Vormatrigine

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Vormatrigine

CAS 2392951-18-5

MF C16H12F6N4O2 MW406.28 g/mol

3-(ethoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine

3-[ethoxydi(fluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl][1,2,4]triazolo[4,3-a]pyridine
sodium channel blocker, PRAX-628, PRAX 628, QU3C48T4NV,

Vormatrigine is a small molecule drug. The usage of the INN stem ‘-trigine’ in the name indicates that Vormatrigine is a sodium channel blocker, signal transduction modulator. Vormatrigine has a monoisotopic molecular weight of 406.09 Da.

Vormatrigine (formerly PRAX-628) is an oral, small-molecule, voltage-gated sodium channel inhibitor being developed by Praxis Precision Medicines for focal onset and generalized epilepsy. Phase II RADIANT trial data indicated that 22% of participants achieved complete seizure freedom, with a 56.3% median reduction in seizure frequency. IGMPI +2

Key Aspects of Vormatrigine:

Mechanism: Targets the hyperexcitable state of NaV channels, acting as a functional state modulator.
Efficacy: In the Phase II RADIANT trial (NCT06908356) for focal epilepsy, the drug showed significant seizure reduction (56.3% median reduction), with 60% of participants achieving a $\ge$50% reduction in seizures.
Dosing: Developed for once-daily, oral administration without the need for complex titration.
Safety Profile: Vormatrigine was generally well-tolerated in clinical studies, with mostly mild, transient adverse events reported, as noted in the Phase 1 PRAX-628-102 study.
Future Development: Praxis is moving forward with Phase III trials (POWER2) following the successful Phase II results, with plans to potentially redefine treatment for patients with treatment-resistant focal epilepsy.
Drug-Drug Interactions: Preliminary data suggests a favorable profile with minimal interaction risks, supporting its potential use in polytherapy. Neurology Live +4

The drug is expected to be a major competitor in the epilepsy market if approved, with potential for high sales due to its efficacy profile compared to existing treatments. IGMPI

SYN

WO2019232209A1

Assignee: Praxis Precision Medicines
Title: Pyridin-3-yl substituted triazolopyrazines / triazolopyridines
Year: 2019
Covers:
- Vormatrigine structure (explicitly or as a close analog)
- General synthetic routes
- Multiple heterocycle construction strategies

This is the core patent used by all CRO/CDMO reverse synthesis work.Example ~178

Patent Landscape

The primary patent coverage for Vormatrigine and its related analogs is held by Praxis Precision Medicines, Inc. The chemical structure is a 1,2,4-triazolo[4,3-a]pyridine derivative.

Primary Compound Patent:WO 2020/033839 (and its US equivalent US 11,447,489).
- Title: Preparation of pyridin-3-yl substituted triazolopyrazines, triazolopyridazines, and triazolopyridines as ion channel modulators.
- Scope: This patent covers the specific structure of Vormatrigine (Example 167 in some filings) and its use as a voltage-gated sodium channel (VGSC) inhibitor.
Other Relevant Filings: * WO 2022/173918: Focuses on specific crystalline forms (polymorphs) and manufacturing improvements.
- CN 116444437 / CN 111087324: While these specific numbers often relate to broader triazolopyridine research (like Darolutamide, which you’ve researched previously), Praxis holds several Chinese counterparts for the PRAX-628 series.

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https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023211859&_cid=P22-MN2K59-36761-1

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https://patentscope.wipo.int/search/en/detail.jsf?docId=US320887466&_cid=P22-MN2K59-36761-1

Example 3: 3-[ethoxy(difluoro)methyl]-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridine

Synthesis of A5: A mixture of 6-bromo-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (300 mg, 1.06 mmol) and EtONa (361.37 mg, 5.31 mmol) in Ethanol (10 mL) was stirred at 80° C. for 24 hours. After cooling to room temperature, the reaction was quenched with sat.NH ₄Cl (10 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na ₂SO ₄, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 40%) to give the product (70 mg, 0.17 mmol) as a solid. LCMS R _t=1.97 min in 4 min chromatography, MS ESI calcd. C ₉H ₉BrF ₂N ₃O [M+H+2] ⁺294.0, found 293.8.

Synthesis of Compound 3: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (84.65 mg, 0.26 mmol), Pd(dppf)Cl ₂(26.3 mg, 0.04 mmol), 6-bromo-3-[ethoxy(difluoro)methyl]-[1,2,4]triazolo[4,3-a]pyridine (70 mg, 0.24 mmol) and K ₂CO ₃(66.25 mg, 0.48 mmol) in 1,4-Dioxane (5 mL) and Water (1 mL) was stirred at 90° C. for 16 hours under N ₂. After cooling to room temperature, the mixture was filtered through Celite, and eluted with EtOAc (10 mL×2), and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge 150 mm×25 mm 5 μm) A=H ₂O (10 mM NH ₄HCO ₃) and B=CH ₃CN; 42-62% B over 8 minutes) to give the product (44.33 mg, 0.11 mmol) as a solid. ¹H NMR (400 MHz, DMSO-d ₆) δ _H=8.73 (s, 1H), 8.46 (d, 1H), 8.35 (br d, 1H), 8.11 (d, 1H), 7.96 (d, 1H), 5.18 (q, 2H), 4.29 (q, 2H), 1.36 (t, 3H) LCMS R _t=1.25 min in 2.0 min chromatography, MS ESI calcd. for C ₁₆H ₁₃F ₆N ₄O ₂[M+H] ⁺407.1, found 407.0.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019232209&_cid=P22-MN2K59-36761-1

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