Zelatriazin,

C₁₈H₁₅F₃N₄O₃, 392.3 g/mol

1929519-13-0

NBI-1065846 or TAK-041

Phase 2

(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

Zelatriazin (NBI-1065846 or TAK-041) is a small-molecule agonist of GPR139. It was developed for schizophrenia and anhedonia in depression but trials were unsuccessful and its development was discontinued in 2023.^{[1][2][3][4][5][6][7]}

SCHEME

SYN

WO2016081736

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016081736&_cid=P21-M0X9BK-38013-1

Example 2: (S)-2-(4-oxobenzo[d][l,2,3]triazin-3(4H)-yl)-N-(l-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

[0166] To a vial containing 2-(4-oxobenzo[d][l,2,3]triazin-3(4H)-yl)acetic acid (15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110 mmol) was added DMF (244 μΕ). After stirring at RT for 5 min, (S)- 1 -(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) and DIPEA (64, 0.366 mmol) were added. The reaction mixture was

allowed to stir at RT for 1 h then water was added (5 mL). The solid was filtered off and washed with water to yield the title compound as a white solid (20 mg, 71 % yield). ^XH NMR

(500 MHz, DMSO-i¾) δ ppm 1.40 (d, J=6.8 Hz, 3 H), 4.98 (quin, J=7.1 Hz, 1 H), 5.09 (s, 2

H), 7.33 (d, J=7.8 Hz, 2 H), 7.44 – 7.49 (m, 2 H), 7.93 – 7.98 (m, 1 H), 8.09 – 8.15 (m, 1 H),

8.21 – 8.29 (m, 2 H), 8.85 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 393.9.

REF

Takeda Pharmaceutical Company Limited, WO2016081736

WO2022058791

Journal of Medicinal Chemistry (2021), 64(15), 11527-11542 

Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment

Publication Name: Journal of Medicinal Chemistry, Publication Date: 2023-10-13, PMID: 37830160

DOI: 10.1021/acs.jmedchem.3c01034

PATENT

US9556130, test 2

https://patents.google.com/patent/US9556130B2/en

Example 2(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110 mmol) was added DMF (244 μL). After stirring at RT for 5 min, (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) and DIPEA (64, 0.366 mmol) were added. The reaction mixture was allowed to stir at RT for 1 h then water was added (5 mL). The solid was filtered off and washed with water to yield the title compound as a white solid (20 mg, 71% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 4.98 (quin, J=7.1 Hz, 1H), 5.09 (s, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.44-7.49 (m, 2H), 7.93-7.98 (m, 1H), 8.09-8.15 (m, 1H), 8.21-8.29 (m, 2H), 8.85 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 393.9.

PATENT

compound 56 [PMID: 34260228]

References

1. ^ Kamel, Amin; Bowlin, Steve; Hosea, Natalie; Arkilo, Dimitrios; Laurenza, Antonio (February 2021). “In Vitro Metabolism of Slowly Cleared G Protein–Coupled Receptor 139 Agonist TAK-041 Using Rat, Dog, Monkey, and Human Hepatocyte Models (HepatoPac): Correlation with In Vivo Metabolism”. Drug Metabolism and Disposition. 49 (2): 121–132. doi:10.1124/dmd.120.000246. PMID 33273044. S2CID 227282766.
2. ^ Schiffer, Hans; Atienza, Josephine; Reichard, Holly; Mulligan, Victoria; Cilia, Jackie; Monenschein, Holger; Collia, Deanna; Ray, Jim; Kilpatrick, Gavin; Brice, Nicola; Carlton, Mark; Hitchcock, Steve; Corbett, Ged; Hodgson, Robert (18 May 2020). “S180. The Selective Gpr139 Agonist Tak-041 Reverses Anhedonia and Social Interaction Deficits in Rodent Models Related to Negative Symptoms in Schizophrenia”. Schizophrenia Bulletin. 46 (Supplement_1): S106–S107. doi:10.1093/schbul/sbaa031.246. PMC 7234360.
3. ^ Yin, Wei; Han, David; Khudyakov, Polyna; Behrje, Rhett; Posener, Joel; Laurenza, Antonio; Arkilo, Dimitrios (August 2022). “A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia”. British Journal of Clinical Pharmacology. 88 (8): 3872–3882. doi:10.1111/bcp.15305. PMC 9544063. PMID 35277995. S2CID 247407736.
4. ^ Rabiner, Eugenii A.; Uz, Tolga; Mansur, Ayla; Brown, Terry; Chen, Grace; Wu, Jingtao; Atienza, Joy; Schwarz, Adam J.; Yin, Wei; Lewis, Yvonne; Searle, Graham E.; Dennison, Jeremy M. T. J.; Passchier, Jan; Gunn, Roger N.; Tauscher, Johannes (June 2022). “Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C]PHNO PET”. Neuropsychopharmacology. 47 (7): 1405–1412. doi:10.1038/s41386-021-01204-1. PMC 9117280. PMID 34675381.
5. ^ Reichard, Holly A.; Schiffer, Hans H.; Monenschein, Holger; Atienza, Josephine M.; Corbett, Gerard; Skaggs, Alton W.; Collia, Deanna R.; Ray, William J.; Serrats, Jordi; Bliesath, Joshua; Kaushal, Nidhi; Lam, Betty P.; Amador-Arjona, Alejandro; Rahbaek, Lisa; McConn, Donavon J.; Mulligan, Victoria J.; Brice, Nicola; Gaskin, Philip L. R.; Cilia, Jackie; Hitchcock, Stephen (12 August 2021). “Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia”. Journal of Medicinal Chemistry. 64 (15): 11527–11542. doi:10.1021/acs.jmedchem.1c00820. PMID 34260228. S2CID 235908256.
6. ^ Münster, Alexandra; Sommer, Susanne; Kúkeľová, Diana; Sigrist, Hannes; Koros, Eliza; Deiana, Serena; Klinder, Klaus; Baader-Pagler, Tamara; Mayer-Wrangowski, Svenja; Ferger, Boris; Bretschneider, Tom; Pryce, Christopher R.; Hauber, Wolfgang; von Heimendahl, Moritz (August 2022). “Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions”. Neuropharmacology. 213: 109078. doi:10.1016/j.neuropharm.2022.109078. PMID 35561791. S2CID 248574904.
7. ^ Taylor, Nick Paul (10 November 2023). “Neurocrine hit with one-two punch as Takeda and Xenon pacts deliver midphase flops”. Fierce Biotech. Retrieved 4 December 2023.

//////Zelatriazin, 1929519-13-0, NBI-1065846, TAK-041, Phase 2