1191237-69-0

Usage

Uses

1. Used in Pharmaceutical Industry:
(2R,3R,4S,5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile can be used as a building block or intermediate in the synthesis of various pharmaceutical compounds. Its unique structure and functional groups may allow for the development of new drugs with novel mechanisms of action.
2. Used in Chemical Research:
(2R,3R,4S,5R)?2?(4?aminopyrrolo[1,2?f][1,2,4]triazin?7?yl)?3,4?dihydroxy?5?(hydroxymethyl)tetrahydrofuran?2?carbonitrile can be utilized in chemical research to study its reactivity, stability, and potential applications in various chemical reactions. Its unique structure may provide insights into new reaction pathways and help develop new synthetic methods.
3. Used in Material Science:
The compound's unique structure and functional groups may also make it a candidate for the development of new materials with specific properties, such as improved mechanical strength, thermal stability, or chemical resistance.
4. Used in Antiviral Applications:
As an example, GS-441524, which is structurally similar to the compound in question, is an antiviral drug that inhibits RNA-dependent RNA polymerases. The compound in question may have potential antiviral properties, which could be explored for the development of new antiviral therapies.
5. Used in Drug Delivery Systems:
Similar to gallotannin, the compound in question may have potential applications in drug delivery systems. Its unique structure and functional groups could be exploited to improve the delivery, bioavailability, and therapeutic outcomes of various drugs.

Mechanism of action

GS-441524 requires intracellular phosphorylation via cellular kinases to a nucleoside monophosphate and subsequently to the active triphosphate metabolite (NTP) ( Cho et al., 2012 ; Sheahan et al., 2017; Warren et al., 2016). The active NTP analog functions as a competitor of the natural nucleoside triphosphates in viral RNA synthesis. The active form of GS-441524 has been shown to inhibit RSV RNA-dependent RNA polymerase mediated transcription by incorporating into the nascent viral transcript and causing premature termination ( Sheahan et al., 2017 ). We hypothesized that GS-441524 would be activated in feline cells, attenuate FIPV replication, have low cytotoxicity in feline cells in vitro and effectively treat cats with experimentally induced FIP.

Pharmacokinetics

A pharmacokinetic (PK) study was performed in laboratory cats to determine the metabolism and acute animal toxicity of GS-441524. GS-441524 was dissolved at a concentration of 12.5 mg/ml in 5% ethanol, 30% propylene glycol, 45% PEG 400, 20% water, and adjusted to pH 1.9 with concentrated HCl. Six laboratory cats were randomly divided into group A (n = 3; IV administration) or B (n = 3; SC administration). At time point zero, Group A cats were administered 5 mg compound/kg body weight intravenously while Group B cats received 5 mg com- pound/kg subcutaneously. Cats were then monitored for signs of acute toxicity (elevated pulse, respiratory distress, cyanosis, diarrhea, anorexia, drooling, vomiting, ataxia, weight loss, and changes in rectal temperature) daily for five days. Serial 0.5 ml whole blood samples in EDTA were obtained by lateral saphenous, superficial brachial or jugular venipuncture from each cat at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h. After collection, blood samples were immediately placed onice and then centrifuged at 5000 rpm for 5 min. The isolated plasma was pipetted into a 1.5 ml microcentrifuge tube and frozen at ? 70 °C for further analysis of free GS-441524. The buffy coat fraction from each blood collection was suspended in 1.5 ml phosphate free Tris-buffered saline (TBS, 50 mM Tris-Cl, pH 7.5, 150 mM NaCl) and PBMC isolated by Ficoll Hypaque density gradient centrifugation. The plasma and PBMC fractions were snap frozen in liquid nitrogen and shipped on dry ice to Gilead Sciences, Inc. (Foster City, CA) for further analyses. (plasma drug concentration and intracellular phosphorylation analyses).

Acquired resistance

Resistance to GS-441524 can exist at the time of diagnosis, but this is uncommon. Rather, it tends to occur during treatment and is often partial at first and necessitates a higher dosage to accommodate for it. It can become total in some cats. Resistance is the biggest problem in cats with neurological disease, especially those that present with neurological disease or develop brain infections during treatment or during a relapse after what appears to have been a successful treatment. Many cats with partial drug resistance can be treated for their disease signs but will relapse as soon as the treatment is stopped. There have been cats "treated" for FIP for over a year with no cure, but ultimately resistance becomes worse or the owner runs out of money.

Biological Activity

GS 441524 is a viral RNA-dependent RNA polymerase (RdRp) inhibitor and broad spectrum antiviral nucleotide; active metabolite of Remdesivir. Competes with natural nucleoside triphosphates, blocking viral RNA synthesis. Exhibits antiviral activity against viruses from Coronaviridae family including SARS-CoV-2 in vitro, and SARS-CoV and feline infectious peritonitis virus (FIPV) in vitro and in vivo. Inhibits SARS-CoV and MERS-CoV- infected HAE cultures (EC50 values are 0.18 and 0.86 μM, respectively) and inhibits murine hepatitis virus (MHV) (EC50 = 1.1 μM).

Side effects

GS-441524 treatment is amazingly free of systemic side effects. It can cause minor kidney damage in some cats, but this does not progress to overt renal disease. Systemic drug reactions of the vasculitis type have been seen in a few cats and can be confused with injection site reactions. However, these drug reactions are at non-injection sites and are often self-limiting or respond well to a short-term low dose of steroids. The major side-effect of GS treatment is pain at the injection sites, which varies from cat to cat and according to the injection prowess of the person doing the treatment (usually the owner). Injection site sores are a problem with some owners and usually occur when the injection site is not moved around the body (stay away from between the shoulders) and not given into the muscle and nerve layers below the subcutis. I recommend selecting sites starting an inch behind the shoulder blades, down the back to 1-2 inches before the tailhead, and one third to one-half of the way down the chest and abdomen. Many people use gabapentin before injections to help ease the pain. Injection site sores are cleared of surrounding hair and gently cleaned 4 or more times a day with sterile cotton balls soaked in 1:5 dilution of household hydrogen peroxide. They usually do not require any more sophisticated treatment and heal within 2 weeks or so.

Preparation and handling

GS-441524 is supplied as a solid. A stock solution may be made by dissolving the GS-441524 in the solvent of choice, which should be purged with an inert gas. GS-441524 is soluble in organic solvents such as DMSO and dimethyl formamide. The solubility of GS-441524 in these solvents is approximately 10 mg/ml. GS-441524 is sparingly soluble in aqueous buffers. For maximum solubility in aqueous buffers, GS-441524 should first be dissolved in DMSO and then diluted with the aqueous buffer of choice. GS-441524 has a solubility of approximately 0.16 mg/ml in a 1:5 solution of DMSO:PBS (pH 7.2) using this method. We do not recommend storing the aqueous solution for more than one day.

References

1) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys: T.K. Warren, et al.; Nature 531, 381 (2016) 2) Late Ebola virus relapse causing meningoencephalitis: a case report: M. Jacobs, et al.; Lancet 388, 498 (2016) 3) Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses: T.P. Sheahan, et al.; Sci. Transl. Med. 9, eaal3653 (2017) 4) Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4- amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses; D. Siegel, et al.; J. Med. Chem. 60, 1648 (2017) 5) Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease: M.L. Agostini, et al.; mBio 9, e00221 (2018) 6) Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir: E.P. Tchesnokov, et al.; Viruses 11, E326 (2019) 7) Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge: M.K. Lo, et al.; Sci. Transl. Med. 11, eaau9242 (2019) 8) Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase: A.J. Brown, et al.; Antiviral Res. 169, 104541 (2019) 9) Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection: R. de Wit, et al.; PNAS (Epub ahead of print) (2020) 10) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro: M. Wang, et al.; Cell Res. 30, 269 (2020)

Upstream product

• 888720-29-4 4-chloropyrrolo[1,2-f][1,2,4]triazine 
• 7677-24-9 trimethylsilyl cyanide 
• 158227-80-6 7-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 
• 57378-89-9 2,3,5-tri-O-benzyl-D-ribofuranosyl bromide 
• 2328091-01-4 C₁₁H₁₃BrN₄O₂ 
• 56522-24-8 tert-butyldimethylsilyl cyanide 
• 19158-51-1 P-toluenesulfonyl cyanide 
• 1355357-49-1 (2R,3R,4R,5R)‐2‐{4‐aminopyrrolo[2,1‐f][1,2,4]triazin‐7‐yl}‐3,4‐bis(benzyloxy)‐5‐[(benzyloxy)methyl]tetrahydrofuran‐2‐carbonitrile 
• 532-20-7 D-Ribose 
• 1355049-94-3 (3R,4R,5R)-2-(4-aminopyrrole-[2,1-f][1,2,4]-triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol 

Downstream Products

• 1355050-10-0 (2S)-isopropyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 
• 1809249-37-3 (2S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 
• 1191237-80-5 (3αR,4R,6R,6αR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile 
• 1911578-75-0 (2S)-2-ethylbutyl 2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 
• 1355050-12-2 (2S)-ethyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 
• 1355050-11-1 (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 

Relevant academic research and scientific papers

Synthesis method of antiviral drug ridexivir and intermediate thereof

The invention discloses a synthesis method of an antiviral drug retegravir, which comprises the following steps: carrying out addition reaction on a compound 1 and a compound 2 to obtain a compound 3,carrying out cyanation reaction under the action of Lewis acid to obtain a compound 4, carrying out copper-catalyzed ammonolysis reaction to obtain a compound 5, carrying out palladium-catalyzed hydrogenation debenzylation to obtain a compound 6, and finally, reacting with a compound 7 to obtain a retegravir product. According to the method, the compound 1 is directly used as a raw material, no extra active hydrogen exists, and the reaction yield is high,the method has the advantages of simple operation, no amino interference, high cyanation reaction yield, clean and efficient palladium-carbon alkylation debenzylation reaction, convenient palladium-carbon recovery, and less three wastes. In addition, the leaving group of the compound 7 is improved to improve the activity of the compound 7, and the unprotected docking reaction of 6 and 7 is optimized by adding a proper auxiliary agent, so that the selectivity and the reaction yield can be greatly improved. The route is simple to operate, high in total yield, high in product purity and suitable for large-scale production.

Preparation process of ridecevir mother nucleus intermediate

The invention discloses a preparation process of a ridecevir mother nucleus intermediate (3aR,4R,6S,6aS)-6-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxo-4-yl)methanol. The preparation method comprises the following steps: carrying out a coupling reaction on a pyrrole triazine halide II serving as a raw material and a halide III under the promotion of a metal reagent MX to obtain a coupling product IV with high stereoselectivity; and carrying out a free radical reaction on the IV and a cyaniding reagent in the presence of an oxidizing agent, and carrying out a boron trichloride debenzylation reaction on the obtained intermediate to obtain the ridecevir mother nucleus intermediate I with high stereoselectivity. The method has the main beneficial effects that the process route is relatively short, the reaction condition is mild, tedious procedures such as strong acidity and column chromatography separation and purification are avoided from the source, the reaction yield is high, the stereoselectivity is good, the method is easy to industrialize, and the method has relatively high implementation value and social and economic benefits.

METHODS OF PREPARING 1'-CYANO NUCLEOSIDES

The present disclosure generally describes methods of preparing l'-cyano nucleosides, such as a compound of Formula (I). For example, the compound of Formula (I) can be prepared from a compound of Formula (Il-a) in a flow reactor.

N-protected heterocyclic compound, preparation method thereof and method for preparing C-nucleoside derivative by using N-protected heterocyclic compound

The invention provides an N-protected heterocyclic compound, a preparation method thereof and a method for preparing a C-nucleoside derivative by using the N-protected heterocyclic compound. Specifically, the invention provides a method for preparing the C-nucleoside derivative by using a heterocyclic compound protected by N-carbobenzoxy or N-tert-butyloxycarboryl. According to the method, halogenation is not needed, temporary amino protection is not needed, protons of the heterocyclic compound are removed by directly using an organic lithium or organic magnesium compound, and addition with ribose lactone is carried out. According to the method, the synthesis route of the C-nucleoside derivative is shortened, and the yield of the reaction of the heterocyclic compound and the ribose lactone is remarkably improved under the condition that no halogen atom is used as a substituent group.

Synthesis method of key intermediate of ridecevir

The invention provides a novel method for preparing a key intermediate of ridecevir as shown in a formula (VII). Benzyl fully-protected lactone as shown in a formula (I) is used as a starting material and is subjected to ring opening to obtain a compound as shown in a formula (II). The hydroxyl of the compound (II) is protected by a proper protecting group to obtain the compound shown in the formula (III). The compound (III) and the compound (IV) are subjected to coupling, protecting group removal and cyclization to obtain an intermediate shown as a formula (V) by a one-pot method. The intermediate (V) is subjected to two-step conversion to obtain the key intermediate (VII) of the ridecevir. According to the method provided by the invention, the compound (I) which can be bought in the market is used as the starting material, and the key intermediate compound (VII) for preparing the ridecevir is obtained at high yield through five-step reaction, so that the cost is greatly reduced, and the method is suitable for industrial mass production.

Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2

The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two L-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3′-isobutyryl ester 5a, the 5′-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.

Method for preparing retegravir by using micro-channel reactor

The invention discloses a method for synthesizing retegravir by using a micro-channel reactor, which realizes continuous flow synthesis of retegravir by using a scale effect of a micro-flow field technology and using a novel micro-channel reactor to repla

Novel compound and application thereof

The invention relates to a novel compound and application thereof, and also relates to an application of the compound in preparation of antiviral drugs and the like. In particular, AIDS virus is present. Application of hepatitis B virus, paramyxovirus and

Synthesis and evaluation of a collection of purine-like C-nucleosides as antikinetoplastid agents

The kinetoplastid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are the causative agents of neglected tropical diseases with a serious burden in several parts of the world. These parasites are incapable of synthesizing purines de nov

Method for synthesizing nucleoside analogue by using continuous flow reactor

The invention discloses a method for synthesizing a nucleoside analogue by using a continuous flow reactor. The method comprises the following steps that: a dichloromethane solution of (2R, 3R, 4R, 5R)-2-(4-aminopyrrolo[1, 2-f][1, 2, 4]triazin-7-yl)-3, 4-dibenzyloxy-5-((benzyloxy)methyl)tetrahydrofuran-2-nitrile used as a raw material solution and a dichloromethane solution of boron trichloride used as an auxiliary material solution of a debenzylation reaction respectively enter a mixer through respective pump systems, then flow through a main reaction pipeline, and then enter an aqueous alkali solution for quenching, and filtering and pulping are carried out so as to obtain a target product (2R, 3R, 4S, 5R)-2-(4-aminopyrrolo[1, 2-f][1, 2, 4] triazin-7-yl)-3, 4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-nitrile. The method disclosed by the invention is simple to operate, efficient, high in product yield, high in purity and suitable for large-scale production.