Imocitrelvir

Imocitrelvir

CAS 343565-99-1

MFC26H29N5O7 MW523.5 g/mol

ethyl (2E,4S)-4-{(2S)-2-[3-(5-methyl-1,2-oxazole-3-carboxamido)-2-oxopyridin-1(2H)-yl]pent-4-ynamido}-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate

ethyl (E,4S)-4-[[(2S)-2-[3-[(5-methyl-1,2-oxazole-3-carbonyl)amino]-2-oxo-1-pyridinyl]pent-4-ynoyl]amino]-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate
protease inhibitor, antiviral, AG-7404, V-7404, AG 7404, V 7404, VQ1AN3OO42

Imocitrelvir is an investigational new drug that is being evaluated for the treatment of viral infections. It is a 3C protease inhibitor in picornaviruses. Originally developed by Pfizer for treating human rhinovirus infections,^[1] this small molecule has shown promise against a broader range of viruses, including polioviruses.^[2][3]

SYN

Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 8. Pharmacological Optimization of Orally Bioavailable 2-Pyridone-Containing Peptidomimetics

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2003-09-17

PMID: 14521419

DOI: 10.1021/jm030166l

PAT

WO-2016044656

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016044656&_cid=P21-MHBDH2-20719-1

PAT

WO-2022235874

PAT

WO-2024206284

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001040189&_cid=P21-MHBDI9-21481-1

EXAMPLE 21
Preparation of Compound 22: tra«5-(4S,3″”S)-4-(2′-{3″-[(5′”-Methylisoxazole-3′”-carbonyl)amino]-2″-oxo-2″H-pyridin- 1 “-yl} acetylamino)-5-(2″”-oxopyrrilidin-3″”-yl)pent-2-enoic Acid Ethyl Ester

Preparation of Intermediate {3-[(5′-Methylisoxazole-3′-carbonyl)amino]-2-oxo-2H-pyridin-l-yl} acetic Acid tert-Butyl Ester
To a solution of 5-methylisoxazole-3-carboxylic acid (2′-hydroxy-4′-methylpyridin-3′-yl)amide (F2, Example 19) (0.520 g, 2.37 mmol, 1 equiv) in TΗF (20 mL) at 0 °C was added NaΗ (0.095 g, 2.37 mmol, 1.0 equiv). The resulting mixture was stirred at 0 °C for 20 min, and then t-butyl bromoacetate (0.385 mL, 2.61 mmol, 1.1 equiv) was added. The reaction mixture was stirred and warmed to room temperature for 30 min, then was partitioned between 0.5 N ΗC1 (100 mL) and EtOAc (2 x 100 mL). The combined organic layers were dried over Na₂SO and were concentrated. Purification of the residue by flash column chromatography (30% EtOAc in hexanes) provided the title intermediate (0.628 g, 79%) as a white solid: IR (cm-¹) 3343, 1743, 1651, 1581, 1156; Η NMR (CDC1₃) δ 1.52 (s, 9H), 2.53 (s, 3H), 4.65 (s, 2H), 6.32 (t, 1H, 7= 7.2), 6.51 (s, IH), 7.01 (dd, 1H, 7= 6.9, 1.8), 8.50 (dd, 1H, 7= 7.5, 1.8), 9.63 (s, br. IH); Anal. C16H19N3O5: C, H, N.

Preparation of Compound 22
The preceding intermediate was transformed into Compound 22 by a process that was analogous to that described in Example 25 for the transformation of V3 to product R3: mp = 102-106 °C; IR (cm”¹) 3336, 1684, 1534, 1457; ^JH NMR (CDCI3) δ 1.27 (t, 3H, 7= 7.2), 1.67-1.75 (m, IH), 1.98-2.09 (m, IH), 2.37-2.49 (m, IH), 2.53 (s, 3H), 2.55-2.61 (m, IH), 3.34-3.46 (m, 2H), 3.51-3.52 (m, IH), 4.17 (q, 2H, 7= 7.2), 4.61-4.78 (m, 3H), 5.98 (dd, IH, 7 = 15.6, 1.5), 6.20 (s, br. IH), 6.35 (t, 1H, 7= 7.8), 6.51 (s, IH), 6.85 (dd, IH, 7= 15.6, 5.1), 7.17 (d, IH, 7= 7.2), 8.33 (d, IH, 7= 7.2), 8.49 (d, IH, 7= 7.5), 9.57 (s, br. IH); Anal.
C₂3H27N₅O₇: C, H, N.

EXAMPLE 24
Preparation of Compound 25: trans-(2’S,3″”‘S,4S)-4-(3^,-(4″-Fluorophenyl)-2′-{3″‘-[(5″”-methylisoxazole-3″”-carbonyl)amino]-2′”-oxo-2′”H-pyridin- “-yl}propionylamino)-5-(2″ oxopyrrolidin-3′””-yl)pent-2-enoic Acid Ethyl Ester

The title compound was prepared from F2 (Example 19) in a manner analogous to that described for the conversion of U2 to 13 in Example 23 utilizing intermediate Y2 (Example 25) where appropriate: IR (cm-¹) 3331, 1690, 1590, 1531, 1455; ^!H NMR (CDCI3) δ 1.30 (t, 3H, 7= 7.0), 1.45-1.55 (m, IH), 1.64-1.75 (m, IH), 2.03-2.31 (m, 3H), 2.49 (s, 3H), 3.10 (dd, IH, 7= 13.7, 7.9), 3.20-3.46 (m, 3H), 4.20 (q, 2H, 7= 7.0), 4.36-4.47 (m, IH), 5.67 (dd, IH, 7 = 15.7, 1.4), 5.85-5.92 (m, IH), 6.29 (t, 1H, 7= 7.2), 6.45 (s, IH), 6.70 (dd, IH, 7= 15.7, 5.7), 6.86 (s, IH), 6.90-6.97 (m, 2H), 7.10-7.16 (m, 2H), 7.60 (dd, IH, 7= 7.2, 1.6), 8.37 (dd, IH, 7 = 7.2, 1.6), 8.51 (d, IH, 7= 6.6), 9.47 (s, IH).

EXAMPLE 25
Preparation of Compound 26: tr_.«5-(2’S,3″”S,4S)-4-(2′-{3″-[(5″‘-Methyl-isoxazole-3′”-carbonyl)amino]-2″-oxo-2″H-pyridin-l”-yl}butyrylamino)-5-(2″”-oxopyrrolidin-3″”-yl)pent-2-enoic Acid Ethyl Ester (R3)

Preparation of Intermediate (2R)-2-Trifluoromethanesulfonyl-oxybutyric acid tert-butyl ester (U3)
Commercially available T3 (0.575 g, 3.59 mmol, 1 equiv) was dissolved in CH2CI2 (25 mL) and cooled in an ice bath. 2,6-Lutidine (0.836 mL, 7.18 mmol, 2 equiv) and trifluoromethanesulfonic anhydride (1.15 mL, 6.84 mmol, 1.9 equiv) were added and the reaction mixture was stirred 30 min. It was then diluted with MTBE (400 mL), washed with a mixture of brine and 1 N HCl (2:1, 100 mL) and brine (100 mL), dried over Na2SO4 and evaporated to provide the title intermediate which was used without further purification.

Preparation of Intermediate (2S)-2- {3′-[(5″-Methylisoxazole-3″-carbonyl)amino]-2′-oxo-2’H-pyri din- l’-yl} butyric Acid tert-Butyl Ester (V3)
Intermediate F2 from above (0.200 g, 0.912 mmol, 1.1 equiv) was suspended in TΗF (6 mL). Sodium hydride (60% dispersion in mineral oil, 0.0332 g, 0.830 mmol, 1 equiv) was added in one portion. After stirring 30 min, a solution of intermediate U3 (0.830 mmol, 1 equiv, based on T3) in TΗF (7 mL) was added dropwise. The resulting mixture was stirred 2 hours, then diluted with EtOAc (200 mL) and washed with brine (2 x 50 mL). The organic phase was dried over MgSO₄ and evaporated. The residue was purified by flash column chromatography (25% EtOAc in hexanes) to provide the title intermediate (0.178 g, 59%) as an oil: R/= 0.30 (25% EtOAc in hexanes); IR (cm”¹) 3331, 1731, 1690, 1649, 1602, 1531 ; *Η NMR (CDCI3) δ 0.93 (t, 3H, 7= 7.3), 1.45 (s, 9H), 1.83-2.01 (m, IH), 2.17-2.31 (m, IH), 2.50 (s, 3H), 5.44-5.51 (m, IH), 6.32 (t, IH, 7= 7.2), 6.48 (s, IH), 7.10 (dd, IH, 7= 7.2, 1.8), 8.45 (dd, 1H, 7= 7.2, 1.8), 9.64 (s, IH); Anal. C₁8H23N3O5: C, H, N.

Preparation of Intermediate (2S)-2- {3′-[(5″-Methylisoxazole-3″-carbonyl)amino]-2′-oxo-2’H-pyridin-l’-yl}butyric Acid (W3)
Intermediate V3 from above (0.143 g, 0.397 mmol, 1 equiv) was stirred for 1 h in a solution of TFA (2 mL) in CΗ2CI2 (3 mL). The volatiles were evaporated. The residue was suspended in toluene (10 mL) and concentrated to dryness, providing the title intermediate which was used without further purification.

Preparation of Intermediate trα«5-(3’S,4S)-4-Amino-5-(2′-oxopyrrolidin-3′-yl)pent-2-enoic Acid Ethyl Ester (Y2)
Intermediate X2, prepared according to the method disclosed in the co-pending application, U.S. Provisional Patent Application No. 60/150,358, filed August 24, 1999(0.130 g, 0.398 mmol, 1 equiv), was stirred for 30 min in a solution of TFA (2 mL) in CH2CI2 (3 mL). The volatiles were evaporated. The residue was suspended in toluene (10 mL) and concentrated to dryness, providing the title intermediate which was used without further purification.

Preparation of Product R3 (Compound 26)
Intermediates W3 and Y2 (as prepared above) were combined in CH2CI2 (7 mL) and cooled in an ice bath. HOBt (0.064 g, 0.47 mmol, 1.2 equiv), iP^NEt (0.484 mL, 2.78 mmol, 7 equiv) and EDC (0.084 g, 0.44 mmol, 1.1 equiv) were added sequentially. The reaction mixture was allowed to warm to 23 °C overnight, then diluted with EtOAc (500 mL) and washed with 5% KHSO₄ , half saturated NaHCO3, and brine (100 mL each). The organic phase was dried over MgSO₄ and evaporated. The residue was purified by flash column chromatography (gradient elution, 2→3% CH3OH in CH2CI2) to provide the title intermediate (0.119 g, 58%) as a white foam: IR (cm”¹) 3331, 1684, 1649, 1590, 1531; ^JH NMR (CDCI3) δ 0.92 (t, 3H, J = 7.3), 1.29 (t, 3H, J = 7.1), 1.47-1.58 (m, IH), 1.62-1.77 (m, IH), 1.85-2.00 (m, IH), 2.08-2.33 (m, 4H), 2.49 (s, 3H), 3.25-3.42 (m, 2H), 4.19 (q, 2H, J = 7.1), 4.39-4.50 (m, IH), 5.73 (dd, IH, J = 8.8, 6.8), 5.97 (dd, IH, J = 15.7, 1.4), 6.34 (t, IH, J = 7.2), 6.46 (s, IH), 6.86 (dd, IH, J = 15.7, 5.9), 7.18 (s, IH), 7.59 (dd, IH, J = 7.2, 1.8), 8.42 (dd, IH, J = 7.2, 1.8), 8.58-8.62 (m, IH), 9.56 (s, 1); Anal. C25H31N5O7O.5OH2O: C, H, N.

PAT

• Treatment of infection by human enterovirus d68Publication Number: US-2020016243-A1Priority Date: 2014-09-17
• Treatment of infection by human enterovirus d68Publication Number: WO-2016044656-A1Priority Date: 2014-09-17
• Treatment of infection by human enterovirus d68Publication Number: US-2021052708-A1Priority Date: 2014-09-17
• Treatment of infection by human enterovirus D68Publication Number: US-11191817-B2Priority Date: 2014-09-17Grant Date: 2021-12-07
• Therapeutic compounds and methodsPublication Number: US-2025051283-A1
• Protease Inhibitors for Treatment or Prevention of Coronavirus DiseasePublication Number: US-2023192660-A1Priority Date: 2020-05-08
• Composition and combined medication method for treating enterovirus infectionPublication Number: US-2019030027-A1Priority Date: 2016-01-29
• Composition and combined medication method for treating enterovirus infectionPublication Number: US-10864210-B2Priority Date: 2016-01-29Grant Date: 2020-12-15
• Treatment of infection by human enterovirus D68Publication Number: US-10328128-B2Priority Date: 2014-09-17Grant Date: 2019-06-25
• Treatment of infection by human enterovirus d68Publication Number: US-2017290893-A1Priority Date: 2014-09-17
• Nucleotide and nucleoside therapeutic compositions, combinations and related uses thereofPublication Number: CN-117881402-APriority Date: 2021-05-05
• Nucleotide and nucleoside therapeutic compositions, combinations and uses related theretoPublication Number: EP-4333859-A1Priority Date: 2021-05-05
• Nucleotide and nucleoside therapeutic compositions, combinations, and related usesPublication Number: JP-2024517807-APriority Date: 2021-05-05
• Nucleotide and nucleoside therapeutic compositions, combinations and uses related theretoPublication Number: WO-2022235874-A1Priority Date: 2021-05-05
• Protease inhibitors for treatment or prevention of coronavirus diseasePublication Number: EP-4146267-A1Priority Date: 2020-05-08
• 4′-substituted nucleosides and nucleotides as antiviral agentsPublication Number: WO-2024227159-A2Priority Date: 2023-04-28
• Therapeutic compoundsPublication Number: WO-2024206284-A2Priority Date: 2023-03-27
• Antibody molecules binding to sars-cov-2Publication Number: WO-2024168061-A2Priority Date: 2023-02-07
• Predictive model for variants associated with drug resistance and theranostic applications thereofPublication Number: WO-2023172635-A1Priority Date: 2022-03-08
• Nucleotide and nucleoside therapeutic compositions, combinations and uses related theretoPublication Number: CA-3216679-A1Priority Date: 2021-05-05

LIT

• Structure and inhibition of SARS-CoV-1 and SARS-CoV-2 main proteases by oral antiviral compound AG7404Publication Name: Antiviral ResearchPublication Date: 2022-12PMCID: PMC9632241PMID: 36336176DOI: 10.1016/j.antiviral.2022.105458
• Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug DesignPublication Name: Journal of Medicinal ChemistryPublication Date: 2021-09-30PMID: 34591488DOI: 10.1021/acs.jmedchem.1c01215
• In Vitro Antiviral Activity of New Oxazoline Derivatives as Potent Poliovirus InhibitorsPublication Name: Journal of Medicinal ChemistryPublication Date: 2018-12-04PMCID: PMC9169555PMID: 30512950DOI: 10.1021/acs.jmedchem.8b01482
• A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus ReplicationPublication Name: Journal of Medicinal ChemistryPublication Date: 2017-06-15PMID: 28581749DOI: 10.1021/acs.jmedchem.7b00175
• Anti-poliovirus activity of protease inhibitor AG-7404, and assessment of in vitro activity in combination with antiviral capsid inhibitor compoundsPublication Name: Antiviral ResearchPublication Date: 2013-05PMID: 23499651DOI: 10.1016/j.antiviral.2013.03.003

AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

• Twitter
• FACEBOOK

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

……

Clinical data
Other names	AG-7404, V-7404
Identifiers
IUPAC name
CAS Number	343565-99-1
PubChem CID	5280053
IUPHAR/BPS	13223
UNII	VQ1AN3OO42
ChEMBL	ChEMBL141157
Chemical and physical data
Formula	C26H29N5O7
Molar mass	523.546 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

References

1.  “Imocitrelvir”. PatSnap.
2.  Xie H, Rhoden EE, Liu HM, Ogunsemowo F, Mainou BA, Burke RM, et al. (November 2024). “Antiviral Development for the Polio Endgame: Current Progress and Future Directions”. Pathogens. 13 (11). Basel, Switzerland: 969. doi:10.3390/pathogens13110969. PMC 11597170. PMID 39599522.
3.  Bandyopadhyay AS, Burke RM, Hawes KM (June 2024). “Polio Eradication: Status, Struggles and Strategies”. The Pediatric Infectious Disease Journal. 43 (6): e207-211. doi:10.1097/INF.0000000000004330. PMID 38564755.

////////Imocitrelvir, protease inhibitor, antiviral, AG-7404, V-7404, AG 7404, V 7404, VQ1AN3OO42