Brezivaptan

CAS 1370444-22-6

ANC-501, THY-1773, TS-121, 575OB1CKN0

MF C25H30ClN5O3 MW 484.0 g/mol

2-[3-(3-chlorophenyl)-1-{4-[2-(morpholin-4-yl)ethyl]phenyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-N-(propan-2-yl)acetamide

2-[3-(3-chlorophenyl)-1-[4-(2-morpholin-4-ylethyl)phenyl]-5-oxo-1,2,4-triazol-4-yl]-N-propan-2-ylacetamide
vasopressin receptor antagonist

• ANC-501 in the Treatment of Adults With Major Depressive DisorderCTID: NCT05439603Phase: Phase 2Status: CompletedDate: 2024-12-31
• A Study to Evaluate the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Major Depressive DisorderCTID: NCT03093025Phase: Phase 2Status: TerminatedDate: 2020-07-14
• Exploratory Study Using Positron Emission Tomography With TS-121 and [11C]TASP0410699 in Healthy Adult Male SubjectsCTID: NCT02448212Phase: Phase 1Status: CompletedDate: 2017-02-14

Brezivaptan^[1] (developmental code names ANC-501, THY-1773, TS-121) is an orally active, selective vasopressin V_1B receptor antagonist which is under development by Taisho Pharmaceutical for the adjunctive treatment of major depressive disorder.^[2][3][4] As of November 2022, it is in phase II clinical trials for this indication.^[2][3][5]

ANC-501 is under investigation in clinical trial NCT05439603 (ANC-501 in the Treatment of Adults With Major Depressive Disorder).

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US90328697&_cid=P11-MFYT6K-98384-1

Synthesis of Example Aa-1

2-[3-(3-Chlorophenyl)-1-{4-[2-(morpholin-4-yl)ethyl]phenyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-N-(propan-2-yl)acetamide

A mixture of the compound (100 mg) prepared in Reference Example P-I1, morpholine (0.03 mL), N,N-diisopropylethylamine (0.35 mL), and MeCN (3.00 mL) was stirred at an outside temperature of 80° C. overnight. After cooling, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (SNAP Cartridge HP-Sil: 10 g, mobile phase: CHCl 3/MeOH=98/2 to 85/15 (v/v); and SNAP Cartridge KP-NH: 28 g, mobile phase: n-hexane/CHCl 3=80/20 to 0/100 (v/v)) and preparative thin-layer chromatography (PTLC) (1.0 mm silica gel 60F 254 plate, mobile phase: EtOAc/MeOH=95/5 (v/v)). The resulting crude product was washed with a solvent mixture of EtOAc and n-hexane (EtOAc/n-hexane=1/4 (v/v)) with stirring to yield the title compound (70 mg, colorless solid).

MS (ESI pos.) m/z: 484 ([M+H] +).

1H-NMR (600 MHz, CDCl 3)δ(ppm); 1.20 (6H, d, J=6.4 Hz), 2.48-2.67 (6H, m), 2.80-2.88 (2H, m), 3.76 (4H, br. s.), 4.06-4.13 (1H, m), 4.36 (2H, s), 6.37-6.45 (1H, m), 7.31 (2H, d, J=8.3 Hz), 7.46-7.50 (1H, m), 7.51-7.55 (1H, m), 7.74-7.77 (1H, m), 7.85-7.88 (1H, m), 7.94 (2H, d, J=8.7 Hz).

PAT

• 1,2,4-triazolone derivativePublication Number: NZ-608729-APriority Date: 2010-10-01
• 1, 2, 4-triazolone derivativePublication Number: US-2013197217-A1Priority Date: 2010-10-01
• 1, 2, 4-triazolone derivative and use thereof as an antagonist on the arginine-vasopressin 1B receptorPublication Number: US-9193695-B2Priority Date: 2010-10-01Grant Date: 2015-11-24
• 1,2,4-triazolone derivative, substance and pharmaceutical compositionPublication Number: BR-112013007389-B1Priority Date: 2010-10-01
• 1,2,4-triazolone derivativePublication Number: EP-2623499-A1Priority Date: 2010-10-01
• 1,2,4-triazolone derivativePublication Number: EP-2623499-B1Priority Date: 2010-10-01Grant Date: 2015-04-22
• DERIVAT 1,2,4-TRIAZOLONAPublication Number: HR-P20150462-T1Priority Date: 2010-10-01
• 1,2,4-triazolone derivativePublication Number: HU-E025729-T2Priority Date: 2010-10-01
• 1,2,4-triazolone derivativePublication Number: IL-225091-APriority Date: 2010-10-01
• Methods of treating depression with 1,2,4-triazolone derivativesPublication Number: WO-2023235785-A1Priority Date: 2022-06-01
• 1,2,4-triazolone derivativePublication Number: AU-2011308403-A1Priority Date: 2010-10-01
• 1,2,4-triazolone derivativePublication Number: AU-2011308403-B2Priority Date: 2010-10-01Grant Date: 2014-08-21
• 1,2,4-Triazolone DerivativesPublication Number: CN-103119028-APriority Date: 2010-10-01
• 1,2,4-Triazolone DerivativesPublication Number: CN-103119028-BPriority Date: 2010-10-01Grant Date: 2016-05-25

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References

1.  PubChem. “Brezivaptan”. pubchem.ncbi.nlm.nih.gov. Retrieved 2024-08-15.
2.  “TS 121 -“. AdisInsight. Springer Nature Switzerland AG.
3.  “New Drug Pipeline – Taisho Pharmaceutical Holdings”.
4.  Kamiya M, Sabia HD, Marella J, Fava M, Nemeroff CB, Umeuchi H, Iijima M, Chaki S, Nishino I (September 2020). “Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study”. Journal of Psychiatric Research. 128: 43–51. doi:10.1016/j.jpsychires.2020.05.017. PMID 32521250. S2CID 219587135.
5.  Inatani S, Mizuno-Yasuhira A, Kamiya M, Nishino I, Sabia HD, Endo H (May 2021). “Prediction of a clinically effective dose of THY1773, a novel V1B receptor antagonist, based on preclinical data”. Biopharmaceutics & Drug Disposition. 42 (5): 204–217. doi:10.1002/bdd.2273. PMC 8252455. PMID 33734452.

External links

• Clinical trial number NCT03093025 for “A Study to Evaluate the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Major Depressive Disorder” at ClinicalTrials.gov

Clinical data
Other names	TS-121; TS121; TS-1211; TS1211; THY1773; THY-1773; ANC-501; ANC501
Routes of administration	By mouth
Identifiers
IUPAC name
CAS Number	1370444-22-6
PubChem CID	56952080
DrugBank	DB18907
ChemSpider	129325033
UNII	575OB1CKN0
ChEMBL	ChEMBL5314910
Chemical and physical data
Formula	C25H30ClN5O3
Molar mass	484.00 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

////////////Brezivaptan, ANC-501, THY-1773, TS-121, ANC 501, THY 1773, TS 121, 575OB1CKN0