261909-49-3Relevant articles and documents
Synthesis of 2′-deoxy-2′-fluoro-2′-C-methyl spiro cyclopentyl carbocyclic uridine analog as potential inhibitors of HCV NS5B polymerase
Chu, Chung K.,Singh, Uma S.
, p. 52 - 68 (2020)
Synthesis of 1-((4 R,5S,6R,7R)-5,6-dihydroxy-7-(hydroxymethyl)spiro[2.4]heptan-4-yl)pyrimidine-2,4(1H,3H)-dione (12) and its phosphoramidate prodrug 18 is reported. The synthesis of the targeted compound 12 was initiated from triol 1. By the introduction of a substituent methylene group at 6-position of 4, followed by Simmons-Smith cyclopropanation and amination, key intermediate 10 was synthesized. The intermediate amine 10 was utilized to synthesize the nucleoside 12. Furthermore, the nucleoside 12 was derivatized to 2′-α-hydroxy-2′-β-methyl (23) and 2′-α-fluoro-2′-β-methyl (27) analogs. All synthesized derivatives of spiro-cyclopropyl carbocyclic uridine analogs 12, 18, 23 and 27 were evaluated for anti-HCV activity, but none of the compounds, reported in this article show any anti-HCV activity.
Prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides can increase anti-HCV activity and enhance nucleotide triphosphate concentrations in vitro
Tyndall, Edward M.,Draffan, Alistair G.,Frey, Barbara,Pool, Brett,Halim, Rosliana,Jahangiri, Saba,Bond, Silas,Wirth, Veronika,Luttick, Angela,Tilmanis, Danielle,Thomas, Jesse,Porter, Kate,Tucker, Simon P.
, p. 869 - 873 (2015)
A number of prodrugs of HCV-active purine nucleoside analogues 2′-C-methyl 4-aza-9-deaza adenosine 1, 2′-C-methyl 4-aza-7,9-dideaza adenosine 2, 2′-C-methyl 4-aza-9-deaza guanosine 3 and 2′-C-methyl 4-aza-7,9-dideaza guanosine 4 were prepared and evaluated to improve potency, selectivity and liver targeting. Phosphoramidate guanosine prodrugs (3a-3k and 4a, b) showed insufficient cell activity for further profiling. Striking enhancement in replicon activity relative to the parent was observed for phosphoramidate imidazo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs (1a-1p), but this was accompanied by an increase in cytotoxicity. Improved or similar potency without a concomitant increase in toxicity relative to the parent was demonstrated for phosphoramidate pyrrolo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs (2a-2k). Carbamate, ester and mixed prodrugs of 2 showed mixed results. Selected prodrugs of 2 were analysed for activation to the triphosphate, with most demonstrating much better activation in hepatocytes over replicon cells. The best activation was observed for a mixed phosphoramidate-3′ester (11) followed by a simple 3′-ester (10).
Synthesis of an Anti-hepatitis B Agent, 2′-Fluoro-6′-methylene-carbocyclic Adenosine (FMCA) and Its Phosphoramidate (FMCAP)
Singh, Uma S.,Mulamoottil, Varughese A.,Chu, Chung K.
, p. 752 - 759 (2019)
2′-Fluoro-6′-methylene-carbocyclic adenosine (FMCA, 12) and its phosphoramidate prodrug (FMCAP, 14) have been proven as a potential anti-HBV agent against both adefovir-resistant as well as lamivudine-resistant double (rtL180M/rtM204V) mutants. Furthermore, in vitro, these agents have demonstrated significant activity against lamivudine/entecavir triple mutants (L180M + S202G + M204V). These preliminary results encourage us for further biological evaluation of FMCA and FMCAP to develop as a potential clinical candidate as an anti-HBV agent, which may overcome the problem of drug resistance in HBV therapy. To support the preclinical exploration, a scalable synthesis of this molecule was needed. In this communication, a practical and scalable synthesis of FMCA, and its prodrug, is reported via ketone 1. The selective opening of the isopropylidene group of 2 led to compound 3. Protection of the allylic hydroxyl group of 3, followed by fluorination and deprotection, afforded the key intermediate 10, which was condensed with a Boc-protected adenine, followed by deprotection, furnished the target nucleoside FMCA (12) in high yield. Further coupling of phosphorochloridate of L-alanine isopropyl ester (13) with FMCA gave its phosphoramidate prodrug FMCAP (14) in good yield.
Compound for treating viral infection and preparation method and application of compound
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Paragraph 0131-0136; 0140-0142, (2021/08/07)
The invention provides a preparation for treating viral infection and pneumovirus subfamily viral infection, a method, a compound as shown in a formula (I) and a method and intermediate for synthesis of the compound as shown in the formula (I).
Compound containing guanidyl group, and preparation method and application thereof
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Paragraph 0122-0126; 0130-0132, (2021/08/07)
The invention provides a preparation containing a guanidino compound and used for treating pneumoviridae virus infection, a method, a compound of a formula I, and a method and an intermediate for synthesizing the compound of the formula I.
4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
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Page/Page column 317-318, (2021/07/10)
Disclosed are halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.
Prodrug compound and application ofprodrug compound in treatment of cancer
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Paragraph 0140; 0142, (2021/03/06)
The present invention provides a compound indicated by a formula (I), pharmaceutically acceptable salts or esters thereof, a pharmaceutical composition of the compound, and application of the compoundand the pharmaceutical composition in the inhibition or regulation of the activity of tyrosine kinase and treating disease symptoms or symptoms including cancer mediated by tyrosine kinase.
Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
Xu, Qin,Taher, Taher E.,Ashby, Elizabeth,Sharif, Maria,Willcox, Benjamin E.,Mehellou, Youcef
, p. 2375 - 2380 (2021/05/26)
Aryloxy triester phosphoramidate prodrugs of the monophosphate derivatives of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) were synthesized as lipophilic derivatives that can improve cell uptake. Despite the structural similarity of IPP and DMAPP, it was noted that their phosphoramidate prodrugs exhibited distinct stability profiles in aqueous environments, which we show is due to the position of the allyl bond in the backbones of the IPP and DMAPP monophosphates. As the IPP monophosphate aryloxy triester phosphoramidates showed favorable stability, they were subsequently investigated for their ability to activate Vγ9/Vδ2 T cells and they showed promising activation of this subset of T cells. Together, these findings represent the first report of IPP and DMAPP monophosphate prodrugs and the ability of IPP aryloxy triester phosphoramidate prodrugs to activate Vγ9/Vδ2 T cells highlighting their potential as possible immunotherapeutics.
SPIROCYCLIC NUCLEOSIDE ANALOGUES FOR THE TREATMENT OF HEPATITIS E
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Page/Page column 28; 38, (2021/10/22)
The present disclosure is directed toward spirocyclic nucleoside analogs, compositions comprising these compounds, and their use for treating hepatitis E infections.
QUINUCLIDINONE ANALOGUES AS ANTICANCER AGENTS
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Page/Page column 46, (2021/08/13)
The disclosure includes compounds of Formula (I) and Formula(A) wherein R1, R2, R3, m, n, k, and L are defined herein. Also disclosed are methods for treating a neoplastic disease, autoimmune disease, or an inflammatory disorder with these compounds.
