cas 261909-49-3, L-Alanine, N-(chlorophenoxyphosphinyl)-, 1-methylethyl ester

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Synthesis of 2′-deoxy-2′-fluoro-2′-C-methyl spiro cyclopentyl carbocyclic uridine analog as potential inhibitors of HCV NS5B polymerase
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.
Chu, Chung K.,Singh, Uma S.
p. 52 - 68
(2020)
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Prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides can increase anti-HCV activity and enhance nucleotide triphosphate concentrations in vitro
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).
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)
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Synthesis of an Anti-hepatitis B Agent, 2′-Fluoro-6′-methylene-carbocyclic Adenosine (FMCA) and Its Phosphoramidate (FMCAP)
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.
Singh, Uma S.,Mulamoottil, Varughese A.,Chu, Chung K.
p. 752 - 759
(2019)
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QUINUCLIDINONE ANALOGUES AS ANTICANCER AGENTS
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.
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Page/Page column 46

(2021/08/13)

Prodrug compound and application ofprodrug compound in treatment of cancer
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.
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(2021/03/06)

Polycyclic pyridinone compounds and pharmaceutical compositions and uses thereof
The invention discloses a polycyclic pyridone compound as well as a pharmaceutical composition and application thereof, and the polycyclic pyridone compound is shown as a formula (I). The compound can be used for preparing anti-virus infection drugs.
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Paragraph 0171-0175

(2021/11/06)

Compound for treating viral infection and preparation method and application of compound
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).
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Paragraph 0131-0136; 0140-0142

(2021/08/07)

Compound containing guanidyl group, and preparation method and application thereof
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.
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Paragraph 0122-0126; 0130-0132

(2021/08/07)

4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
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.
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Page/Page column 317-318

(2021/07/10)

Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
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.
Xu, Qin,Taher, Taher E.,Ashby, Elizabeth,Sharif, Maria,Willcox, Benjamin E.,Mehellou, Youcef
p. 2375 - 2380
(2021/05/26)

SPIROCYCLIC NUCLEOSIDE ANALOGUES FOR THE TREATMENT OF HEPATITIS E
The present disclosure is directed toward spirocyclic nucleoside analogs, compositions comprising these compounds, and their use for treating hepatitis E infections.
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Page/Page column 28; 38

(2021/10/22)

2,4,7-SUBSTITUTED-7-DEAZA-2'-DEOXY-2'-FLUOROARABINOSYL NUCLEOSIDE AND NUCLEOTIDE PRO-DRUGS AND USES THEREOF
The present disclosure is concerned with 2,4,7-substituted-7-deaza-2'-deoxy-2'- fluoroarabinosyl nucleoside and nucleotide prodrugs that are capable of inhibiting viral infections and methods of treating viral infections such as, for example, human immunodeficiency virus (HIV), human papillomavirus (HPV), herpes simplex virus (HSV), human cytomegalovirus (HCMV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), zika (ZIKV), 229E, NL63, OC43, HKU1, Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus disease 2019 (SARS-CoV-2), using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
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Paragraph 00352

(2020/12/30)

Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs: A Proof of Concept Study
The specific targeting of protein-protein interactions by phosphoserine-containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinder its uptake into cells. To address these issues, we herein report the synthesis of phosphoserine aryloxy triester phosphoramidates as phosphoserine prodrugs that are enzymatically metabolized to release phosphoserine. This phosphoserine-masking approach was applied to a phosphoserine-containing inhibitor of 14-3-3 dimerization, and the generated prodrugs exhibited improved pharmacological activity. Collectively, this provided a proof of concept that the masking of phosphoserine with biocleavable aryloxy triester phosphoramidate masking groups is a viable intracellular delivery system for phosphoserine-containing molecules. Ultimately, this will facilitate the discovery of phosphoserine-containing small-molecule therapeutics.
Dhiani, Binar A.,James, Edward,Kadri, Hachemi,Lambourne, Olivia A.,Mehellou, Youcef,Miccoli, Ageo,Thornton, Peter J.
supporting information

(2020/03/30)

PRODRUGS OF A CDK INHIBITOR FOR TREATING CANCERS
There are provided compounds of Formula I, and pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions thereof, used for inhibition or modulation of the activity of cyclin dependent kinases (CDK) and/or glycogen synthase kinase-3 (GSK-3), for the treatment of disease states or conditions mediated by cyclin dependent kinases and/or glycogen synthase kinase-3, including cancers. (I)
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Paragraph 00131

(2020/11/03)

Pyrrolotriazine compound, composition and application thereof
The invention relates to a pyrrolotriazine compound, a composition and an application thereof, the pyrrolotriazine compound has a structure as shown in a formula (I), and the definitions of R1-R11 areas defined in claim 1. The pyrrolotriazine compound has an excellent antiviral effect, and particularly can be used for preparing drugs for treating feline coronavirus infection-resistant diseases, such as feline infectious peritonitis.
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Paragraph 0092-0096

(2020/02/14)

Compound for treating metabolic diseases as well as preparation method and application thereof
The invention provides a compound for treating metabolic diseases, the compound has a structure represented by formula (I) or formula (II), or a racemate, a stereoisomer, a geometric isomer, a tautomer, a solvate, a hydrate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. The compounds provided by the invention are FXR and/or TGR5 receptor activators, and the compounds havethe activity of activating FXR and/or TGR5 receptors, and can be used for preparing medicines for treating chronic liver diseases, metabolic diseases or portal hypertension.
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Paragraph 0221-0224

(2019/07/04)

Targeting GNE Myopathy: A Dual Prodrug Approach for the Delivery of N-Acetylmannosamine 6-Phosphate
ProTides comprise an important class of prodrugs currently marketed and developed as antiviral and anticancer therapies. The ProTide technology employs phosphate masking groups capable of providing more favorable druglike properties and an intracellular activation mechanism for enzyme-mediated release of a nucleoside monophosphate. Herein, we describe the application of phosphoramidate chemistry to 1,3,4-O-acetylated N-acetylmannosamine (Ac3ManNAc) to deliver ManNAc-6-phosphate (ManNAc-6-P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG) caused by mutations in GNE that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac3ManNAc-6-phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug 12b showed rapid activation in a carboxylesterase (CPY) enzymatic assay and favorable ADME properties, while also being more effective than ManNAc at increasing sialic acid levels in GNE-deficient cell lines. These results provide a potential platform to address substrate deficiencies in GNE myopathy and other CDGs.
Morozzi, Chiara,Sedláková, Jana,Serpi, Michaela,Avigliano, Marialuce,Carbajo, Rosangela,Sandoval, Lucia,Valles-Ayoub, Yadira,Crutcher, Patrick,Thomas, Stephen,Pertusati, Fabrizio
p. 8178 - 8193
(2019/09/10)

PROCESSES FOR PREPARING COMPOUNDS/INTERMEDIATES USEFUL IN THE TREATMENT OF VIRAL INFECTIONS
An improved process for preparing the compound (I) is provided: which may be used in the synthesis of e.g. AL-335; AL-355 is a nucleoside inhibitor of NS3B polymerase, which plays an important role in the replication of the hepatitis C virus.
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Page/Page column 11; 12

(2020/01/08)

4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
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.
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Page/Page column 297; 298

(2019/10/01)

UREA DERIVATIVES AS INHIBITORS OF ASK1
The present technology is directed to compounds, compositions, and methods related to inhibition of ASK1. In particular, the present compounds (e.g., compounds of Formula I as defined herein) and compositions may be used to treat ASK1-mediated disorders and conditions, including, e.g., fibrotic diseases and acute and chronic liver diseases, among others.
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Paragraph 0119

(2019/06/05)

Synthesis of 1′,2′-methano-2′,3′-dideoxynucleosides as potential antivirals
The synthesis of constrained nucleosides has become an important tool to understand the SAR in the interaction between biological and synthetic nucleotides in the context of antisense oligonucleotide therapy. The incorporation of a cyclopropane into a furanose ring of a nucleoside induces some degree of constrain without affecting significantly the steric environment of a nucleoside. Here, we report a new, short and stereocontrolled synthesis of two constrained nucleosides analogues, 1′,2′- methano-2′,3′-dideoxyuridine 9, and the corresponding cytidine analog 12. X-ray crystallography revealed that the furanose ring in the constrained uridine and cytidine analogues was flattened with virtual loss of pseudorotation. The phosphoramidate esters of the novel constrained uridine and cytidine nucleosides, intended as prodrugs, were tested in cell-based assays for viral replication across the herpes virus family and HIV inhibition courtesy of Merck laboratories, Rahway. They were also tested in antiproliferative assays against colorectal and melanoma cell lines. Unfortunately, none of the compounds showed activity in these assays.
Rico, Lorena,Hanessian, Stephen
supporting information
p. 597 - 600
(2019/01/08)

SPIROTHIETANE NUCLEOSIDES
The present invention relates to 2'-spirothietane nucleosides, and the phosphates and the prodrugs thereof, and the pharmaceutically acceptable salts and solvates thereof, and the use of such compounds as a medicament, in particular in the prevention and/or treatment of viral infections caused by viruses belonging to the Flaviviridae family and/or to the alphavirus genus. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the compounds, and to the compositions or preparations for use as a medicament, more preferably for the prevention or treatment of viral infections caused by viruses belonging to the Flaviviridae family and/or to the alphavirus genus. The invention also relates to processes for the preparation of the compounds.
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Page/Page column 46

(2019/03/17)

Y27632 prodrug, preparation method thereof and application of Y27632 prodrug to medicine
The invention relates to a Y27632 prodrug, a preparation method thereof and application of the Y27632 prodrug in medicine. The prodrug is a compound shown as a general formula I (please see the specifications for the general formula I) or a pharmaceutically acceptable salt of the compound, the prodrug further includes a solvate and an optical isomer of the compound shown as the general formula I (please see the specifications for the general formula I) or the pharmaceutically acceptable salt of the compound, and the prodrug can treat hepatic diseases, especially hepatic fibrosis diseases. It is proved by experiments that the compound has the hepatic-targeting property, the hepatic tissue fibrosis level is significantly lowered in a hepatic fibrosis model animal, and the content of extracellular matrix (ECM) protein related components is decreased; and activation of hepatic stellate cells in hepatic tissue is significantly inhibited, collagen degradation is promoted, the Y27632 prodrugserves as an active ingredient to be used for preparing anti-hepatic fibrosis drugs and is more efficient and lower in toxicity than a mother drug Y27632, a new drug way is provided for treatment andprevention of hepatic fibrosis, thus the optional range of clinical medication is expanded, and good application and development prospects are achieved.
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Paragraph 0054-0057

(2020/01/03)

2'-SUBSTITUTED-N6-SUBSTITUTED PURINE NUCLEOTIDES FOR RNA VIRUS TREATMENT
The use of described compounds or pharmaceutically acceptable salts or compositions thereof for the treatment of a host infected with an RNA virus other than HCV, or other disorder more fully described herein.
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Page/Page column 220; 221

(2018/03/28)

Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution
The preparation of Sofosbuvir, the potent key component of recent Hepatitis C (HCV) infection therapies, is reported. The process is based on the dynamic kinetic resolution of the stereochemically unstable isopropyl-2-{[chloro(phenoxy)phosphoryl]-amino}propanoate (8). A high stereoselectivity was obtained when the right protective group for 3′-OH was chosen. Ester and carbonate-based protective groups gave lower stereoselectivities, but benzyl protection allowed the phosphorylation to occur with a 92:8 ratio in favour of the product with the right configuration at the P-stereogenic centre. Starting from the γ-lactone of 2-deoxy-2-fluoro-2-methylpentonic acid, the synthesis was accomplished in eight steps in 40 % overall yield using commercially available reagents, and without any enzymatic or chemical resolution technique.
Cini, Elena,Barreca, Giuseppe,Carcone, Luca,Manetti, Fabrizio,Rasparini, Marcello,Taddei, Maurizio
p. 2622 - 2628
(2018/04/30)

Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cell Immune Responses
The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This work highlights the promise of this prodrug technology in the discovery of novel immunotherapeutics.
Davey, Martin S.,Malde, Roshni,Mykura, Rory C.,Baker, Alfie T.,Taher, Taher E.,Le Duff, Cécile S.,Willcox, Benjamin E.,Mehellou, Youcef
p. 2111 - 2117
(2018/03/21)

Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization
Since loss of function mutations of PINK1 lead to early onset Parkinson’s disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability, and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.
Osgerby, Laura,Lai, Yu-Chiang,Thornton, Peter J.,Amalfitano, Joseph,Le Duff, Cécile S.,Jabeen, Iqra,Kadri, Hachemi,Miccoli, Ageo,Tucker, James H. R.,Muqit, Miratul M. K.,Mehellou, Youcef
p. 3518 - 3524
(2017/05/05)

NICOTINAMIDE RIBOSIDE AND NICOTINAMIDE MONONUCLEOTIDE DERIVATIVES FOR USE IN THE TREATMENTS OF MITOCHONDRIAL-RELATED DISEASES
Provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, and compositions comprising such compounds that are useful for increasing the amount of NAD+ in cells. Also disclosed are methods of using the disclosed compounds and compositions for treating mitochondrial-related diseases or disorders.
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(2017/06/20)

Kinase-independent phosphoramidate S1P1receptor agonist benzyl ether derivatives
Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P1-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents.
James, Edward,Pertusati, Fabrizio,Brancale, Andrea,McGuigan, Chris
p. 1371 - 1378
(2017/03/08)

NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 77; 78

(2017/07/14)

NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 152

(2017/09/27)

ALKYNE CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 317

(2017/12/09)

Antiviral nucleoside phosphoramidate and pharmaceutical composition and applications thereof
The invention provides an antiviral nucleoside phosphoramidate and a pharmaceutical composition and applications thereof. The nucleoside phosphoramidate compound is prepared by connecting nucleoside with phosphate through phosphorus-oxygen bonds. The structural formulas of the nucleoside phosphoramidate compound are represented by a, a1, a2, b, b1, and b2. The invention also discloses stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, or crystals of the nucleoside phosphoramidate compound. The anti-hepatitis C activity of the provided novel nucleoside phosphoramidate is obviously better than that of sofosbuvir used in clinic. On the saccharide ring, the fluorine atoms are replaced by chlorine atoms, and the cytotoxicity of measure cell lines is prominently reduced. By systematically modifying and optimizing the basic groups, saccharide rings, and prodrugs, the anti-hepatitis C activity of partial synthesized compounds is 2 to 10 times higher than that of sofosbuvir. At the same time, the key parts of metabolism are optimized, the metabolism stability and chemical stability of synthesized compounds in plasma are better, compared with those of sofosbuvir.
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Paragraph 0086-0089

(2017/05/06)

PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL AGENT
This invention provides a process for providing phosphoramidate derivatives, comprising performing a nucleophilic substitution reaction at phosphorous, where a phosphoryl chloride derivative is reacted with an oxime derivative to provide activated phosphoramidate intermediates, the intermediates find utility in a second nucleophilic substitution reaction where an activated phosphoramidate is reacted with a primary alcohol-containing sugar derivative, wherein the product of the reaction is sofosbuvir.
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Page/Page column 14

(2017/03/14)

Nucleoside analogs of the phosphate prodrug and its application
The invention provides a phosphate prodrug of a nucleoside analog as shown in the general formula I as well as all possible isomers and medicinal salts of the phosphate prodrug. The invention also provides an application of the compound to preparation of drugs for preventing and treating tumor diseases or virus related diseases.
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Paragraph 0086; 0087

(2017/08/25)

Anti-hepatitis b virus drug
The invention relates to a novel anti-hepatitis B virus drug represented in a formula I, and a nontoxic pharmaceutically acceptable salt and a hydrate thereof: (img file= 'DSA00000804267600011.TIF' wi= '739' he= '766' /), wherein R1 is alkyl or naphthenic base, of which the carbon number is 1-6, and R2 is H or alkyl of which the carbon number is 1-6.
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Paragraph 0043

(2017/10/06)

SYNTHESIS OF 2'-FLUORO-6'-METHYLENE-CARBOCYCLIC ADENOSINE (FMCA) AND 2'-FLUORO-6'-METHYLENE-CARBOCYCLIC GUANOSINE (FMCG)
The invention provides a new convergent approach for the synthesis of 2'-fluoro-6'- methylene-carbocyclic adenosine (FMCA) and 2'-fluoro-6'-methylene-carbocyclic guanosine (FMCG) from a readily available starting material in eight steps. An efficient and practical methodology for stereospecific preparation of a versatile carbocyclic key intermediate, (1S,3R, 4R)-3-tert-butoxy-4-(tert-butoxymethyl)-2-fluoro-5-methylenecyclopentanol (compound 8 of scheme 1A or a) in only six (6) steps is also provided. Prodrugs of these compounds are also prepared.
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Page/Page column 40; 41

(2017/11/04)

A PROCESS FOR THE PREPARATION OF SOFOSBUVIR INTERMEDIATES and ITS POLYMORPH
The present invention provides a novel process for preparation N-[(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2) and resolving the formula 2 in the presence base to form N-[(S)-(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2').
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Page/Page column 7

(2016/12/01)

METHODS FOR TREATING FILOVIRIDAE VIRUS INFECTIONS
Provided are compounds, methods, and pharmaceutical compositions for treating Filoviridae vims infections by administering ribosides, riboside phosphates and prodrugs thereof, of Formula (IV): The compounds, compositions, and methods provided are particularly useful for the treatment of Marburg virus, Ebola virus and Cueva virus infections.
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Paragraph 0177; 0179

(2016/05/19)

NUCLEOSIDE PHOSPHORAMIDATES USEFUL FOR THE TREATMENT OF VIRAL INFECTIONS AND PREPARATION THEREOF
The present invention relates to an industrially applicable process for the preparation of phosphoramidates useful for the treatment of viral infections, such as sofosbuvir, and to intermediates useful for the preparation thereof. Formula (I):
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Page/Page column 19; 20

(2016/10/11)

A PROCESS FOR THE PREPARATION OF NUCLEOSIDE PHOSPHORAMIDATE
The present invention pertains to process for preparing nucleoside phosphoramidate and its intermediate. The present invention provides novel intermediate, its process for preparation and its use for the preparation of Sofosbuvir.
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Page/Page column 6; 7

(2016/03/12)

Deuterated nucleoside derivative
The present invention relates to deuterated nucleoside derivative, particularly to a compound having a structure represented by a formula I or a pharmaceutically acceptable salt thereof. According to the present invention, the compound represented by the formula I has excellent pharmacokinetic properties and is expected to reduce the clinical dose so as to reduce the treatment and benefit more patients. The formula I is defined in the specification.
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Paragraph 0145; 0165-0170

(2016/10/07)

Sofosbuvir intermediate and preparation method thereof
The invention provides a sofosbuvir intermediate and a preparation method thereof. The intermediate adopts the structure shown in the specification. The intermediate is prepared from 4-(trifluoromethoxy)phenol and (S)-2-phenoxy-chloro-phosphoryl aminopropionic acid isopropyl ester through a reaction. In a sofosbuvir preparation process, the intermediate has the good splitting effect and is suitable for industrial production, and the overall reaction yield is high.
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Paragraph 0014; 0020

(2016/10/31)

Preparation method of sofosbuvir
The invention provides a preparation method of sofosbuvir. The preparation method takes 4-trifluoromethoxyphenol as a leaving group to react with (S)-2-phenoxy-chloro-phosphoryl amino isopropyl propionate to obtain racemized (S)-2-[(4-trifluoromethoxy-phenoxy)-phenoxy-phosphorylamino] isopropyl propionate; after the resolution, the racemized (S)-2-[(4-trifluoromethoxy-phenoxy)-phenoxy-phosphorylamino] isopropyl propionate reacts with (2minuteR)-2minute-deoxy-2minute-fluoro-2minute-methyluridine to obtain the sofosbuvir. The method provided by the invention takes the 4-trifluoromethoxyphenol as the leaving group and the resolution effect is good, so that the reaction yield is improved and the method is suitable for industrial production.
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Paragraph 0012; 0018

(2017/03/14)

SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Picornavirus and/or Flaviviridae infection with one or more nucleosides, nucleotides and nucleotide analogs.
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(2015/04/21)

SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
Disclosed herein are nucleosides, nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a Filoviridae virus infection with one or more nucleosides and/or nucleotide analogs.
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(2016/03/11)

SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Coronaviridae virus, a Togaviridae virus, a Hepeviridae virus and/or a Bunyaviridae virus infection with one or more nucleosides, nucleotides and nucleotide analogs.
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(2016/03/08)

METHODS OF PREPARING SUBSTITUTED NUCLEOTIDE ANALOGS
Disclosed herein are methods of preparing a phosphoroamidate nucleotide analog, which are useful in treating diseases and/or conditions such as viral infections.
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Paragraph 0076-0077

(2016/01/15)

NUCLEOTIDE AND NUCLEOSIDE COMPOSITIONS AND USES RELATED THERETO
This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 238; 239

(2015/03/28)

USE OF A L,3J5-TRIAZIN-2-YL PHOSPHORAMIDATE COMPOUND IN THE SYNTHESIS OF SOFOSBUVIR
The present invention relates to a new type of 1,3.5-triazin-2-yl phosphoramidates of general formula I with the absolute configuration (S) at the phosphorus atom, an Sp diastereoisomer, wherein R1 and R2 can independently be H, a C1-C6 (un)branched alkyl, a C1-C6 (un)branched alkoxy group, a C1-C6 (un)branched alkylsulfanyl group, C1-C6 (un)branched monoalkylamino or dialkylamino group, including cyclic amino groups, e.g. pyrrolidino, piperidino or morpholino group; and to their use for the production of biologically active phosphoramidate prodrugs, especially sofosbuvir of formula II. Sofosbuvir II is a nucleotide inhibitor of the RNA polymerase, used for the treatment of hepatitis C in the form of a prodrug, releasing the active antiviral agent 2'-deoxy-2'-a-fluoro- P-C-methyluridine-5'-triphosphate in the organism.
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Page/Page column 16; 17

(2015/11/09)