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WO2025155830A1 - Formes cristallines de 3-(7-chloro-1h-indazol-5-yl)-2,5-bis(trifluorométhyl)-3h-imidazo[4,5-b]pyridine et leur utilisation dans le traitement de l'épilepsie - Google Patents

Formes cristallines de 3-(7-chloro-1h-indazol-5-yl)-2,5-bis(trifluorométhyl)-3h-imidazo[4,5-b]pyridine et leur utilisation dans le traitement de l'épilepsie

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Publication number
WO2025155830A1
WO2025155830A1 PCT/US2025/012047 US2025012047W WO2025155830A1 WO 2025155830 A1 WO2025155830 A1 WO 2025155830A1 US 2025012047 W US2025012047 W US 2025012047W WO 2025155830 A1 WO2025155830 A1 WO 2025155830A1
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Prior art keywords
crystalline form
ray powder
powder diffraction
diffraction peaks
angles
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PCT/US2025/012047
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English (en)
Inventor
Gregg F. Keaney
Jun Xu
Lingtao JI
Xin Zhao
Philippe Fernandes
Raymond Rynberg
Tracy EHIWE
Alicia NG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Rapport Therapeutics Inc
Original Assignee
Janssen Pharmaceutica NV
Rapport Therapeutics Inc
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Publication of WO2025155830A1 publication Critical patent/WO2025155830A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • ⁇ -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are tetrameric, glutamate gated transmembrane ion channels which mediate the majority of fast neurotransmission across synaptic gaps.
  • AMPA ⁇ -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • AMPA receptor activity is so ubiquitous within CNS, general antagonism affects most areas of the CNS, resulting in undesired effects, such as ataxia, sedation, and/or dizziness, which are shared by all known general AMPA receptor antagonists.
  • Transmembrane AMPA Receptor Regulatory Proteins are a family of proteins that have been found to associate with and modulate the activity of AMPA receptors. See e.g. Gill and Bredt., Neuropsychopharmacology 201136(1): 362-363.
  • Several TARPs exhibit regiospecific expression in the brain, leading to physiological differentiation of the AMPA receptor activity. For example, TARP ⁇ 2-dependent AMPA receptors are primarily localized in the cerebellum and cerebral cortex while TARP ⁇ 8-dependent AMPA receptors are localized primarily in the hippocampus.
  • 3-(7-chloro-1H-indazol-5-yl)-2,5- bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine is one that has potential as a clinical drug candidate.
  • 1 ME151785720v.1 139260-00120 properties of this compound as well as to facilitate isolation, bolster large-scale manufacturing, and/or promote formulation develop and long-term storage, the need for alternative forms exists.
  • SUMMARY [0006] Provided herein are crystalline forms of 3-(7-chloro-1H-indazol-5-yl)-2,5- bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Form A was found to be the most stable and the preferred crystalline form based on at least the stability and interconversion experiments described in the Exemplification section below.
  • pharmaceutical compositions comprising the described crystalline forms as well as methods for their preparation and uses for treating conditions responsive to the modulation of TARP ⁇ 8-dependent AMPA receptor activity are also included.
  • Figure 1 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form A of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 2 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form B of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 3 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form C of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 4 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form D of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 5 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form E of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 6 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form F of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 7 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form G of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 8 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form H of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 9 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form I of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 10 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form J of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 11 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form L of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • XRPD X-ray powder diffraction pattern
  • Figure 12 depicts an X-ray powder diffraction pattern (XRPD) for crystalline Form M of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine.
  • Figure 46 depicts an X-ray powder diffraction pattern (XRPD) for 3-(7-chloro-1H- indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine prepared as described in WO 2016/176460.
  • XRPD X-ray powder diffraction pattern
  • the XRPD patterns / assignments recited herein are not to be construed as absolute and can vary ⁇ 0.2 degrees. It is well known in the art that this variability will account for the above factors without hindering the unequivocal identification of a crystal form.
  • the 2-theta values provided herein were obtained using Cu K ⁇ 1 radiation. 6 ME151785720v.1 139260-00120 [0063] Temperature values, e.g., for DSC peaks herein may vary slightly from one instrument to another and also depending on variations in sample preparation, batch to batch variation, heating rate of the method, and environmental factors.
  • the crystalline Form A is characterized by an X-ray powder diffraction peak at 2 ⁇ angle 13.7 and at least three additional X-ray powder diffraction peaks at 2 ⁇ angles selected from 12.3, 12.9, 22.0, 24.5, and 25.2. In embodiments, the crystalline Form A is characterized by an X-ray powder diffraction peak at 2 ⁇ angle 13.7 and at least four additional X-ray powder diffraction peaks at 2 ⁇ angles selected from 12.3, 12.9, 22.0, 24.5, and 25.2. In embodiments, the crystalline Form A is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 12.3, 12.9, 13.7, 22.0, 24.5, and 25.2.
  • the crystalline Form H is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 11.7, 14.3, 17.5, 19.5, and 24.8. In embodiments, the crystalline Form H is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 9.7, 11.7, 12.7, 14.3, 17.5, 18.6, 19.5, 22.0, 23.1, and 24.8. In embodiments, the crystalline Form H is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, or at least fourteen X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 8.
  • the crystalline Form H is characterized by an X-ray powder diffraction substantially similar to Figure 8. 15 ME151785720v.1 139260-00120 Table 8 [0087]
  • a crystalline Form I of 3-(7-chloro-1H-indazol- 5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine is provided herein.
  • the crystalline Form I is characterized by at least three X-ray powder diffraction peaks at 2 ⁇ angles selected from 7.9, 10.6, 12.3, 18.6, and 19.0.
  • the crystalline Form L is characterized by an X-ray powder diffraction substantially similar to Figure 11.
  • Table 11 18 ME151785720v.1 139260-00120
  • the crystalline Form M is characterized by at least three X-ray powder diffraction peaks at 2 ⁇ angles selected from 8.8, 17.7, 24.6, 26.6, and 30.8.
  • the crystalline Form M is characterized by at least four X-ray powder diffraction peaks at 2 ⁇ angles selected from 8.8, 17.7, 24.6, 26.6, and 30.8. In embodiments, the crystalline Form M is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 8.8, 17.7, 24.6, 26.6, and 30.8. In embodiments, the crystalline Form M is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 6.7, 8.8, 14.2, 17.7, 20.9, 22.0, 24.6, 25.8, 26.6, and 30.8.
  • the crystalline Form N is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 9.1, 9.4, 18.2, 18.8, and 24.1. In embodiments, the crystalline Form N is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 9.1, 9.4, 14.8, 18.2, 18.8, 19.4, 23.3, 24.1, 27.2, and 29.7. In embodiments, the crystalline Form N is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or at least eleven X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 13.
  • the crystalline Form O is characterized by at least four X-ray powder diffraction peaks at 2 ⁇ angles selected from 11.7, 12.8, 17.6, 19.5, and 25.7. In embodiments, the crystalline Form O is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 11.7, 12.8, 17.6, 19.5, and 25.7. In embodiments, the crystalline Form O is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 9.7, 11.7, 12.8, 17.6, 18.6, 19.5, 22.0, 23.9, 25.7, and 30.1.
  • the crystalline Form O is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or at least thirteen X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 14.
  • the crystalline Form O is characterized by an X-ray powder diffraction substantially similar to Figure 14.
  • Table 14 [0099]
  • the crystalline Form P is characterized by X-ray 21 ME151785720v.1 139260-00120 powder diffraction peaks at 2 ⁇ angles 11.7, 12.9, 14.4, 17.6, 19.8, 22.3, 23.3, 25.1, 25.9, and 30.3.
  • the crystalline Form P is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, or at least sixteen X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 15.
  • the crystalline Form P is characterized by an X-ray powder diffraction substantially similar to Figure 15.
  • Table 15 [00101]
  • the crystalline Form Q is characterized by at least three X- ray powder diffraction peaks at 2 ⁇ angles selected from 11.7, 17.6, 19.8, 24.3, and 25.2.
  • the crystalline Form Q is characterized by at least four X-ray powder diffraction peaks at 2 ⁇ angles selected from 11.7, 17.6, 19.8, 24.3, and 25.2. In embodiments, the crystalline Form Q is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 11.7, 17.6, 19.8, 24.3, and 25.2. In embodiments, the crystalline Form Q is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 11.0, 11.7, 12.9, 16.6, 17.6, 19.8, 24.3, 25.2, 25.9, and 30.4.
  • the crystalline Form Q is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at 22 ME151785720v.1 139260-00120 least ten, at least eleven, at least twelve, at least thirteen, or at least fourteen X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 16.
  • the crystalline Form Q is characterized by an X-ray powder diffraction substantially similar to Figure 16.
  • a crystalline Form R of 3-(7-chloro-1H- indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine is characterized by at least three X-ray powder diffraction peaks at 2 ⁇ angles selected from 5.7, 11.3, 13.4, 17.0, and 28.5. In embodiments, the crystalline Form R is characterized by at least four X-ray powder diffraction peaks at 2 ⁇ angles selected from 5.7, 11.3, 13.4, 17.0, and 28.5.
  • the crystalline Form R is characterized by an X-ray powder diffraction substantially similar to Figure 17. 23 ME151785720v.1 139260-00120 Table 17 [00105]
  • a crystalline Form S of 3-(7-chloro-1H- indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine is provided herein.
  • the crystalline Form S is characterized by at least three X-ray powder diffraction peaks at 2 ⁇ angles selected from 8.2, 10.9, 13.6, 17.1, and 19.1.
  • the crystalline Form S is characterized by at least four X-ray powder diffraction peaks at 2 ⁇ angles selected from 8.2, 10.9, 13.6, 17.1, and 19.1. In embodiments, the crystalline Form S is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 8.2, 10.9, 13.6, 17.1, and 19.1. In embodiments, the crystalline Form S is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 8.2, 10.9, 13.6, 16.4, 17.1, 19.1, 19.5, 21.9, 22.8, and 24.6.
  • the crystalline Form S is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, or at least nineteen X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 18.
  • the crystalline Form S is characterized by an X-ray powder diffraction substantially similar to Figure 18.
  • a crystalline Form U of 3-(7-chloro-1H- indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine is provided herein.
  • the crystalline Form U is characterized by at least three X- ray powder diffraction peaks at 2 ⁇ angles selected from 12.0, 12.6, 21.4, 24.7, and 25.3.
  • the crystalline Form U is characterized by at least four X-ray powder diffraction peaks at 2 ⁇ angles selected from 12.0, 12.6, 21.4, 24.7, and 25.3.
  • the crystalline Form U is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 12.0, 12.6, 21.4, 24.7, and 25.3. In embodiments, the crystalline Form U is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 12.0, 12.6, 16.6, 18.4, 19.5, 20.6.21.4, 23.8, 24.7, and 25.3. In embodiments, the crystalline Form U is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, or at least fourteen X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 19.
  • the crystalline Form W is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 6.7, 7.1, 7.9, 13.5, and 14.2. In embodiments, the crystalline Form W is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 6.7, 7.1, 7.9, 11.4, 13.5, 14.2, 15.7, 17.3, 21.4, and 28.6. In embodiments, the crystalline Form W is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 21.
  • the crystalline Form W is characterized by an X-ray powder diffraction substantially similar to Figure 21.
  • Table 21 27 ME151785720v.1 139260-00120
  • the crystalline Form X is characterized by at least three X- ray powder diffraction peaks at 2 ⁇ angles selected from 7.1, 7.9, 11.0, 14.2, and 24.7.
  • the crystalline Form X is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 22.
  • the crystalline Form X is characterized by an X-ray powder diffraction substantially similar to Figure 22.
  • Table 22 [00115]
  • the crystalline Form Y is characterized by at least three X- ray powder diffraction peaks at 2 ⁇ angles selected from 7.1, 7.4, 7.8, 11.7, or 14.8. In embodiments, the crystalline Form Y is characterized by at least four X-ray powder diffraction peaks at 2 ⁇ angles selected from 7.1, 7.4, 7.8, 11.7, or 14.8. In embodiments, the crystalline Form Y is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 7.1, 7.4, 7.8, 11.7, or 14.8.
  • a crystalline Form Z of 3-(7-chloro-1H- indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine is characterized by at least three X-ray powder diffraction peaks at 2 ⁇ angles selected from 7.6, 8.0, 10.1, 14.2, and 15.9.
  • the crystalline Form Z is characterized by at least four X-ray powder diffraction peaks at 2 ⁇ angles selected from 7.6, 8.0, 10.1, 14.2, and 15.9.
  • the crystalline Form Z is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 7.6, 8.0, 10.1, 14.2, and 15.9. In embodiments, the crystalline Form Z is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 7.6, 8.0, 10.0, 13.2, 14.2, 15.2, 15.9, 19.8, and 30.7. In 29 ME151785720v.1 139260-00120 embodiments, the crystalline Form Z is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 24.
  • the crystalline Form Z is characterized by an X-ray powder diffraction substantially similar to Figure 24.
  • Table 24 [00119]
  • the crystalline Form AA is characterized by at least three X- ray powder diffraction peaks at 2 ⁇ angles selected from 8.1, 10.8, 13.5, 17.0, and 19.0.
  • the crystalline Form AA is characterized by at least four X-ray powder diffraction peaks at 2 ⁇ angles selected from 8.1, 10.8, 13.5, 17.0, and 19.0. In embodiments, the crystalline Form AA is characterized by X-ray powder diffraction peaks at 2 ⁇ angles 8.1, 10.8, 13.5, 17.0, and 19.0. In embodiments, the crystalline Form AA is characterized by X- ray powder diffraction peaks at 2 ⁇ angles 8.1, 10.8, 13.5, 16.2, 17.0, 19.0, 19.4, 21.7, 23.0, and 24.8.
  • the crystalline Form AA is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eighth, at least twenty- nine, or at least thirty X-ray powder diffraction peaks at 2 ⁇ angles selected from those in Table 25.
  • the crystalline Form AA is characterized by an X-ray powder diffraction substantially similar to Figure 25.
  • the crystalline forms and compositions described herein are generally useful for modulating the activity of AMPA receptor.
  • the crystalline forms and compositions described herein are useful in the inhibition of TARP ⁇ 8-dependent AMPA receptor activity.
  • the crystalline forms and compositions described herein are negative AMPA allosteric modulators.
  • the crystalline forms and pharmaceutical compositions described herein are useful in treating a condition associated with AMPA receptor function.
  • the crystalline forms and pharmaceutical compositions described herein are useful in treating a condition associated with TARP ⁇ 8-dependent AMPA receptor function.
  • methods of treating a condition associated with AMPA receptor function or TARP ⁇ 8-dependent AMPA receptor function comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form described herein or a pharmaceutical composition comprising a disclosed crystalline form.
  • a crystalline form described herein, or a pharmaceutical composition comprising a disclosed crystalline form for the manufacture of a medicament for treating a condition associated with AMPA receptor function or TARP ⁇ 8- dependent AMPA receptor function.
  • crystalline form described herein or a pharmaceutical composition comprising a disclosed crystalline form for use in treating a condition associated with AMPA receptor or TARP ⁇ 8-dependent AMPA receptor function.
  • the crystalline forms and pharmaceutical compositions described herein are useful in treating epilepsy, epilepsy disorders, seizures, seizure disorders, pain, a psychiatric disorder, or a neurodegenerative disease in a subject in need thereof.
  • the crystalline forms and pharmaceutical compositions described herein are useful in treating epilepsy or seizures.
  • the crystalline forms and pharmaceutical compositions described herein are useful in treating focal onset epilepsy or focal onset seizures.
  • a crystalline form described herein or a pharmaceutical composition comprising a disclosed crystalline form.
  • a crystalline form described herein, or a pharmaceutical composition comprising a disclosed crystalline form for the manufacture of a medicament for treating pain, a psychiatric disorder, or a neurodegenerative disease.
  • a crystalline form described herein or a pharmaceutical composition comprising a disclosed crystalline form for use in treating pain, bipolar disorder, a psychiatric disease, or a neurodegenerative disease.
  • the epilepsy, epilepsy disorder, seizures, or seizure disorder is focal onset epilepsy or focal onset seizures, absence epilepsy, early infantile developmental end epileptic encephalopathy, childhood absence epilepsy, childhood epilepsy centrotemporal spiked (benign Roland epilepsy), Dravet syndrome, epilepsy eyelid myoclonia je fruits syndrome, epilepsy of infancy with migrating focal seizure, epilepsy myoclonic absences, developmental/epileptic encephalopathy with spike wave activation in sleep, fired febrile infection-related epilepsy syndrome, Hypothalamic hamartoma, indantile spasms (west 32 ME151785720v.1 139260-00120 syndrome), juvenile myoclonic epilepsy, Lennox-Gastaut syndrome (LGS), myoclonic epilepsy in infancy, Panayiotopoulos syndrome, progressive myoclonic epilepsies, Rasmussen’s ence
  • the pain is a neuropathic pain, acute pain, or inflammatory pain.
  • the psychiatric disease is bipolar disorder, acute mania, acute depression, major depressive disorder, or post- traumatic stress disorder (PTSD).
  • the neurodegenerative disease is Alzheimer’s disease.
  • the pharmaceutical compositions are administered orally. [00127] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • Acetone (1V) and purified water (2V) were added to a reaction flask. To this flask was added more acetone (2V) and 3-(7- chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)-3H-imidazo[4,5-b]pyridine, followed by the 0.5V acetone wash of the addition funnel. The reaction mixture was stirred at RT until clear. Afterwards, water (0.75) was added dropwise over ⁇ 30 minutes. Then the reaction mixture was heated to 50 o C and stirred for 3 hour at 50 o C, cooled to RT and stirred at 2 hours at RT.
  • Form B was obtained via anti-solvent addition of starting material in a Toluene/n- Heptane system.
  • the XRPD pattern of Form B is shown in Figure 2.
  • the TGA/DSC curves are shown in Figure 27, which showed a two-step weight loss of 1.59% up to 80 oC and 8.71% from 80 oC to 150 oC and two endotherms at 115.9 and 224.2 oC (peak).
  • Form C [00139] Form C was obtained via slurring Form A in MeOH with temperature cycling (50 oC ⁇ 5 oC, 0.1 oC/min, 2 cycles).
  • the XRPD pattern of Form C is shown in Figure 3.
  • Form J was obtained via a slow cooling of Form A in IPA.
  • the XRPD pattern of Form J is shown in Figure 10.
  • the TGA/DSC curves are shown in Figure 34, which showed a two-step weight loss of 0.71% up to 50 oC and 9.56% from 50 oC to 150 oC and two endotherms at 71.6 and 225.1 oC (peak).
  • 38 ME151785720v.1 139260-00120 Form L [00147] Form L was obtained via a slow cooling of Form A in IPA followed by drying at RT.
  • the XRPD pattern of Form L is shown in Figure 11.
  • Form Q was obtained via slurring Form A in MeOH with temperature cycling (50 oC ⁇ 5 oC, 0.1 oC/min, 2 cycles) followed by drying at RT.
  • the XRPD pattern of Form Q is shown in Figure 16.

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Abstract

L'invention concerne des formes cristallines de of 3-(7-chloro-1H-indazol-5-yl)-2,5-bis(trifluorométhyl)-3H-imidazo[4,5-b]pyridine, des compositions pharmaceutiques comprenant la forme cristalline, et leur utilisation dans le traitement d'états associés à l'activité d'AMPA dépendant de TARP γ8, tels que l'épilepsie, les troubles épileptiques, les crises, les troubles associés aux crises, la douleur, les maladies psychiatriques ou les maladies neurodégénératives.
PCT/US2025/012047 2024-01-17 2025-01-17 Formes cristallines de 3-(7-chloro-1h-indazol-5-yl)-2,5-bis(trifluorométhyl)-3h-imidazo[4,5-b]pyridine et leur utilisation dans le traitement de l'épilepsie Pending WO2025155830A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016176460A1 (fr) 2015-04-29 2016-11-03 Janssen Pharmaceutica Nv Azabenzimidazoles et leur utilisation en tant que modulateurs des récepteurs ampa

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016176460A1 (fr) 2015-04-29 2016-11-03 Janssen Pharmaceutica Nv Azabenzimidazoles et leur utilisation en tant que modulateurs des récepteurs ampa

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GILLBREDT, NEUROPSYCHOPHARMACOLOGY, vol. 36, no. 1, 2011, pages 362 - 363
KNOPP ET AL., J PHARMACAL EXP THER., vol. 369, no. 3, June 2019 (2019-06-01), pages 345 - 363

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