Rocavorexant

CAS 2115665-09-1

MFC18H19F3N8O MW420.39

N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoromethyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-
carboxamide
orexin-1 receptor antagonist, INDV-2000, C4X-3256, INDV 2000, C4X 3256,

Rocavorexant (developmental codes INDV-2000 and C4X-3256) is a potent, selective, oral orexin-1 receptor (OX₁R) antagonist originally developed to treat opioid use disorder and other substance-related disorders.

Clinical development of the drug has been suspended. In April 2026, Indivior announced that it would not advance the drug internally for opioid use disorder because the Phase 2 proof-of-concept trial failed to meet its primary endpoint of “no treatment failure”.

Key Drug Profile

• Mechanism of Action: Highly selective antagonist for the human orexin-1 receptor (pIC50 of 9.1) compared to the orexin-2 receptor (pIC50 of 6.0).
• Target Pathway: Aims at relapse-related neural circuitry, anxiety modulation, and stress-induced addictive behaviors.
• Chemical Formula: C₁₈H₁₉F₃N₈O.
• Current Status: Suspended internally by Indivior, which is actively seeking external business development and out-licensing opportunities due to positive secondary data regarding abstinence and safet

Rocavorexant (INNTooltip International Nonproprietary Name; developmental code names C4X-3256 and INDV-2000) is an orexin OX₁ receptor antagonist which is under development for the treatment of opioid-related disorders and other substance-related disorders.^[1][2][3][4] It is taken orally.^[1] The drug is under development by C4X Discovery and/or Indivior.^[1][2] As of May 2026, development for all indications has been suspended.^[1] The drug has reached phase 2 clinical trials for opioid-related disorders and phase 1 trials for substance-related disorders.^[1][2][4]

Rocavorexant is the antagonist for orexin-1 receptor with pIC₅₀ of 9.1 for human OX1 (while pIC₅₀ for human OX2 is 6.0).

1. Primary patent — most important reference

WO2017129829A1 — “Therapeutic compounds”
Inventor: Barrie P. Martin
Priority: 29 January 2016
Publication: 3 August 2017

WO2017129829A1 – Google Patents

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017129829&_cid=P12-MTJHA5-23107-1

This patent explicitly identifies Rocavorexant as:

N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoromethyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide, and provides its preparation as Example 1.

The patent is particularly useful because it contains large-scale examples, not merely milligram medicinal-chemistry experiments.

Preparation of A/,6-dimethyl-3-(2H-1 ,2,3-triazol-2-yl)-A/-r(2S)-1 -f r5-(trifluoro methyl)pyrazin-2-yllamino)propan-2-yllpyridine-2-carboxamide (Example 1 , Scheme 3)

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To a stirred solution of Int 11 (0.58 g, 2.1 mmol) in THF (2 mL) was added DIPEA (1 .0 mL, 5.8 mmol) followed by 2-chloro-5-(trifluoromethyl)pyrazine (0.39 g, 2.1 mmol) and the mixture was heated at 70 °C for 4 hrs. The reaction mixture was allowed to cool to ambient temperature and allowed to stand over the weekend. The reaction mixture was heated at 70 °C for a further 4 hrs with stirring and allowed to cool to ambient temperature. The reaction mixture was evaporated in vacuo. The residue was purified by preparative HPLC (Column: Waters Xbridge C18 (10 μιτι, 30 x 100 mm). Conditions: Water + 0.2% ammonium hydroxide [Eluent A]; MeCN + 0.2% ammonium hydroxide [Eluent B]. Gradient: 10 to 95% B) and then lyophilised to give title compound as a white solid (0.32 g)

LCMS (Method C): Two peaks at 4.20 and 4.39 min, 421 [M+H]⁺

1 H NMR (500 MHz, d4-MeOH) δ 8.38 (d, 0.15 H), 8.34 (bs, 0.15 H), 8.24 (d, 0.85 H), 8.03 (bs, 0.85 H), 7.99 (s, 0.30 H), 7.97 (s, 1 .70 H), 7.85 (bs, 1 .00 H), 7.57 (d, 0.15 H),

7.41 (d, 0.85 H), 4.98 (m, 0.15 H), 4.06 (bm, 0.85 H), 3.50 (d, 0.15 H), 3.47 (d, 0.85 H),

3.42 (d, 0.85 H), 3.39 (d, 0.15 H), 3.05 (s, 2.55 H), 2.83 (s, 0.45 H), 2.65 (s, 0.45 H), 2.45 (bs, 2.55 H), 1 .38 (d, 0.45 H), 1 .07 (bs, 2.55 H). Preparation of A/,6-dimethyl-3-(2H-1 ,2,3-triazol-2-yl)-A/-r(2S)-1 -U5-(trifluoro methyl)pyrimidin-2-yllamino)propan-2-yllpyridine-2-carboxamide

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US patent

US 11,130,746 B2 — Therapeutic compounds

US11130746B2 – Google Patents

This is especially relevant because its claims specifically cover processes for preparing the compounds, including:

Route A: reaction of the pyridine acid/lithium salt with an amide-coupling reagent and the chiral amine.

Route B: reaction of
N-[(2S)-1-aminopropan-2-yl]-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide
with an appropriate heteroaryl leaving-group compound in the presence of a base.

The patent specifically lists thionyl chloride among the coupling reagents and DIPEA as an appropriate base for the heteroaryl substitution route.

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Other patent-family references

• US 10,696,654 B2
• US 11,130,746 B2
• US 11,753,398
• US 12,441,709 B2

The later US family documents retain the Rocavorexant compound/process disclosure. For example, US10696654B2 reproduces the Example 1 synthesis and the Int 14 preparation.

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References

1.  “Rocavorexant”. AdisInsight. 12 May 2026. Retrieved 5 June 2026.
2.  “Delving into the Latest Updates on Rocavorexant with Synapse”. Synapse. 9 May 2026. Retrieved 5 June 2026.
3.  Raymond JS, Vareed RD, Peters J, James MH (October 2025). “Found in translation: orexin receptor antagonism for the treatment of opioid use disorder”. Translational Psychiatry. 15 (1) 432. doi:10.1038/s41398-025-03571-5. PMC 12552597. PMID 41136352.
4.  Lorente JS, Sokolov AV, Ferguson G, Schiöth HB, Hauser AS, Gloriam DE (June 2025). “GPCR drug discovery: new agents, targets and indications”. Nature Reviews. Drug Discovery. 24 (6): 458–479. doi:10.1038/s41573-025-01139-y. PMID 40033110.

Clinical data
Other names	C4X-3256; C4X3256; INDV-2000; INDV2000
Routes of administration	Oral[1]
Drug class	Orexin OX1 receptor antagonist
Identifiers
IUPAC name
CAS Number	2115665-09-1
PubChem CID	130295635
ChemSpider	133325612
UNII	8RJN30TJM6
KEGG	D13324
Chemical and physical data
Formula	C18H19F3N8O
Molar mass	420.400 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

////rocavorexant, anax labs, orexin-1 receptor antagonist, INDV-2000, C4X-3256, INDV 2000, C4X 3256,

#rocavorexant, #anax labs, #orexin-1 receptor antagonist, #INDV-2000, #C4X-3256, #INDV 2000, #C4X 3256,