Ensitrelvir
S-217622, S 217622, Xocova, SHIONOGI, 6-[(6-chloro-2-methylindazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione CAS 2647530-73-0| C22H17ClF3N9O2531.9 | |
| Synonyms |
BDBM513874
bioRxiv20220126.477782, S-217622
|
|---|
Ensitrelvir fumarate
CAS No. : 2757470-18-9
| Formula: | C26H21ClF3N9O6 |
|---|---|
| M. Wt. : | 647.95 |
YN
J.Med.Chem.2024,67,4376−4418
Ensitrelvir fumaric acid (3), also referred to as S-217622, is an oral noncovalent SARS-CoV-2 main protease (Mpro) inhibitordeveloped by Shionogi & Co. that was approved by the japan Pharmaceuticals and Medical Devices Agency (PMDA)for the treatment of disease caused by SARS-CoV-2 (COVID
19) infection. Dosed once daily for 5 days, ensitrelvirsuppresses the replication of SARS-CoV-2 in infected patients as a result of its inhibition of the viral mpro.25,26
Ensitrelvir retains potent inhibitory activity against many of the most common M mutants and exhibits antiviral activity against a wide variety of circulating SARS-CoV-2 variants. 27is the second Mpro
Ensitrelvir inhibitor approved for the treatment of 28 disease caused by COVID-19. Unlike the first approved treatment, Paxlovid, ensitrelvir does not require coadministration with a CYP3A4 inhibitor to attenuate metabolism in vivo.
Furthermore, crystal structures of ensitrelvir in complex with the main proteases of three other human-infecting coronaviruses (MERS-CoV, SARS-CoV, and HCoV-NL63)
A convergent, kilogram-scale synthesis of ensitrelvir suitable for manufacturing has been described in the literature by researchers at Shionogi. 30 The synthetic approach involved the union of two key building blocks indazole 3.7 and 1,3,5triazinone 3.14, each necessitating development of a scale worthy route. The preparation of triazinone 3.14 necessitated construction of a triazolyl methylene chloride subunit which
began with the reduction of triazole ester 3.1 with aluminum hydride 3.2 (a less pyrophoric alternative to LAH yet still required aqueous Rochelle salt quench to chelate excess aluminum) 31to provide alcohol 3.3, which was then convertedto the corresponding chloride and isolated as the triazole HCl
salt 3.4 (Scheme 6). Assembly of indazole intermediate 3.7began with regioselective nitration of benzaldehyde 3.5followed by treatment with hydrazine hydrate in aqueous EtOHtoprovide indazole3.6(Scheme7).Fascinatingly, the Shionogi team isolated a variety of byproducts during the
conversionof3.5to3.6whichsupportedtheirhypothesisforareaction mechanism that likely equilibrated through a dibenzylidenehydrazine intermediateenroute tothedesired
indazole3.6.Ascreenofelectrophilicmethyl sourcesrevealed thatMeerwein’s salt facilitatedthebest conversionof 3.6to the correspondingN2-monomethylated indazole; subsequenthydrogenative nitro reduction furnished the key indazole intermediate 3.7.Construction of the ensitrelvir core started with reaction of carboximidamide 3.8 with t-butyl isocyanate followed by N,N′carbonyldiimidazole (CDI) to secure 1,3,5-triazinone 3.10(Scheme 8). Subsequent N-alkylation with bromide 3.11provided benzyl triazinone 3.12. Substitution of the pyrazolewith m-cresol was accomplished under acidic conditions. The
authors report that m-cresol was identified as a leaving group that facilitated introduction of indazole 3.7 with a minimal number of byproducts in a later step of the synthesis. The TFA-mediated reaction concomitantly removed the N-tertbutyl group providing compound 3.13 in 91% yield. Nalkylation with chloride 3.4 in the presence of a base resulted in intermediate 3.14 which was then treated with building
block 3.7 in the presence of anhydrous acetic acid. Isolation of ensitrelvir fumaric acid was achieved by exposure to fumaric acid in aqueous acetone.
(25) Yotsuyanagi, H.; Ohmagari, N.; Doi, Y.; Imamura, T.;
Sonoyama, T.; Ichihashi, G.; Sanaki, T.; Tsuge, Y.; Uehara, T.;
Mukae, H. A phase 2/3 study of S-217622 in participants with SARS
CoV-2 infection (Phase 3 part). Medicine 2023, 102, No. e33024.
(26) Mukae, H.; Yotsuyanagi, H.; Ohmagari, N.; Doi, Y.; Imamura,
T.; Sonoyama, T.; Fukuhara, T.; Ichihashi, G.; Sanaki, T.; Baba, K.;
Takeda, Y.; Tsuge, Y.; Uehara, T. A randomized phase 2/3 study of
ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in
Japanese patients with mild-to-moderate COVID-19 or asymptomatic
SARS-CoV-2 infection: results of the phase 2a part. Antimicrob. Agents
Chemother. 2022, 66, No. 00697.
(27) Kawashima, S.; Matsui, Y.; Adachi, T.; Morikawa, Y.; Inoue, K.;
Takebayashi, S.; Nobori, H.; Rokushima, M.; Tachibana, Y.; Kato, T.
Ensitrelvir is effective against SARS-CoV-2 3CL protease mutants
circulating globally. Biochem. Biophys. Res. Commun. 2023, 645, 132−
136.
(28) Unoh, Y.; Uehara, S.; Nakahara, K.; Nobori, H.; Yamatsu, Y.;
Yamamoto, S.; Maruyama, Y.; Taoda, Y.; Kasamatsu, K.; Suto, T.;
et al. Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL
protease inhibitor clinical candidate for treating COVID-19. J. Med.
Chem. 2022, 65, 6499−6512
(29) Lin, C.; Jiang, H.; Li, W.; Zeng, P.; Zhou, X.; Zhang, J.; Li, J.
Structural basis for the inhibition of coronaviral main proteases by
ensitrelvir. Structure 2023, 31, 1016.
(30) Kawajiri, T.; Kijima, A.; Iimuro, A.; Ohashi, E.; Yamakawa, K.;
Agura, K.; Masuda, K.; Kouki, K.; Kasamatsu, K.; Yanagisawa, S.; et al.
Development of a manufacturing process toward the convergent
synthesis of the COVID-19 antiviral Ensitrelvir. ACS Cent. Sci. 2023,
9, 836−843.
(31) Gugelchuk, M.; Silva, III, L. F.; Vasconcelos, R. S.; Quintiliano,
S. A. P. Sodium bis(2-methoxyethoxy)aluminum hydride. In
Encyclopedia of Reagents for Organic Synthesis; Charette, A., Bode, J.,
Rovis, T., Shenvi, R., Eds.; John Wiley & Sons, Ltd., 2007.
Chemistry
The synthetic scheme for compound 1 is described in Scheme 1. Starting from the pyrazole derivative 4, cyclization with Ethyl isocyanatoacetate and CDI was conducted, giving 5 in 90% yield. Then, an alkylation with 5-bromomethyl-1,2,3-trifluorobenzene followed by introduction of a 4-difluoromethoxy-2-methylaniline unit, to give 7 (40% in 2 steps). The ester group in 7 was hydrolyzed and then amidated with methylamine, yielding 1 (58% in 2 steps). Compound 2 was synthesized similarly as shown in Scheme 2.
S-217622 (3) was synthesized as described in Scheme 3. Starting from known compound 9,21 an alkylation with 1-(bromomethyl)-2,4,5-trifluorobenzene gave 10 in 93% yield. Then, the 3-tert-Bu group was removed and the triazole unit was introduced, and the substitution of the SEt moiety with the indazole unit finally gave S-217622 (3).
21 Kai, H.; Kameyama, T.; Horiguchi, T.; Asahi, K.; Endoh, T.; Fujii, Y.; Shintani, T.; Nakamura, K.; Matsumoto, S.; Hasegawa, T.; Oohara, M.; Tada, Y.; Maki, T.; Iida, A. Preparation of triazine derivatives and pharmaceutical compound that contains same and exhibits analgesic activity. WO 2012020749 A1, Feb 16, 2012
Scheme 1.
Reagents and Conditions: (a) ethyl isocyanato-acetate, DBU, CDI, DMA, –10 °C to rt, 90%; (b) 5-bromomethyl-1,2,3-trifluorobenzene, N,N-diisopropylethylamine, DMA, 60 °C; (c) 4-difluoromethoxy-2-methylaniline, tert-butanol, 100 °C, 40% in 2 steps; (d) (i) NaOH aq., THF/MeOH, rt; (ii) methylamine, HATU, N,N-diisopropylethylamine, THF, rt., 58% in 2 steps.
Scheme 2.
Reagents and Conditions: (a) 6-chloro-2-methyl-2H-indazol-5-amine, tert-amyl alcohol, 100 °C, 44% in 2 steps from 5; (b) (i) NaOH aq., THF/MeOH, rt; (ii) methylamine, HATU, N,N-diisopropylethylamine, THF, rt., 29% in 2 steps.
Scheme 3.
Reagents and Conditions: (a) 1-(bromomethyl)-2,4,5-trifluorobenzene, K2CO3, MeCN, 80 °C, 93%; (b) TFA, rt, 97%; (c) 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, K2CO3, DMF, 60 °C, 45%; (d) 6-chloro-2-methyl-2H-indazol-5-amine, LHMDS, THF, 0 °C to rt., 25%.
(6E)-6-[(6-Chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione (3, S-217622)
To a solution of 12 (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF; 1.46 mL, 1.46 mmol) dropwisely at 0 °C. The reaction mixture was stirred at 0 °C for 2.5 h and then at rt for 40 min. The reaction was quenched with aqueous NH4Cl solution, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH gradient, 0-20% MeOH). The solid was recrystallized from acetone/H2O to afford 3 (S-217622) (95.3 mg, 25%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6, DCl in D2O) δ 3.90 (3H, s), 4.15 (3H, s), 5.04 (2H, s), 5.26 (2H, s), 7.44 (1H, m), 7.52-7.65 (2H, m), 7.73 (1H, s), 8.40 (1H, s), 9.31 (1H, s). 13C NMR (100 MHz, DMSO-d6, DCl in D2O) δ 37.34, 38.04, 40.06, 40.29, 106.16 (dd, J = 28.2, 21.6 Hz), 116.46-116.70, 116.70, 120.54-120.76, 120.76, 125.93, 129.10, 132.35, 143.84, 145.98, 146.38 (ddd, J = 241.4, 12.5, 3.7 Hz), 146.60, 148.52 (td, J = 247.7, 13.6 Hz), 150.43, 150.50, 155.22 (ddd, J = 244.3, 10.3, 2.2 Hz), 155.58. HRMS-ESI (m/z): [M + H]+ calcd for [C22H18 F3ClN9O2]+ 532.1219; found 532.1221.
Preparation of Compound 3 (S-217622) fumaric acid co-crystal
A mixture of 3 (S-217622) (1.17 g, 2.2 mmol) and fumaric acid (278 mg, 2.4 mmol) in EtOAc (5.9 mL) was stirred at room temperature for 45 min. The suspension was filtrated to afford 3 (S-217622) fumaric acid co-crystal (1.37 g, 95 %) as a white solid. 1H NMR (400 MHz, pyridine-d5) δ 3.64 (s, 3H), 3.99 (s, 3H), 5.56 (s, 2H), 5.61 (s, 2H), 7.16-7.25 (m, 2H), 7.44 (s, 2H), 7.81 (s, 1H), 7.89 (s, 1H), 7.89-7.97 (m, 1H), 8.32 (s, 1H).
Notes
SHIONOGI has applied for a patent covering 1, 2, and 3 (S-217622). Y.U., S.U., K.N., H.N., Y.Y., S.Y., Y.M., Y.T., K.K., T.S., K.K., A.N., S.K., T.S., S.T., K.U., T.M., S.A., A.S., T.S., T.K., and Y.T. are employees of SHIONOGI & Co., Ltd. S.U., K.N., H.N., Y.M., Y.T., K.K., T.S., K.K., S.K., TS, S.T., K.U., T.S., and T.K. are shareholders in SHIONOGI & Co., Ltd. M.S., Y.O., and H.S. are financially supported by the joint research fund from SHIONOGI & Co., Ltd.
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Supporting information[supplements/477782_file02.pdf]
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EMAIL. amcrasto@amcrasto ///////////////////////////////////////////////////////////////////////////// Oral antiviral medications, in addition to vaccines, are expected to play an important role in treating coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory disease coronavirus-2 (SARS-CoV-2). These drugs must have significant antiviral activity, as well as target specificity, oral bioavailability, and metabolic stability. Although several antiviral compounds have been reported as possible SARS-CoV-2 inhibitors in vitro, only a few of these drugs have been shown to be effective in vivo.Ensitrelvir, a novel SARS-CoV-2 antiviral
Ensitrelvir (code name S-217622, brand name Xocova), is a new inhibitor of the SARS-CoV-2 major protease (Mpro), also known as 3C-like protease, has been shown to reduce the viral load and help alleviate the severity of SARS-CoV-2 in infected hamsters. In cells, low nanomolar to sub-micromolar doses of S-217622 suppress viral growth. In hamsters, oral treatment of S-217622 showed excellent pharmacokinetic qualities and hastened recovery from acute SARS-CoV-2 infection. S-217622 also demonstrated antiviral effectiveness against SARS-CoV-2 variants of concern (VOCs), such as the highly pathogenic Delta variant and the newly discovered Omicron variant. Overall, these findings show that S-217622, which is an antiviral drug that is currently being tested in Phase II/III clinical trials, has impressive antiviral efficiency and effectiveness against SARS-CoV-2 and could be a viable oral treatment option for COVID-19.History
It has reached Phase III clinical trials.[3] The Japanese government is reportedly considering allowing Shionogi permission to apply for approval for medical use before the final steps of trials are completed, potentially speeding up the release for sale. This conditional early approval system has previously been used in Japan to accelerate the progression to market of other antiviral drugs targeting COVID-19, including remdesivir and molnupiravir.[6] In a study of 428 patients, viral load was reduced, but symptoms were not significantly reduced. [7] It became the first Japanese domestic pill to treat COVID-19, third to be regulatorally approved in Japan; in February 2022.[8]References
- ^ World Health Organization (2021). “International Nonproprietary Names for Pharmaceutical Substances. Proposed INN: List 126” (PDF). WHO Drug Information. 35 (4): 1135.
- ^ Xocova: Powerful New Japanese Pill for Coronavirus Treatment. BioPharma Media, February 2022
- ^ Jump up to:a b Unoh Y, Uehara S, Nakahara K, Nobori H, Yamatsu Y, Yamamoto S, et al. (January 2022). “Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19”. bioRxiv. doi:10.1101/2022.01.26.477782. S2CID 246367525.
- ^ “Shionogi presents positive Ph II/III results for COVID-19 antiviral S-217622”. thepharmaletter.com. 31 January 2022.
- ^ Shionogi’s new COVID pill appears to ease omicron symptoms. Nikkei Asia, 21 December 2021
- ^ Japan to consider early approval for Shionogi COVID-19 pill. Japan Times, 8 February 2022
- ^ https://www.reuters.com/business/healthcare-pharmaceuticals/japans-shionogi-seeks-approval-oral-covid-19-drug-2022-02-25/[bare URL]
- ^ “Japan’s Shionogi seeks approval for COVID-19 pill”. Reuters. Reuters. 25 February 2022.
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| Clinical data | |
|---|---|
| Other names | S-217622 |
| Identifiers | |
| PubChem CID | |
| Chemical and physical data | |
| Formula | C22H17ClF3N9O2 |
| Molar mass | 531.88 g·mol−1 |
| 3D model (JSmol) | |
- Sasaki, M., Tabata, K., Kishimoto, M., et al. (2022). Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases the viral load and accelerates recovery from clinical aspects of COVID-19. bioRxiv. doi:10.1101/2022.02.14.480338. https://www.biorxiv.org/content/10.1101/2022.02.14.480338v1.full.
///////////Ensitrelvir, S-217622, S 217622, Xocova, SHIONOGI, CORONA VIRUS,
Cn1cnc(CN2C(=O)N(Cc3cc(F)c(F)cc3F)C(=N\c3cc4cn(C)nc4cc3Cl)\NC2=O)n1
https://patentscope.wipo.int/search/en/detail.jsf?docId=JP321880865&_cid=P12-L0AEFS-91454-7