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US-12617794-B2 - GABAA positive allosteric modulator compounds, methods of making, and uses thereof

US12617794B2US 12617794 B2US12617794 B2US 12617794B2US-12617794-B2

Abstract

Described herein are polymorphs comprising 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]tri-azin-7-yl]biphenyl-2-carbonitrile (TPA023B) or salts thereof. In one aspect, disclosed herein is a crystalline polymorphic salt or co-crystal of TPA023B with phosphoric acid. In another aspect, disclosed herein is a crystalline polymorphic salt or co-crystal of TPA023B with sulfuric acid. Also described herein are methods of making and using the same.

Inventors

  • Matthew TOCZKO
  • Jed Hubbs
  • YuXi NING
  • Zheng Jane Li
  • Yunliang HE
  • Xianglei Liu

Assignees

  • NEUROCYCLE THERAPEUTICS, INC.

Dates

Publication Date
20260505
Application Date
20201022

Claims (19)

  1. 1 . A crystalline form of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo [1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with sulfuric acid, wherein the crystalline form has at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern the same as shown in FIG. 61 , when measured using X-Ray wavelength of Cu: K-Alpha; (b) an XRPD pattern having at least three characteristic peak locations, in terms of 2-Theta, selected from 6.1±0.2 degrees, 10.9±0.2 degrees, 11.3±0.2 degrees, 11.8±0.2 degrees, 12.2±0.2 degrees, 13.8±0.2 degrees, 14.8±0.2 degrees, 16.1±0.2 degrees, 16.8±0.2 degrees, 17.3±0.2 degrees, 17.9±0.2 degrees, 18.3±0.2 degrees, 19.2±0.2 degrees, 19.6±0.2 degrees, 21.4±0.2 degrees, 21.8±0.2 degrees, 22.8±0.2 degrees, 23.6±0.2 degrees, 24.4±0.2 degrees, 25.4±0.2 degrees, 27.2±0.2 degrees, 29.9±0.2 degrees, 30.5±0.2 degrees, 31.5±0.2 degrees, 32.6±0.2 degrees, 33.9±0.2 degrees, or 39.1±0.2 degrees when measured using X-Ray wavelength of Cu: K-Alpha; (c) a differential scanning calorimetry (DSC) thermogram the same as shown in FIG. 53 C ; (d) a DSC thermogram with an endothermic peak at about 192° C.; (e) stable for at least 3 days at about 40° C.; or (f) stable for at least 3 days at about 60° C.
  2. 2 . The crystalline form of claim 1 , wherein the crystalline form provides an XRPD pattern having at least three characteristic peak locations, in terms of 2-Theta, selected from 6.1±0.2 degrees, 12.2±0.2 degrees, 16.1±0.2 degrees, 21.8±0.2 degrees, 24.4±0.2 degrees, or 25.4±0.2 degrees, when measured using X-Ray wavelength of Cu: K-Alpha.
  3. 3 . The crystalline form of claim 1 , wherein the crystalline form provides an XRPD pattern having characteristic peak locations, in terms of 2-Theta, of 6.1±0.2 degrees, 12.2±0.2 degrees, and 21.8±0.2 degrees when measured X-Ray wavelength of Cu: K-Alpha.
  4. 4 . The crystalline form of claim 1 , wherein the crystalline form is a salt or a co-crystal.
  5. 5 . A crystalline form of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo [1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile selected from: (i) a salt with hydrochloric acid, wherein the crystalline form has at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern the same as shown in FIG. 63 , when measured using X-Ray wavelength of Cu: K-Alpha; (b) an XRPD pattern having at least three characteristic peak locations, in terms of 2-Theta, selected from 6.3 ±0.2 degrees, 11.7±0.2 degrees, 12.8±0.2 degrees, 14.1±0.2 degrees, 15.1±0.2 degrees, 16.5±0.2 degrees, 17.6±0.2 degrees, 18.8±0.2 degrees, 19.3±0.2 degrees, 20.6±0.2 degrees, 21.8±0.2 degrees, 23.2±0.2 degrees, 24.3±0.2 degrees, 25.7±0.2 degrees, 26.5±0.2 degrees, 26.9±0.2 degrees, 28.5±0.2 degrees, 30.3±0.2 degrees, 32.2±0.2 degrees, 32.7±0.2 degrees, or 33.5±0.2 degrees, when measured using X-Ray wavelength of Cu: K-Alpha; (c) a differential scanning calorimetry (DSC) thermogram substantially the same as one labelled Chloride Form C in FIG. 52 F ; (d) a DSC thermogram with an endothermic peak at about 179° C.; (e) the same XRPD pattern post-storage at 40° C. and 75% RH for at least 3 days; and (f) the same XRPD pattern post-storage at 60° C. and 75% RH for at least 3 days; (ii) a chloride salt, which provides the same XRPD pattern as shown in FIG. 62 ; or (iii) a besylate salt, which provides the same XRPD pattern as an XRPD pattern labelled Besylate Form A shown in FIG. 57 A .
  6. 6 . The crystalline form of claim 5 , wherein the crystalline form provides an XRPD pattern having at least three characteristic peak locations, in terms of 2-Theta, selected from 6.3±0.2 degrees, 11.7±0.2 degrees, 12.8±0.2 degrees, 16.5±0.2 degrees, 17.6±0.2 degrees, or 21.8±0.2 degrees when measured using X-Ray wavelength of Cu: K-Alpha.
  7. 7 . The crystalline form of claim 5 , wherein the crystalline form provides an XRPD pattern having characteristic peak locations, in terms of 2-Theta, of 11.7±0.2 degrees, 12.8±0.2 degrees, and 21.8±0.2 degrees when measured using X-Ray wavelength of Cu: K-Alpha.
  8. 8 . A crystalline polymorph of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile, wherein the crystalline polymorph, which is Form E, provides an XRPD pattern having characteristic peak locations, in terms of 2-Theta, of 7.5±0.2 degrees, 9.6±0.2 degrees, and 10.3±0.2 degrees when measured using X-Ray wavelength of Cu: K-Alpha.
  9. 9 . A crystalline polymorph of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile, wherein the crystalline polymorph, which is Form F, provides an XRPD pattern having characteristic peak locations, in terms of 2-Theta, of 7.7±0.2 degrees, 8.1±0.2 degrees, and 13.1±0.2 degrees when measured using X-Ray wavelength of Cu: K-Alpha.
  10. 10 . A crystalline polymorph of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile, wherein the crystalline polymorph, which is Form G, provides an XRPD pattern having characteristic peak locations, in terms of 2-Theta, of 6.3±0.2 degrees, 8.0±0.2 degrees, and 13.3±0.2 degrees when measured using X-Ray wavelength of Cu: K-Alpha.
  11. 11 . A crystalline polymorph of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile, wherein the crystalline form, which is Form H, provides an XRPD pattern having characteristic peak locations, in terms of 2-Theta, of 7.9±0.2 degrees, 12.7 ±0.2 degrees, and 14.0±0.2 degrees when measured using X-Ray wavelength of Cu: K-Alpha.
  12. 12 . A crystalline form of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo [1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with phosphoric acid, Form J, wherein the crystalline form has at least one of the following properties: a) an XRPD pattern having characteristic peak locations, in terms of 2-Theta, of 6.3±0.2 degrees, 13.2±0.2 degrees, 14.0±0.2 degrees, 15.7±0.2 degrees, 17.0±0.2 degrees, 17.3±0.2 degrees, 18.0±0.2 degrees, 19.0±0.2 degrees, 20.2±0.2 degrees, 20.7±0.2 degrees, and 26.4±0.2 degrees when measured using X-Ray wavelength of Cu: K-Alpha; b) a DSC thermogram with an endothermic peak at about 200° C.; or c) a DSC thermogram with an endothermic peak having an onset temperature at about 197° C.
  13. 13 . The crystalline form of claim 12 , wherein the crystalline form provides an XRPD pattern having characteristic peak locations, in terms of 2-Theta, of 6.3±0.2 degrees, 7.4±0.2 degrees, 10.1 ±0.2 degrees, 12.6±0.2 degrees, 13.2±0.2 degrees, 14.0±0.2 degrees, 15.7±0.2 degrees, 17.0±0.2 degrees, 17.3±0.2 degrees, 18.0±0.2 degrees, 19.0±0.2 degrees, 20.2±0.2 degrees, 20.7±0.2 degrees, 26.4±0.2 degrees, 27.2±0.2 degrees, and 27.5±0.2 degrees, when measured using X-Ray wavelength of Cu: K-Alpha.
  14. 14 . The crystalline form of claim 12 , wherein the crystalline form is a salt or a co-crystal.
  15. 15 . A therapeutic or prophylactic composition comprising the compound of claim 1 .
  16. 16 . A method of treating a condition or a disorder associated with GABA receptors in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 1 to said subject.
  17. 17 . The method of claim 16 , wherein the condition or disorder is associated with a2/a3 GABAA receptor.
  18. 18 . The method of claim 16 , wherein the condition or disorder is selected from: pain, anxiety, epilepsies, muscle spasms, pruritus, itch, cognitive impairment, alcohol dependence, drug addiction, schizophrenia, depression, autism, panic disorder, or generalized anxiety disorder.
  19. 19 . A method of administering a compound to a subject, wherein the compound is the compound of claim 1 .

Description

CROSS-REFERENCE This application is a 371 of International Application No. PCT/US2020/056750 which claims benefit of U.S. Provisional Patent Application No. 62/924,276 filed on Oct. 22, 2019, which is hereby incorporated by reference in its entirety. SUMMARY OF THE INVENTION In one aspect, the present disclosure pertains to salts and polymorphs of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (designated herein as TPA023B), including but not limited to stable polymorphs of the salt of TPA023B with sulfuric acid: Polymorphs of the free base compound are also described. These polymorphs are suitable for use as the active pharmaceutical ingredient of products intended for therapeutic use in mammals, humans or animals, and also as chemical intermediates in the synthesis of active pharmaceutical ingredients. In one aspect, described herein is a crystalline form of 2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile with sulfuric acid, wherein the crystalline form has at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 61, when measured using the parameters described in Table 26-4; (b) an XRPD pattern having characteristic peak locations of at least three of the values selected from the group consisting of: about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees, 2-Theta, when measured using the parameters described in Table 26-4; (c) a differential scanning calorimetry (DSC) thermogram substantially the same as shown in FIG. 53C; (d) a DSC thermogram with an endothermic peak at about 192° C.; (e) stable for at least 3 days at about 40°; and (f) stable for at least 3 days at about 60° C. In some embodiments, the crystalline form provides an XRPD pattern substantially the same as shown in FIG. 61, when measured using the parameters described in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak locations of at least three of the values selected from the group consisting of: about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees, 2-Theta, when measured using the parameters described in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak locations of at least six of the values selected from the group consisting of: about 6.1, 10.9, 11.3, 11.8, 12.2, 13.8, 14.8, 16.1, 16.8, 17.3, 17.9, 18.3, 19.2, 19.6, 21.4, 21.8, 22.8, 23.6, 24.4, 25.4, 27.2, 29.9, 30.5, 31.5, 32.6, 33.9, and 39.1±0.2 degrees, 2-Theta, when measured using the parameters described in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak locations of at least three of the values selected from the group consisting of; about 6.1, 10.9, 12.2, 16.1, 16.8, 21.4, 21.8, 25.4, and 27.2±0.2 degrees, 2-Theta, when measured using the parameters described in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak locations of at least three of the values selected from the group consisting of: about 6.1, 12.2, 16.1, 21.8, 24.4 and 25.4±0.2 degrees, 2-Theta, when measured using the parameters described in Table 26-4. In some embodiments, the crystalline form provides an XRPD pattern having characteristic peak locations of all of the values selected from the group consisting of: about 6.1, 12.2, and 21.8±0.2 degrees, 2-Theta, when measured using the parameters described in Table 26-4. In some embodiments, the crystalline form provides a DSC thermogram substantially the same as shown in FIG. 53C. In some embodiments, the crystalline form provides a DSC thermogram with an endothermic peak at about 192° C. In some embodiments, the crystalline form is stable for at least a month at about 40° C. In some embodiments, the crystalline form is stable for at least a month at about 60° C. In some embodiments, the crystalline form provides substantially the same XRPD pattern post-storage at 40° C. and 75% RH for at least 3 days. In some embodiments, the crystalline form provides substantially the same XRPD pattern post-storage at 40° C. and 75% RH for at least 7 days. In some embodiments, the crystalline form provides substantially the same XRPD pattern post-storage at 60° C. and 75% RH for at least 3 days. In some embodiments, the crystalline form provides substantially the same XRPD pattern post-storage at 60° C. and 75% RH for at least 7 days. In some embodiments, the crystalline form is a salt. In some embodiments, the crystalline form is a co-crystal. In one aspect, described herein is a crystalline form of 2′,6-difluoro-5′-[3-(1-hyd