# US 11,897,875 B2 · Deuterated Alpha5 subunit-selective negative allosteric modulators of gamma-aminobutyric acid type a receptors as fast acting treatment for depression and mood disorders > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,897,875 B2 - Document ID: US11897875B2 - Status: Granted - Kind: B2 - Application number: 17/883,734 - Filed: 2022-08-09 - Published: 2022-12-15 - Granted: 2024-02-13 - Earliest claimed: 2017-08-28 - Assignees: University of Maryland, Baltimore; The United States of America, as represented by the Secretary, Department of Health and Human Services - Applicants: University of Maryland, Baltimore; The United States of America, AS Represented By the Secretary, Department of Health and Human Services - Inventors: Scott Thompson; Adam Van Dyke; Craig Thomas; Patrick Morris - Web page: https://patentgrep.com/patent/US11897875B2 ## CPC - C07D 417/14: containing three or more hetero rings - A61K 31/42: Oxazoles - A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl - A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) - A61K 31/541: Non-condensed thiazines containing further heterocyclic rings - A61K 31/5517: condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam - A61P 25/24: Antidepressants - C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms - C07D 413/12: linked by a chain containing hetero atoms as chain links - C07D 413/14: containing three or more hetero rings - A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - C07B 2200/05: Isotopically modified compounds, e.g. labelled - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - 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 - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) ## Abstract The present invention relates to novel alpha5 subunit-selective negative allosteric modulators of GABAA receptors that have been deuterated to improve their medicinal properties by prolonging their half-lives, rendering them useful as fast-acting pharmaceutical treatments for depression related disorders. ## Claims ### Claim 1 A method of treating a depression-related disorder in a human subject in need thereof, comprising administering a therapeutically effective amount of the deuterated GABAA5-NAM compound of Formula Ito the subject: wherein R1, R2, and R3 each independently are H or D, with the proviso that at least one of R1, R2 and R3 is D, and wherein R4 and R5 each independently are H or D. ### Claim 2 (depends on 1) The method of claim 1, wherein the deuterated GABAA5-NAM compound is Formula II: ### Claim 3 (depends on 1) The method of claim 1, wherein the deuterated GABAA5-NAM compound is administered orally, intradermally, intramuscularly, intraperitoneally, intravenously, via insufflation, or in a dermal patch. ### Claim 4 (depends on 1) The method of claim 1, wherein the deuterated GABAA5-NAM compound is administered to the subject every 0.5, 1, 2, 3 or 4 days. ### Claim 5 (depends on 1) The method of claim 1, wherein the deuterated GABAA5-NAM compound is administered to the subject in combination with one or more additional therapies for the treatment or amelioration of depression. ### Claim 6 (depends on 5) The method of claim 5, wherein the one or more additional therapies comprises administration of an antidepressant drug selected from the group consisting of a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a triple reuptake inhibitor, a modulator of CNS acetylcholine function, a stimulant, an anti-glucocorticoids, an NMDA-type glutamate receptor antagonist, a tricylic antidepressants, and any combination thereof. ### Claim 7 (depends on 1) The method of claim 1, wherein the depression-related disorder is selected from the group consisting of general depression, major depressive disorder, dysthymia, suicidality, unipolar depression, bipolar depression, psychotic depression, atypical depression, seasonal affective disorder, premenstrual dysphoric disorder, endogenous depression, catatonic depression, post-traumatic stress disorder, postpartum depression, depression arising from illness or injury, depression arising from drugs or alcohol, treatment resistant depression, and any combination thereof. ### Claim 8 (depends on 1) The method of claim 1, wherein the deuterated GABAA5-NAM compound is selected from the group consisting of (3-(4-fluophenyl)-5-(methyl-d3)isoxazol-4yl)methanol; 6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4yl-methoxy)nicotinonitrile; 6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)nicotinic acid; and (1,1-dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)pyridine-3-yl)methadone. ### Claim 9 (depends on 1) The method of claim 1 wherein the depression-related disorder is one in which the symptoms occur as a secondary consequence of another medical condition. ### Claim 10 (depends on 9) The method of claim 9 wherein the other medical condition is selected from the group consisting of tumor, trauma, substance abuse disorder, and alcoholism.