Veonetinib

 

Veonetinib

👉CAS 1210828-09-3

MF C27H28FN3O4 MW 477.5 g/mol

5-[2-[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxyethyl]-5-azaspiro[2.4]heptan-7-ol

5-AZASPIRO(2.4)HEPTAN-7-OL, 5-(2-((4-((4-FLUORO-2-METHYL-1H-INDOL-5-YL)OXY)-6-METHOXY-7-QUINOLINYL)OXY)ETHYL)-

5-(2-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol

(7RS)-5-[2-({4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin7-yl}oxy)ethyl]-5-azaspiro[2.4]heptan-7-ol
tyrosine kinase inhibitor, antineoplastic, U7PA8S6XGJ

👉SYN

[WO2010021918]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010021918&_cid=P21-MN159E-69738-1

Example 3

5-(2-(4-(4-fluoro-2-methyl-lH-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol

The above product from Example 2 (75 mg) was dissolved into MeOH (8 ml) and stirred at RT.

NaBH₄ (75 mg) was added to the reaction and stirred at RT for 30 min. The reaction was evaporated and purified by column chromatography to give title compound (60 mg). Mass: (M + 1), 478

Patent Scope

• Covers:
  • Quinoline–indole kinase inhibitors
  • VEGFR / angiogenesis targets
  • Broad Markush structures

Fragment A: Indole Phenol

4-fluoro-2-methyl-1H-indol-5-ol

Typical Preparation

1. Fischer indole synthesis or substituted aniline cyclization
2. Fluorination / directed substitution
3. Hydroxyl introduction at C-5

---

Fragment B: Quinoline Electrophile

4-chloro-6-methoxy-7-(leaving group) quinoline

Typical Route

1. Start from 6-methoxyaniline
2. Skraup / Doebner–Miller → quinoline core
3. Chlorination at C-4
4. Functionalization at C-7 (OH or halide)

---

Fragment C: Chiral Spiro Amine

(R)-5-azaspiro[2.4]heptan-7-ol

• Usually from:
  • Chiral pool OR
  • Resolution of racemate
• Important: defines final stereochemistry

---

4. STEP-BY-STEP SYNTHESIS (PATENT-ALIGNED)

Step 1: Indole–Quinoline Ether Formation

Reaction: SNAr / Ullmann-type coupling

Indole phenol + 4-chloroquinoline → aryl ether

Conditions

• Base: K2CO3 / Cs2CO3
• Solvent: DMF / DMSO
• Temp: 80–120°C

Forms:
Indole–O–quinoline core

---

Step 2: Introduction of Linker (C-7 substitution)

If quinoline has OH:

Quinoline–OH + Br–CH2–CH2–X → O–CH2CH2–X

If halide:Direct alkylation

Conditions

• Base: NaH / K2CO3
• Solvent: DMF
• Temp: 50–90°C

Product:
Quinoline–O–CH2CH2–X

---

Step 3: Coupling with Spiro Amine

Quinoline–O–CH2CH2–X + spiro amine → final amine linkage

Reaction Type

• SN2 substitution

Conditions

• Base: DIPEA / Et3N
• Solvent: ACN / DMF
• Temp: 50–80°C

---

Step 4: Final Deprotection / Purification

• Remove protecting groups (if any)
• Chiral purity control
• Crystallization

Step 1: Preparation of Indole–Quinoline Ether

Starting materials:

• 4-fluoro-2-methyl-1H-indol-5-ol
  → 1.00 equiv (e.g., 5.0 g, ~30 mmol)
• 4-chloro-6-methoxyquinoline
  → 1.10 equiv (~33 mmol)

Reagents:

• Potassium carbonate (K₂CO₃) → 2.0 equiv (~60 mmol)
• Solvent: DMF (50–60 mL)

Procedure:

1. Charge indole phenol and K₂CO₃ in DMF under nitrogen.
2. Add 4-chloroquinoline portionwise.
3. Heat to 100–110°C.
4. Stir for 8–12 h.

Workup:

• Cool to RT
• Pour into water (200 mL)
• Extract with EtOAc (3×)
• Wash with brine, dry (Na₂SO₄)
• Concentrate

Purification:

• Silica gel chromatography (EtOAc/hexane)

Yield: ~70–80%
Product: Indole–quinoline ether intermediate

---

Step 2: Installation of Ethylene Linker

Starting material: Step 1 product (~25 mmol)

Reagents:

• 1,2-dibromoethane → 1.5–2.0 equiv
• Base: K₂CO₃ → 2 equiv
• Solvent: DMF (40 mL)

Procedure:

1. Dissolve intermediate in DMF
2. Add K₂CO₃
3. Add dibromoethane
4. Heat to 80–90°C for 6–8 h

Workup:

• Pour into water
• Extract with EtOAc
• Dry and concentrate

Product: Quinoline–O–CH₂CH₂–Br

Yield: ~65–75%

---

Step 3: Coupling with Chiral Spiro Amine

Starting materials:

• Bromo intermediate → 1.0 equiv (~15–20 mmol)
• (R)-5-azaspiro[2.4]heptan-7-ol → 1.2 equiv

Reagents:

• DIPEA or Et₃N → 2 equiv
• Solvent: Acetonitrile or DMF (30–40 mL)

Procedure:

1. Combine bromo intermediate and amine in solvent
2. Add DIPEA
3. Heat to 60–70°C
4. Stir 12–16 h

Workup:

• Remove solvent
• Dissolve in EtOAc
• Wash with water + brine
• Dry and concentrate

Yield: ~70–85%

---

Step 4: Final Purification

Purification options:

• Silica chromatography OR
• Recrystallization (EtOAc/hexane or IPA)

Optional:

• Convert to pharmaceutically acceptable salt

Final Yield (overall): ~35–45%

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US43556759&_cid=P21-MN152D-66699-1

EXAMPLE 1

4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(5,8-Dioxa-10-azadispiro[2.0.4.3]-undecane)ethoxy]quinoline

Preparation of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline

Method A:

4-Chloro-7-benzyloxy-6-methoxy-quinoline (WO2008112407, 1.5 g) was mixed with DMAP (1.5 eq), 2-methyl-4-fluoro-5-hydroxyindole (WO0047212) (1 eq) in dioxane (20 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (600 mg).

Method B:

4-Chloro-7-benzyloxy-6-methoxy-quinoline (WO2008112407, 1.5 g) was mixed with 3-(2,2-dimethoxypropyl)-2-fluoro-4-nitrophenol (WO0047212) (1.5 eq) in dioxane (30 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 7-(benzyloxy)-4-(3-(2,2-dimethoxypropyl)-2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (650 mg). This product was mixed with 2NHCl (3 ml) and acetone (30 ml) and refluxed for 6 hours. The reaction was diluted with EtOAc and neutralized with saturated NaHCO 3, further extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 1-(3-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-2-fluoro-6-nitrophenyl)propan-2-one (500 mg) which was mixed with iron (500 mg) and NH 4Cl (50 mg) in EtOH/H 2O (20 ml, 4/1). The reaction was refluxed for 4 hours, filter through Celite and evaporated. The residue was extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (250 mg).

4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (600 mg) was mixed with HCONH 4 (600 mg) and Pd/C (10%, 100 mg) followed by refluxing 30 min. The reaction was filtered while it was hot and the filtrate was evaporated and washed with water followed by filtration to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline (400 mg).

Preparation of Title Compound

Method C:

4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline (400 mg) was mixed with 1,2-dibromoethane (2 eq) and K 2CO 3 (2 eq) in DMF (5 ml). The reaction was heated at 100° C. for 5 hours and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column. The product was mixed with NaI (250 mg) in acetonitrile (15 ml) and refluxed for 30 min. The reaction was cooled, DIPEA (500 μL) and 5,8-Dioxa-10-azadispiro[2.0.4.3]-undecane (300 mg) were added into the reaction which was refluxed overnight. The reaction was diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give title compound (150 mg). Mass: (M+1), 520

Method D:

4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline (400 mg) was mixed with 2-bromo-1,1-dimethoxyethane (2 eq) and K 2CO 3 (2 eq) in DMF (5 ml). The reaction was heated at 100° C. for 8 hours and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column. The product was mixed with 1NHCl (2 ml) in EtOH (10 ml) and refluxed for 5 hours. The reaction was evaporated and neutralized with saturated NaHCO 3, further extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give the aldehye adduct (400 mg) which was mixed with 5,8-Dioxa-10-azadispiro[2.0.4.3]-undecane (200 mg) with NaBH(OAc)3 (2 eg) in DCM (10 ml). The reaction was stirred at RT for 2 hours then diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column give title compound (250 mg). Mass: (M+1), 520,

EXAMPLE 2

5-(2-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-one

The above product from Example 1 (100 mg) was mixed with 1N HCl (4 ml) and acetone (20 ml). The reaction was refluxed overnight and evaporated. The solution was basified with 2N NaOH and extracted with EtOAc. The combined organic layer was washed with H 2O followed by brine, dried over Na 2SO 4 and evaporated. The residue was purified by column chromatography to give title compound (75 mg). Mass: (M+1), 476

EXAMPLE 3

5-(2-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol

The above product from Example 2 (75 mg) was dissolved into MeOH (8 ml) and stirred at RT. NaBH 4 (75 mg) was added to the reaction and stirred at RT for 30 min. The reaction was evaporated and purified by column chromatography to give title compound (60 mg). Mass: (M+1), 478

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023239945&_cid=P21-MN15DA-71816-1

PAT

CN201710900497.6 CN201610649732.2 → leads to US10689361B2

PAT

• Compounds as kinase inhibitorsPublication Number: CA-2733250-CPriority Date: 2008-08-19Grant Date: 2016-06-21
• Compounds that act as kinase inhibitorsPublication Number: ES-2617678-T3Priority Date: 2008-08-19Grant Date: 2017-06-19
• Compounds as kinase inhibitorsPublication Number: WO-2010021918-A1Priority Date: 2008-08-19
• Compounds as kinase inhibitorsPublication Number: EP-2312950-A1Priority Date: 2008-08-19
• Compounds as kinase inhibitorsPublication Number: US-8211911-B2Priority Date: 2008-08-19Grant Date: 2012-07-03
• Compounds as kinase inhibitorsPublication Number: JP-2012500269-APriority Date: 2008-08-19
• Compounds as kinase inhibitorsPublication Number: KR-20110044749-APriority Date: 2008-08-19
• Compounds as kinase inhibitorsPublication Number: EP-2312950-B1Priority Date: 2008-08-19Grant Date: 2016-11-30
• Biological activities of 5-(2-(4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol crystalline, phosphoric acid salt and its enantiomersPublication Number: US-2023399313-A1Priority Date: 2022-06-10
• Btological activities of 5-(2-(4-(4-fluoro-2-methyl-1h-indol-5- yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan- 7-ol crystalline, phosphoric acid salt and its enantiomersPublication Number: WO-2023239945-A1Priority Date: 2022-06-10
• Btological activities of 5-(2-(4-(4-fluoro-2-methyl-1h-indol-5- yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan- 7-ol crystalline, phosphoric acid salt and its enantiomersPublication Number: EP-4536652-A1Priority Date: 2022-06-10
• Compounds as kinase inhibitorsPublication Number: CA-2733250-A1Priority Date: 2008-08-19
• Compounds As Kinase InhibitorsPublication Number: US-2010048599-A1Priority Date: 2008-08-19

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REF

//////////veonetinib, ANAX LAB, tyrosine kinase inhibitor, antineoplastic, U7PA8S6XGJ

#veonetinib, #ANAX LAB, #tyrosine kinase inhibitor, #antineoplastic, #U7PA8S6XGJ

Vormatrigine

 

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.

SYN

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

SYN

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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REF

PAT

• Ion channel modulatorsPublication Number: TW-202012403-APriority Date: 2018-05-30
• 3-(ethoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine as an ion channel modulatorPublication Number: US-11731978-B2Priority Date: 2018-05-30Grant Date: 2023-08-22
• Ion channel modulatorsPublication Number: EP-3801535-A1Priority Date: 2018-05-30
• Ion channel modulatorsPublication Number: EP-4487916-A2Priority Date: 2018-05-30
• Ion channel modulatorsPublication Number: US-2022024930-A1Priority Date: 2018-05-30
• 3-(ethoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine as an ion channel modulatorPublication Number: US-11014931-B2Priority Date: 2018-05-30Grant Date: 2021-05-25
• Ion channel modulatorPublication Number: KR-20210024500-APriority Date: 2018-05-30
• Ion channel modulatorsPublication Number: US-2021163488-A1Priority Date: 2018-05-30
• Ion channel modulatorsPublication Number: US-2022220118-A1Priority Date: 2018-05-30
• 3-(ethoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine as an ion channel modulatorPublication Number: US-11731976-B2Priority Date: 2018-05-30Grant Date: 2023-08-22
• Treatment of neurological disordersPublication Number: WO-2023211859-A1Priority Date: 2022-04-26
• Methods for the treatment of neurological disordersPublication Number: WO-2023211856-A1Priority Date: 2022-04-26
• Ion channel modulatorsPublication Number: US-11866439-B2Priority Date: 2018-05-30Grant Date: 2024-01-09
• Ion channel modulatorsPublication Number: US-2024132501-A1Priority Date: 2018-05-30
• Ion channel modulatorsPublication Number: US-2021087197-A1Priority Date: 2018-05-30

////////////vormatrigine, ANAX LAB, sodium channel blocker, PRAX-628, PRAX 628, QU3C48T4NV,

#vormatrigine, #ANAX LAB, #sodium channel blocker, #PRAX-628, #PRAX 628, #QU3C48T4NV,

Zanvipixant

 

Zanvipixant

CAS 2166558-11-6

MF C17H12F5N7O MW 425.3 g/mol

[(6S)-1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridin-5-yl]-[3-fluoro-2-(trifluoromethyl)-4-pyridinyl]methanone

METHANONE, ((6S)-1-(5-FLUORO-2-PYRIMIDINYL)-1,4,6,7-TETRAHYDRO-6-METHYL-5H-1,2,3-TRIAZOLO(4,5-C)PYRIDIN-5-YL)(3-FLUORO-2-(TRIFLUOROMETHYL)-4-PYRIDINYL)-

[(6S)-1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl][3-fluoro-2-
(trifluoromethyl)pyridin-4-yl]methanone
purinoreceptor (P2X) antagonist, JNJ-55308942, JNJ 55308942, B7YN3CQ7S7,

JNJ-55308942 is under investigation in clinical trial NCT05328297 (A Study of JNJ-55308942 in the Treatment of Bipolar Depression).

JNJ-55308942 is an investigational drug that works as a P2X7 antagonist with a downstream effect of reducing interleukin-1β release.^[1][2][3] It is developed by Janssen Pharmaceuticals for bipolar depression.^[4]

Zanvipixant (JNJ-55308942) is an investigational small-molecule, brain-penetrant, and potent antagonist of the P2X7 receptor developed by Janssen (J&J). It is primarily studied for its potential to treat neuroinflammation-related conditions, including mood disorders and depression, by inhibiting P2X7-mediated IL-1β release. 

Key Details for Zanvipixant:

• Target: P2X7 Receptor (P2X7R).
• Mechanism: Brain-penetrant antagonist reducing neuroinflammation, specifically inhibiting microglial IL-1β release.
• Chemical Properties: Structure typically includes a triazolopyridine moiety.
• Development Status: Evaluated as a potential CNS treatment for conditions related to neuroinflammation, with research highlighting its pharmacological profile, including good CNS partitioning.
• Alternative Name: JNJ-55308942.

Research indicates that the P2X7 receptor is activated by high levels of extracellular ATP during stress, leading to inflammation and behavioral deficits associated with depression. Zanvipixant has been studied in this context as a potential therapeutic intervention.

• A Study of JNJ-55308942 in the Treatment of Bipolar DepressionCTID: NCT05328297Phase: Phase 2Status: CompletedDate: 2025-07-11
• A Study in Healthy Participants to Evaluate the Effects of Multiple Doses of JNJ-55308942 on Cytochrome P450 Substrate Activity and on the Pharmacokinetics of Levonorgestrel/Ethinyl EstradiolCTID: NCT03547024Phase: Phase 1Status: CompletedDate: 2025-04-27
• A Positron Emission Tomography (PET) Study to Investigate P2X7 Receptor Occupancy by JNJ-55308942 Using [18F]-JNJ-64413739CTID: NCT03437590Phase: Phase 1Status: CompletedDate: 2025-04-27
• A Study to Investigate the Safety, Tolerability, and Pharmacokinetics of JNJ-55308942 in Healthy Male and Female ParticipantsCTID: NCT03151486Phase: Phase 1Status: CompletedDate: 2025-04-27
• A Randomized, Stratified, Double-blind, Placebo-Controlled Study to Investigate the Efficacy, Safety and Tolerability of JNJ-55308942 in Bipolar Depression
• EudraCT: 2021-004790-31
• Phase: Phase 2
• Status: Ongoing, Completed
• Date: 2022-05-31

SYN

A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2017-12-20

PMID: 29211470

DOI: 10.1021/acs.jmedchem.7b01279

SYN

US9464084,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US152971783&_cid=P20-MN4071-78379-1

Example 228

(S*)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone

MS (ESI) mass calcd C ₁₇H ₁₂F ₅N ₇O, 425.1 m/z. found, 426.1 [M+H] ⁺.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014152604&_cid=P20-MN3ZS0-66502-1

Example 228 (S)-(3 -fluoro-2-(trifluoromethyl)pyridin-4-yl)( 1 -(5 -fluoropyrimidin-2-yl)-6-methyl-6J-dihvdro-lH-ri,2,31triazolor4,5-c1pyridin-5(4H)-yl)methanone

he title compound was prepared as described in Example 65, substituting (S)-l-(5-fluoropyrimidin-2-yl)-6-methyl-4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine-hydrochloride salt (prepared as Step 2 intermediate of method II synthesis) in Example 220 for l-pyrimidin-2-yl-4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine, 3-fluoro-2-(trifluoromethyl)isonicotinic acid for 2-chloro-3-(trifluoromethyl)benzoic acid and Hunig's base (3.0 equiv) for Et₃N. The powder x-ray diffraction pattern for this compound is shown in Figure 2. Alternatively, the title compound was synthesized using the following procedure:

Step 1 : (S)-l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)-2-methylpiperidin-4-one

(S)-l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)-2-methylpiperidin-4-one.: (S)-2-methylpiperidin-4-one, TFA salt (108 g, 478 mmol, 1.0 equiv.) was suspended in DCM (1.4 L). Et₃ (265 mL, 1.9 mol, 4.0 equiv.) and 3-fluoro-2-(trifluoromethyl)isonicotinoyl

chloride (1 19 g, 526 mmol, 1.1 equiv.) were added sequentially. The reaction solution was stirred at room temperature for 1 h. The precipitated solid was filtered and washed with EtOAc. The filtrate solution was concentrated and the residue was re-dissolved in EtOAc (500 mL). The organic layer was washed with saturated aHC03 aqueous solution, water and brine, dried over Na₂S0₄, and concentrated. The crude product was triturated from EtOAc/hexanes to afford (S)-l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)-2-methylpiperidin-4-one (103 g, 368 mmol, 77%), which was used without further purification. MS = 305.1 (positive mode)

Step 2: (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(l-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihvdro-lH-ri ,2,31triazolor4,5-c1pyridin-5(4H)-yl)methanone and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(l-(5-fluoropyrimidin-2-yl)-4-methyl-6J-dihydro-lH

[ 1.2.3 Itriazolo [4.5 -c]pyridin-5 (4H)-yl)methanone

In a 5 L, three-neck, round-bottom flask equipped with a mechanic stirring, Dean-Stark trap, reflux condenser and an internal thermometer, to the solution of (S)-l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)-2-methylpiperidin-4-one, prepared in Step 1 above (100 g, 328 mmol, 1.0 equiv.) in toluene (1.5 L), -toluenesulphonic acid (0.62 g, 3.29 mmol, 0.01 equiv.), pyrrolidine (33 mL, 394 mmol, 1.2 equiv.) and 2-azido-5-fluoropyrimidine (59.4 g, 427 mmol, 1.3 equiv.) were added sequentially. The reaction mixture was heated to reflux temperature for 4 hours and then cooled to room temperature. aHC03 (55.2 g, 657 mmol, 2.0 equiv.) and mCPBA (162 g, 657 mmol, 2.0 equiv.) solution in EtOAC (-250 mL) were added sequentially. After stirring at room temperature for 2 hours, water and EtOAc were added. The organic layer was washed sequentially with 1M a₂S0₃, saturated aHC0₃ aqueous solution, and brine, dried over Na₂S0₄, and concentrated. The crude product was purified via column chromatography to afford a mixture of (S)-(3-fluoro-2-

(trifluoromethyl)pyridin-4-yl)(l-(5-flu^

[l,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone and (S)-(3-fluoro-2- (trifluoromethyl)pyridin-4-yl)(l-(5-fl^^

[l,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone in a 10: 1 ratio (97 grams).

Step 3 : (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(l -(5-fluoropyrimidin-2-yl)-6-methyl-6.7-dihvdro-lH-ri.2.31triazolor4.5-c1pyridin-5(4H)-yl)methanone

HPLC purification of the mixture from Step 2 was performed via achiral SFC (Stationary phase: Chiralcel OD-H 5μιη 250x30mm), (Mobile phase: 75% C0₂, 25% MeOH) to afford pure (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(l-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone (73 gram, 172 mmol, 52%). MS (ESI) mass calcd Ci₇H₁₂F_{5 7}0, 425.1 m/z found, 426.1 [M+H]⁺. ^XH NMR (500 MHz, CDC1₃) δ 8.84 - 8.69 (m, 2H), 8.68 - 8.57 (m, 1H), 7.71 - 7.49 (m, 1H), 5.90 -5.68 (d, J = 16.4 Hz, 0.5H), 5.66 - 5.54 (m, 0.5H), 4.76 - 4.58 (d, J = 15.8 Hz, 0.5H), 4.58 - 4.48 (m, 0.5H), 4.45 - 4.33 (m, 0.5H), 4.20 - 4.09 (m, 0.5H), 3.56 - 3.12 (m, 2H), 1.48 -1.18 (m, 3H).

2-chloro-3-(trifluoromethyl)benzoic acid and Hunig's base (3.0 equiv) for Et₃N. MS (ESI) mass calcd Ci₇H₁₂F₅ 70, 425.1 m/z found, 426.1 [M+H]⁺.

PAT

• P2X7 modulatorsPublication Number: US-9464084-B2Priority Date: 2013-03-14Grant Date: 2016-10-11
• P2X7 MODULATORSPublication Number: PT-2970267-TPriority Date: 2013-03-14
• P2X7 modulatorsPublication Number: US-11225478-B2Priority Date: 2013-03-14Grant Date: 2022-01-18
• P2X7 modulatorPublication Number: JP-6293861-B2Priority Date: 2013-03-14Grant Date: 2018-03-14
• P2X7 modulatorsPublication Number: AU-2019203186-A1Priority Date: 2013-03-14
• P2X7 modulatorsPublication Number: TW-201446762-APriority Date: 2013-03-14
• P2X7 regulatorsPublication Number: CN-110003200-APriority Date: 2013-03-14
• P2X7 modulatorsPublication Number: US-9066946-B2Priority Date: 2013-03-14Grant Date: 2015-06-30

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References

 "CTG Labs - NCBI". clinicaltrials.gov. Retrieved 27 November 2023.

 Bhattacharya, Anindya; Lord, Brian; Grigoleit, Jan-Sebastian; He, Yingbo; Fraser, Ian; Campbell, Shannon N.; Taylor, Natalie; Aluisio, Leah; O’Connor, Jason C.; Papp, Mariusz; Chrovian, Christa; Carruthers, Nicholas; Lovenberg, Timothy W.; Letavic, Michael A. (December 2018). "Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia". Neuropsychopharmacology. 43 (13): 2586–2596. doi:10.1038/s41386-018-0141-6. ISSN 0893-133X. PMC 6224414. PMID 30026598.

 Bhattacharya, Anindya; Ceusters, Marc (January 2020). "Targeting neuroinflammation with brain penetrant P2X7 antagonists as novel therapeutics for neuropsychiatric disorders". Neuropsychopharmacology. 45 (1): 234–235. doi:10.1038/s41386-019-0502-9. ISSN 0893-133X. PMC 6879571. PMID 31477815.

 Kolb, Hartmuth C.; Barret, Olivier; Bhattacharya, Anindya; Chen, Gang; Constantinescu, Cristian; Huang, Chaofeng; Letavic, Michael; Tamagnan, Gilles; Xia, Chunfang A.; Zhang, Wei; Szardenings, Anna Katrin (August 2019). "Preclinical Evaluation and Nonhuman Primate Receptor Occupancy Study of 18 F-JNJ-64413739, a PET Radioligand for P2X7 Receptors". Journal of Nuclear Medicine. 60 (8): 1154–1159. doi:10.2967/jnumed.118.212696. ISSN 0161-5505. PMID 30733317. S2CID 73454130.

Clinical data
Trade names	Zanvipixant
Legal status
Legal status	Investigational New Drug
Identifiers
IUPAC name
CAS Number	2166558-11-6
PubChem CID	90408860
DrugBank	DB19110
ChemSpider	76771276
UNII	B7YN3CQ7S7
ChEMBL	ChEMBL3914857
Chemical and physical data
Formula	C17H12F5N7O
Molar mass	425.323 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

////////zanvipixant, ANAX LAB, purinoreceptor (P2X) antagonist, JNJ-55308942, JNJ 55308942, B7YN3CQ7S7,

#zanvipixant, #ANAX LAB, #purinoreceptor (P2X) antagonist, #JNJ-55308942, #JNJ 55308942, #B7YN3CQ7S7,