# US 11,299,472 B2 · Fumarate salt of (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2- trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl) urea, methods of preparation, and uses thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,299,472 B2 - Document ID: US11299472B2 - Status: Granted - Kind: B2 - Application number: 16/767,842 - Filed: 2018-12-07 - Published: 2020-09-24 - Granted: 2022-04-12 - Earliest claimed: 2017-12-11 - Assignees: Helsinn Healthcare SA - Applicants: Helsinn Healthcare SA - Inventors: Silvina Garcia Rubio; Mauro Perseghini; Angelo Guainazzi; Claudio Pietra; Claudio Giuliano - Web page: https://patentgrep.com/patent/US11299472B2 ## CPC - C07D 401/12: linked by a chain containing hetero atoms as chain links - A61P 5/06: of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH - A61P 25/30: for treating abuse or dependence - C07B 2200/13: Crystalline forms, e.g. polymorphs - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - 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 Provided are various embodiments relating to fumarate salt of (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl) urea, and methods of producing and using the same to treat conditions and disorders associated with an increase of ghrelin level, such as food abuse, alcohol addiction, and other disorders (e.g., Prader-Willi syndrome). Also provided are various embodiments relating to crystalline HM04 free base, different crystalline forms of HM04 fumarate salt, and methods of producing the same. ## Claims ### Claim 1 A 1:1 (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea:fumarate salt, wherein the salt is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% in crystalline form, and wherein the salt comprises at least one crystalline form chosen from Form 1, Form 2, Form 3, and Form 4. ### Claim 2 (depends on 1) The salt of claim 1 comprising Form 1 having an XRPD pattern substantially similar to the XRPD pattern of FIG. 12 as determined by XRPD using Cu K alpha radiation. ### Claim 3 (depends on 1) The salt of claim 1 comprising Form 2 characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG. 3 as determined by XRPD using Cu K alpha radiation. ### Claim 4 (depends on 1) The salt of claim 1, comprising Form 3 characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG. 15 as determined by XRPD using Cu K alpha radiation. ### Claim 5 (depends on 1) The salt of claim 1, comprising Form 4 characterized by an XRPD pattern substantially similar to the XRPD pattern of FIG. 16 as determined by XRPD using Cu K alpha radiation. ### Claim 6 (depends on 1) The salt of claim 1, comprising Form 1 characterized by an XRPD pattern, using Cu K alpha radiation, comprising peaks at 7.8±0.2, 9.5±0.2, 14.3±0.2, 16.7±0.2, 17.2±0.2, 18.5±0.2, 18.8±0.2, 19.3±0.2, 20.0±0.2, 20.7±0.2, 22.4±0.2, 23.2±0.2, 25.6±0.2, 27.2±0.2, 31.7±0.2, and 32.4±0.2 degrees 2 theta. ### Claim 7 (depends on 1) The salt of claim 1, comprising Form 3 characterized by an XRPD pattern, using Cu K alpha radiation, comprising peaks at 7.2±0.2, 9.4±0.2, 9.7±0.2, 10.8±0.2, 14.3±0.2, 15.1±0.2, 16.2±0.2, 17.9±0.2, 18.7±0.2, 18.9±0.2, 19.6±0.2, 21.5±0.2, 22.7±0.2, 23.7±0.2, 24.3±0.2, 25.1±0.2, 27.4±0.2, 28.7±0.2, and 34.9±0.2 degrees 2 theta. ### Claim 8 (depends on 1) The salt of claim 1 comprising Form 4 characterized by an XRPD pattern, using Cu K alpha radiation, comprising peaks at 12.2±0.2, 13.2±0.2, 15.0±0.2, 15.4±0.2, 17.6±0.2, 18.1±0.2, 19.5±0.2, 20.2±0.2, 20.9±0.2, 21.4±0.2, 23.0±0.2, 23.4±0.2, 24.4±0.2, 24.8±0.2, 25.9±0.2, 27.9±0.2, 28.9±0.2, 29.6±0.2, 30.7±0.2 degrees 2 theta. ### Claim 9 Crystalline (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea having an XRPD pattern substantially similar to the XRPD pattern of FIG. 1A as determined by XRPD using Cu K alpha radiation. ### Claim 10 (depends on 1) A drug product comprising the salt of claim 1. ### Claim 11 (depends on 1) A composition comprising the salt of claim 1. ### Claim 12 (depends on 1) A method of preparing the salt of claim 1 comprising combining (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea with fumaric acid. ### Claim 13 (depends on 12) The method of claim 12, wherein the (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea is in solid form when combined with fumaric acid. ### Claim 14 (depends on 12) The method of claim 12, wherein the (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea is in solution when combined with fumaric acid. ### Claim 15 (depends on 12) The method of claim 12, wherein the (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea is subjected to acid/base extraction prior to being combined with fumaric acid. ### Claim 16 (depends on 12) The method of claim 12, wherein the (R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea is not subjected to an acid/base extraction prior to being combined with fumaric acid. ### Claim 17 (depends on 1) A method of reducing ghrelin signaling activity in a cell comprising exposing the cell to the salt of claim 1. ### Claim 18 (depends on 17) The method of claim 17, wherein the cell is exposed to the salt in vitro. ### Claim 19 (depends on 17) The method of claim 17, wherein the ghrelin signaling activity is measured by level of intracellular calcium as detected by fluorescence imaging plate reader (FLIPR) assay. ### Claim 20 (depends on 1) A method of reducing ghrelin signaling activity in a subject comprising administering to the subject the salt of claim 1. ### Claim 21 (depends on 1) A method of treating a subject having a condition or disorder associated with an increase in ghrelin level, comprising administering to the subject a therapeutically effective amount of the salt of claim 1, wherein the condition or disorder is chosen from food abuse, alcohol addiction, and Prader-Willi syndrome. ### Claim 22 (depends on 21) The method of claim 21, wherein the condition or disorder is chosen from binge eating, obesity, post-dieting body weight rebound, and hyperphagia.