 (depends on 1) The composition of claim 1, wherein the compound is formulated into a pharmaceutical composition for pulmonary, alveolar, enteral, parenteral, intravenous, topical, or oral administration. ### Claim 11 (depends on 1) The compound composition of claim 1, further comprising an additional therapeutic agent selected from the group consisting of corticosteroids, bronchodilators, anticholinergics, vasodilators, diuretics, anti-hypertensive agents, acetazolamide, antibiotics, antivirals, immunosuppressive drugs, and surfactants. ### Claim 12 (depends on 1) The composition of claim 1, wherein the compound is provided in an amount that competitively inhibits inflammation and activates macrophages to protect lung tissue damage or limit lung tissue injury; the compound is provided in an amount that is a TLR4 modulator and upregulates IL-10, the compound is provided in an amount that is a TLR2, TLR4, TLR7 and TLR8 inhibitor and downregulates IL-1β, or the compound is a TLR9 inhibitor and down regulates IFN-α. ### Claim 13 A method of treating a subject in need of immunomodulation comprising: identifying a subject in need of immunomodulation; and providing the subject with an effective amount of a composition comprising a compound selected from at least one of: and a pharmaceutically acceptable carrier, excipient, buffer, salt, or combinations thereof. ### Claim 14 (depends on 13) The method of claim 13, wherein the compound inhibits the immune response at a first concentration, and activates the immune response at a second concentration, wherein the compound is formulated into a low or a high dose composition comprising: % inhibition % activation Compound Concentration over control over control Number Structure (μM) TLR4 TLR2 TLR4 TLR2. 8 1-10 75-100 +++ + ++ ++ ### Claim 15 (depends on 13) The method of claim 13, wherein the compound inhibits the immune response at a first concentration, and activates the immune response at a second concentration, wherein the compound is formulated into a low composition comprising: provided in an amount effective to inhibit activation of TLR4, TLR2, or both, wherein the amount is between 1-50 micromolar. ### Claim 16 (depends on 13) The method of claim 13, wherein the compound inhibits the immune response at a first concentration, and activates the immune response at a second concentration, wherein the compound is formulated into a high dose composition comprising: provided in an amount effective to activate TLR2, wherein the amount is greater than 50 micromolar. ### Claim 17 (depends on 13) The method of claim 13, wherein the compound inhibits a TLR4, a TLR2, or both a TLR2 and TLR4 receptor and has the formula, and concentration below: % inhibition % activation Compound Concentration over control over control Number Structure (μM) TLR4 TLR2 TLR4 TLR2. 1 1 100 +++ +++ 2 1 100 ++ +++ + +++ 3 1 100 ++ +++ ++ +++ 6 1 100 ++ +++ 7 1 100 +++ +++ ++ +++ 8 1 100 +++ + ++ ++ 11 1 100 + + 14 1 100 +++ +++ 23 1 100 + + + ++ 32 1 100 +++ +++ +++ + 35 1 100 +++ ++ 38 1 100 ++ + 39 1 100 + 40 1 100 + ### Claim 18 (depends on 13) The method of claim 13, wherein the compound inhibits the immune response at a first concentration, and activates the immune response at a second concentration, comprising, and the composition is formulated into a low or a high dose: % inhibition % activation Compound Concentration over control over control Number Structure (μM) TLR4 TLR2 TLR4 TLR2 17 1 100 ++ +++ ++ 28 1 100 + ++ 29 1 100 + ++ + 30 1 100 + + 35 1 100 +++ ++ ### Claim 19 (depends on 13) The method of claim 13, wherein the compound has the formula and is formulated into a composition formulated at a low concentration of between 0.1-50 milligrams/kg to inhibit an immune response. ### Claim 20 (depends on 13) The method of claim 13, wherein the compound has the formula: and is formulated into a composition formulated at a high concentration greater than 50 milligrams/kg to activate an immune response. ### Claim 21 (depends on 13) The method of claim 13, wherein the compound is provided in an amount sufficient to treat hyperinflammation-lung injury, irritable bowel disease, sepsis, fibrosis, retinopathy, neuropathy, neuroinflammatory diseases, acute kidney injury, necrotizing enterocolitis, and inflammatory bowel disease and is provided at a low concentration to inhibit an immune response, wherein the compound is selected from: ### Claim 22 (depends on 13) The method of claim 13, wherein the compound is formulated into a composition to activate the immune response as a vaccine adjuvant, antimicrobial, or immune stimulator, wherein the compound is selected from: ### Claim 23 (depends on 13) The method of claim 13, wherein the compound is formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, liposomes, polymers, surfactants, buffers, salts, an aerosol, a nebulizer, or an inhaler. ### Claim 24 (depends on 13) The method of claim 13, wherein the compound is formulated into a pharmaceutical composition adapted for pulmonary, alveolar, enteral, parenteral, intravenous, topical, or oral administration. ### Claim 25 (depends on 13) The method of claim 13, further comprising adding an additional therapeutic agent selected from at least one of: corticosteroids, bronchodilators, anticholinergics, vasodilators, diuretics, anti-hypertensive agents, acetazolamide, antibiotics, supplemental oxygen, or immunosuppressive drugs. ### Claim 26 (depends on 13) The method of claim 13, further comprising providing the compound in an amount that competitively inhibits inflammation and activates macrophages to protect lung tissue damage or limit lung tissue injury. ### Claim 27 (depends on 13) The method of claim 13, further comprising identifying that the subject has a pulmonary disorder selected from Acute Respiratory Distress Syndrome (ARDS), Adult Respiratory Distress Syndrome (Adult RDS), hyperoxic lung injury, or Bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), exacerbated COPD, Cystic Fibrosis, Asthma, severe Asthma, exacerbated Asthma, allergic Asthma, Acute lung injury, Idiopathic pulmonary fibrosis, Airway remodeling, or Bronchiolitis obliterans syndrome, or the subject is a premature infant born at an age of about 24 to about 32 weeks gestation, an infant and the weight of the infant at birth is about 1500 grams or less, an infant and the weight of the infant at birth is about 1000 grams or less, or an infant and the at least one additional agent or therapy is selected from the group consisting of oxygen therapy, ventilator therapy, and a bronchodilator. ### Claim 28 (depends on 13) The method of claim 13, wherein the compound is a TLR4 inhibitor and upregulates IL-10, the compound is a TLR7/8/9 inhibitor at low concentration and TLR7/8activator at high concentration, the compound is a TLR6 activator, the compound inhibits cancer cell proliferation and induces cancer cell death, the compound inhibits angiogenesis, or the compound is provided in an amount sufficient to competitively inhibit inflammation and angiogenesis and protect from ocular angiogenesis related injury. ### Claim 29 A compound selected from: ### Claim 30 (depends on 29) A composition comprising the compound of claim 29, wherein the compound is formulated into a composition that comprises an amount sufficient to at least one of: treat hyperinflammation-lung injury, irritable bowel disease, sepsis, fibrosis, retinopathy, neuropathy, neuroinflammatory diseases, acute kidney injury, necrotizing enterocolitis, or inflammatory bowel disease, and is provided at a concentration that inhibits an immune response.