Nedizantrep

CAS 2376824-99-4

MF C20H19ClN6O3 MW 426.9 g/mol

• 1-[[3-[(3R,5R)-5-(4-chlorophenyl)oxolan-3-yl]-1,2,4-oxadiazol-5-yl]methyl]-2,7-dimethylpurin-6-one
• 1-[[3-[(3R,5R)-5-(4-Chlorophenyl)tetrahydro-3-furanyl]-1,2,4-oxadiazol-5-yl]methyl]-1,7-dihydro-2,7-dimethyl-6H-purin-6-one
• 6H-Purin-6-one, 1-[[3-[(3R,5R)-5-(4-chlorophenyl)tetrahydro-3-furanyl]-1,2,4-oxadiazol-5-yl]methyl]-1,7-dihydro-2,7-dimethyl-

1-[[3-[(3R,5R)-5-(4-chlorophenyl)oxolan-3-yl]-1,2,4-oxadiazol-5-yl]methyl]-2,7-dimethylpurin-6-one

1-({3-[(3R,5R)-5-(4-chlorophenyl)oxolan-3-yl]-1,2,4-oxadiazol-5-yl}methyl)-2,7-dimethyl-1,7-dihydro-6Hpurin-6-one
transient receptor potential (TRP) ion channel antagonist, GDC-6599, GDC 6599, RG 6341, RG-6341, ENQ95FVE4X

Nedizantrep (also known by its developmental code GDC-6599) is a potent, selective, and orally active chemical compound developed as a transient receptor potential ankyrin 1 (TRPA1) cation channel antagonist. It was originally designed by Roche Holding AG/Genentech to manage respiratory conditions, particularly chronic cough associated with asthma and Chronic Obstructive Pulmonary Disease (COPD).

Key Characteristics & Mechanism

• Target Engagement: It acts as a TRPA1 inhibitor with high potency, exhibiting an IC50 value of 5.3 nM in humans. [1, 2]
• Therapeutic Purpose: It blocks TRPA1 cation channels, which are thermoTRP channels known to function as sensor transducers for temperature, pain, and environmental irritants. Inhibiting this pathway prevents the sensory nerve hypersensitivity that triggers chronic coughing fits.
• Research Status: As per data recorded by platforms like the IUPHAR/BPS Guide to PHARMACOLOGY, its chemical structure was publically disclosed in late 2023, and it has been evaluated through Phase 2 clinical trials
• A Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamic Effects Of GDC-6599 In Patients With Chronic Cough
• CTID: NCT05660850
• Phase: Phase 2
• Status: Completed
• Date: 2025-12-16

PAT

US10710994,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US251637879&_cid=P12-MRBG82-53830-1

Example 8: 1-((3-((3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2,7-dimethyl-1H-purin-6(7H)-one

The overall Example 8 reaction scheme is as follows:

Step 4: Preparation of 1-((3-((3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2,7-dimethyl-1H-purin-6(7H)-one

5-(chloromethyl)-3-[(3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl]-1,2,4-oxadiazole (8.40 g, 28.1 mmol, prepared according to a similar procedure as example 1), 2,7-dimethyl-1H-purin-6(7H)-one (5.07 g, 30.9 mmol) and potassium carbonate (11.6 g, 84.2 mmol) were charged in a 200 mL RBF. DMF (56 mL) was added and the mixture was stirred in a 40° C. oil bath for 2 hours. Heat was removed and the reaction mixture was transferred to a separatory funnel containing EtOAc (100 mL) and water (500 mL). The mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with a mixture of water (40 mL) and brine (40 mL), dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure to give the crude product (77% purity by LCMS). The crude brown oil was dissolved in EtOAc (100 mL) and Heptane (60 mL) was added dropwise which led to the slow formation of a solid. The mixture was stirred at 0° C. for 30 min. and the solid was collected on a Büchner funnel, rinsed with heptane and air dried for 15 min. to give a first lot of 1-((3-((3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2,7-dimethyl-1H-purin-6(7H)-one (8.0 g, 18.7 mmol, 67% yield, 92% purity by LCMS) as a yellow solid. The filtrate was concentrated and it was purified by reverse phase chromatography (C18, MeCN/10 mM NH 4HCO 2 in H 2O, pH 3.8, 0 to 60% gradient) to afford a second lot of 1-((3-((3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2,7-dimethyl-1H-purin-6(7H)-one (950 mg, 2.23 mmol, 8% yield, >99% purity by LCMS) as a white solid.

The first lot of desired product (8.0 g, 92% purity by LCMS) was combined with a third lot obtained from a previous batch (1.3 g, 96% purity by LCMS). The material was dissolved in EtOAc (250 mL) and the solvent was displaced with iPrOH on the rotavap (3 cycles of iPrOH addition (50 mL)/evaporation of 50 mL of solvent). During the process, a solid crashed out and the solvent was reduced to ˜100 mL on the rotavap. The suspension was cooled to 0° C. and the solid was collected on a Büchner funnel, rinsed with cold iPrOH and air dried for 15 min. to give a fourth lot of 1-((3-((3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2,7-dimethyl-1H-purin-6(7H)-one (8.50 g, 99% purity by LCMS) as a light beige solid. Still not satisfied with the color of the purified material, it was dissolved in EtOAc (500 mL) and the brown solution was treated with 8 g of activated charcoal. The mixture was allowed to stir for 15 min. The suspension was filtered on celite and the cake was rinsed with EtOAc. The colorless filtrate was evaporated under reduced pressure to give a fifth lot of 1-((3-((3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2,7-dimethyl-1H-purin-6(7H)-one (7.50 g, 99% purity by LCMS) as a white solid. Finally, the second lot (950 mg, >99% purity by LCMS) and the fifth lot (7.50 g, 99% purity by LCMS) were combined in a 200 mL RBF and iPrOH (100 mL) was added. The suspension was stirred in a 100° C. oil bath until full dissolution and water was added (3 mL). The flask was removed from oil bath and the light yellow clear solution was allowed to cool down at room temperature. The suspension was cooled in an ice bath and the solid was collected on a Buchner funnel, rinsed with cold iPrOH (20 mL) and air dried for 24 hours to give the title compound 1-((3-((3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-2,7-dimethyl-1H-purin-6(7H)-one (7.3 g) as a white solid. LCMS: purity=99.4%, MH +=427.2/429.2. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.46-7.33 (m, 4H), 5.63 (s, 2H), 5.00 (t, J=7.4 Hz, 1H), 4.35 (dd, J=8.4, 7.5 Hz, 1H), 3.93 (s, 3H), 3.95-3.88 (m, 1H), 3.79-3.70 (m, 1H), 2.60 (s, 3H), 2.63-2.53 (m, 1H), 2.13 (ddd, J=12.7, 8.9, 7.8 Hz, 1H).

PAT

[WO2019182925A1]

EG 8

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References

Oxadiazole compounds as transient receptor potential channel inhibitors

Publication Number: EP-3768260-B1

Priority Date: 2018-03-19

Grant Date: 2025-10-08

• Oxadiazole transient receptor potential channel inhibitorsPublication Number: TW-202003510-APriority Date: 2018-03-19
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: US-10710994-B2Priority Date: 2018-03-19Grant Date: 2020-07-14
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: TW-I829676-BPriority Date: 2018-03-19Grant Date: 2024-01-21
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: US-2025122184-A1Priority Date: 2018-03-19
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: EP-3768260-A1Priority Date: 2018-03-19
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: US-2019284179-A1Priority Date: 2018-03-19
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: KR-20230070333-APriority Date: 2018-03-19
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: US-12202824-B2Priority Date: 2018-03-19Grant Date: 2025-01-21
• Oxadiazole transient receptor potential channel inhibitorPublication Number: KR-102533094-B1Priority Date: 2018-03-19Grant Date: 2023-05-16
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: TW-202438496-APriority Date: 2018-03-19
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: US-2020308161-A1Priority Date: 2018-03-19
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: US-2023121700-A1Priority Date: 2018-03-19
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: WO-2019182925-A1Priority Date: 2018-03-19
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: US-11655245-B2Priority Date: 2018-03-19Grant Date: 2023-05-23
• Oxadiazole transient receptor potential channel inhibitorsPublication Number: CN-111867585-APriority Date: 2018-03-19

////////////nedizantrep, anax labs, transient receptor potential (TRP) ion channel antagonist, GDC-6599, GDC 6599, RG 6341, RG-6341, ENQ95FVE4X