- A Simple Solution to the Age Old Problem of Regioselective Functionalization of Guanine: First Practical Synthesis of Acyclic N9- and/or N7-Guanine Nucleosides Starting from N2,N9-Diacetylguanine
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Regioselective alkylation of guanine, a long-lasting challenge, has been overcome by understanding the role of acids as catalyst in the coupling reaction of DAG (10) with OBDDA (11). The acid-catalyzed and noncatalyzed reactions of 10 with OBDDA which mainly give N7 and N9 isomers, respectively, appear to follow different mechanisms. The practical utility of the noncatalyzed reaction, which gives almost quantitative yields of N9 derivatives, is demonstrated by synthesizing acylovir/gancyclovir in high yields.
- Singh, Dharmendra,Wani, Mukesh J.,Kumar, Ashok
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- Synthesis and antiherpetic activity of acyclovir phosphonates
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Phosphonate derivatives of acyclovir containing phosphorous acid and ethoxy-carbonylphosphonic acid residues as well as their isopropyl esters were prepared. They selectively inhibited the herpes simplex virus 1 reproduction in Vero cell culture, the effi
- Karpenko, Inna L.,Jasko, Maxim V.,Andronova, Valeriya L.,Ivanov, Alexander V.,Kukhanova, Marina K.,Galegov, Georgy A.,Skoblov, Yury S.
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- Synthesis of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) from guanosine
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A convenient synthesis of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) from guanosine by chemical transpurination was developed. The isomerization of the 7-isomer to the desired 9-isomer and the purification of the 9- isomer was achieved simply by concentration, heating and further crystallization.
- Shiragami,Koguchi,Tanaka,Takamatsu,Uchida,Ineyama,Izawa
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- Spectrofluorimetric and TLC-densitometric methods for a stability indicating assay of valacyclovir hydrochloride in the presence of its degradation product
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Two stability-indicating methods were developed and validated for determination of valacyclovir HCl (VAC) in the presence of its degradation product, acyclovir. The first was a TLC-densitometric method, in which chloroform:::methanol:::ammonia (50:::14:::2 v/v/v) was used as a mobile phase. Silica gel 60 F254 was used as a stationary phase and the chromatogram was scanned at 253 nm. Using this chromatographic system, VAC can be readily separated from its degradation product and gives a compact spot at an RF value of (0.55 ± 0.03). The peak area concentration plot is rectilinear over the range 20-300 ng per band. The second method represents the first attempt for spectrofluorimetric determination of VAC. The method was based on the reaction between VAC and 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) in an alkaline medium (pH 8.5) to form a highly fluorescent product that was measured at 500 nm after excitation at 465 nm. The fluorescence intensity concentration plot is rectilinear over the range 1-10 μg ml-1. The proposed methods were successfully applied for the determination of VAC in its commercial tablets with average percentage recovery of 100.13 ± 0.33 and 98.50 ± 1.75 for TLC-densitometric and spectrofluorimetric methods, respectively, without interference from common excipients. The results of the proposed methods were statistically analyzed and found to be in accordance with those given by a reported method. In addition the proposed methods were extended to a stability study of VAC, where the drug was exposed to acidic, alkaline, oxidative and photolytic degradation according to ICH guidelines. This journal is
- Derayea, Sayed M.,Mostafa, Islam M.,Omar, Mahmoud A.
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- Synthesis and physico-chemical characterization of a β-cyclodextrin conjugate for sustained release of Acyclovir
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We report the synthesis of an oligomeric prodrug of the antiviral agent Acyclovir (Acy) conjugated to β-cyclodextrin (β-CyD). The drug was selectively linked through a succinic spacer to one of the primary hydroxyl groups of β-CyD by ester linkage in a 1:1 molar ratio. The conjugate was purified by semipreparative reverse-phase chromatography and characterized by FAB mass spectrometry and NMR experiments. The release of Acy from the conjugate was evaluated both in acidic and in neutral conditions and in the presence of porcine liver esterase. In all cases we observed the release of both free Acy and Acy succinate (AcySucc) at differing rates as a function of the hydrolysis conditions. In the presence of esterase the release of free Acy was favoured over AcySucc, showing a release rate of 100% of Acy within 7 days.
- Pedotti, Sonia,Pistarà, Venerando,Cannavà, Carmela,Carbone, Claudia,Cilurzo, Felisa,Corsaro, Antonino,Puglisi, Giovanni,Ventura, Cinzia Anna
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- Phosphoramidate derivatives of acyclovir: Synthesis and antiviral activity in HIV-1 and HSV-1 models in vitro
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The antiviral activity against HIV and HSV and the chemical stability of ACV phosphoramidate derivatives were studied. The phosphoramidates of ACV demonstrated moderate activity. The best compound appeared to be 9-(2-hydroxymethyl)guanine phosphoromonomor
- Zakirova, Natalia F.,Shipitsyn, Alexander V.,Jasko, Maxim V.,Prokofjeva, Maria M.,Andronova, Valeria L.,Galegov, Georgiy A.,Prassolov, Vladimir S.,Kochetkov, Sergey N.
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- 5-Cyanoamino-4-imidazolecarboxamide and Nitrosative Guanine Deamination: Experimental Evidence for Pyrimidine Ring-Opening during Deamination
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5-Cyanoamino-4-imidazolecarboxamide 4a (R = CH2-O-CH2-CH2-OH) has been synthesized, purified, and fully characterized by MS, MS/MS, HRMS, IR spectroscopy, and by 1H and 13C NMR spectroscopy. It is shown that cyclization of 4a yields the guanine 6a and the isoguanine 12a. Our findings provide experimental evidence in support of our hypothesis that the formation of oxanine and xanthine in nitrosative guanine deamination may proceed via pyrimidine ring-opened intermediates. The observed formation of 6a from the amide 4a (XH2 = NH2) shows that, in analogy, oxanine can be formed from 3 (XH = OH). The formation of 12a from 4a reveals for the first time the possibility that oxanine might be formed by a second pathway that involves electrocyclic reaction of 3. Finally, the new chemistry suggests the possibility for a new dG-to-dG cross-link. Copyright
- Qian, Ming,Glaser, Rainer
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- Method for synthesizing acyclovir and ganciclovir by carbon-hydrogen bond activation
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The invention discloses a method for synthesizing acyclovir and ganciclovir by carbon-hydrogen bond activation and belongs to the field of organic synthesis. The method comprises that inexpensive guanine as a raw material undergoes methyl protection on 9th NH, a high-valent iodine reagent and monoacetyl-protected ethylene glycol or 1, 2-isopropylidene-protected glycerol are added into the raw material under catalysis of palladium acetate, the mixture undergo a heating reaction to produce acetyl-protected acyclovir or acetyl-protected ganciclovir, and the acetyl group is removed by an inorganicalkali alcohol solution so that acyclovir and ganciclovir are obtained. The method utilizes cheap and easily available raw materials, prevents use risk and corrosive reagents, has the advantages of short reaction route, simple operation, high atomic economy and high total product yield, provides a novel synthesis route of acyclovir and ganciclovir and has a potential application prospect.
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Paragraph 0020; 0028; 0029' 0030
(2019/01/07)
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- Synthesis method of cobalt catalysis-modified acyclovir
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The invention discloses a synthesis method of cobalt catalysis-modified acyclovir and belongs to the technical field of pharmaceutical intermediates. The synthesis method comprises that potassium t-butoxide as a reaction base and toluene as a reaction solvent undergo a reaction in the presence of [(NH-C3H5)Tr(NHP(iPr)2)2CoCl2] as a catalyst in one process to produce a desired product acyclovir. The synthesis method has simple processes and an acyclovir yield greatly higher than that of the traditional three-step reaction, is free of sodium bisulfate and acetic acid in the whole reaction process, prevents the contamination of sulfate and protonic acid and facilitates the post-treatment. The product is white crystalline powder, is odorless and tasteless and has high purity. The improved synthesis path greatly improves a yield, reduces a cost, improves safety, saves energy and satisfies the modern industrial production requirements of the eco-friendly reaction.
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Paragraph 0013; 0014; 0015
(2018/11/22)
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- Comparative Analysis of Acyclovir Esters Stability in Solutions: The Influence of the Substituent Structure, Kinetics, and Steric Effects
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Reversed-phase high-performance liquid chromatography has been applied to the determination of acyclovir (ACV) esters such as acetate, isobutyrate, pivalate, ethoxycarbonate, and nicotinate. All analyses were carried out at laboratory temperature using a column LiChrospher RP-18 (250 × 4 mm, 5 μm) and a proper mobile phase consisting of acetonitrile and phosphate buffer (pH 6 or 6.7) or acetonitrile and potassium dihydrogen phosphate, and acetic acid. The methods were validated by the determination of the following parameters: selectivity, precision, accuracy, and linearity. Kinetic studies on the hydrolysis were investigated in solutions at 310 K over the pH range 0.42-1.38. The pH-profiles indicated specific acid-catalyzed and spontaneous water-catalyzed degradation. The stability of the studied ACV esters were determined not only by steric factors. In the case of ethoxycarbonyl ester of ACV, the hydrolysis was a two-step reaction.
- Lesniewska, Monika A.,Gola, Micha?,Dutkiewicz, Zbigniew,Muszalska, Izabela
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p. 724 - 733
(2015/10/06)
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- Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme
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We herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solid-phase synthesis of the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding tetrapeptide amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug.
- Diez-Torrubia, Alberto,Cabrera, Silvia,De Castro, Sonia,García-Aparicio, Carlos,Mulder, Gwenn,De Meester, Ingrid,Camarasa, María-José,Balzarini, Jan,Velázquez, Sonsoles
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p. 456 - 468
(2013/11/19)
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- Biocatalytic synthesis of valaciclovir using commercial enzymes
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Proof-of-concept has been demonstrated for the biocatalytic transformation of aciclovir into valaciclovir, attaining high conversions from a solid-to-solid biotransformation in l-valine methyl ester using various formulations of Subtilisin Carlsberg activated for use in organic solvent.
- McClean, Kathleen,Preston, Christopher,Spence, David,Sutton, Peter W.,Whittall, John
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p. 215 - 218
(2011/02/26)
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- Structure-activity relationships for dipeptide prodrugs of acyclovir: Implications for prodrug design
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A series of water-soluble dipeptide ester prodrugs of the antiviral acyclovir (ACV) were evaluated for their chemical stability, cytotoxicity, and antiviral activity against several strains of Herpes Simplex-1 and -2, vaccinia, vesicular stomatitis, cytom
- Santos, Cledir R.,Capela, Rita,Pereira, Claudia S.G.P.,Valente, Emilia,Gouveia, Luis,Pannecouque, Christophe,De Clercq, Erik,Moreira, Rui,Gomes, Paula
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p. 2339 - 2346
(2009/12/07)
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- Synthesis, antiviral activity, and stability of nucleoside analogs containing tricyclic bases
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A series of 3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine nucleosides (tricylic nucleosides) were synthesized from 9-[4-α-(hydroxymethyl)cyclopent-2-ene-1-α-yl]guanine (CBV) 5, (-)-β-D-(2R,4R)-1,3-dioxolane-guanosine (DXG) 6, 3′-azido-3′-deoxy-guanosine (AZG)
- Amblard, Franck,Fromentin, Emilie,Detorio, Mervi,Obikhod, Alexander,Rapp, Kimberly L.,McBrayer, Tamara R.,Whitaker, Tony,Coats, Steven J.,Schinazi, Raymond F.
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p. 3845 - 3851
(2009/12/04)
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- Method for site-specific labeling of RNA using a deoxyribozyme
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The present invention is a method for site-specific internal RNA modification. In accordance with the present method, a deoxyribozyme (DNA enzyme) is used as a catalyst to attach a tagging RNA to a pre-determined internal position of a target RNA molecule, wherein the tagging RNA is coupled to a label prior to or after attachment to the target RNA molecule thereby labeling the target RNA.
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- Oral Medicament For The Modified Release Of At Least One Active Principle, In Multimicrocapsule Form
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The field of the invention is that of oral medicaments or pharmaceutical compositions, in particular of the type including one or more active principles. The aim of the invention is to provide an improved oral medicament to be administered in one or several daily doses and enabling the modified release of active principles (in particular of one active principle), whereby the prophylactic and therapeutic effectiveness of said medicament is improved. This aim is achieved by the oral multimicrocapsule galenic form according to the invention, in which the active principle release is controlled by a dual release trigger mechanism: “time-dependent trigger” and “pH-dependent trigger”. Said medicament includes microcapsules providing the modified release of the active principle, each comprising a core containing
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- Engineering a selective small-molecule substrate binding site into a deoxyribozyme
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A small goal: An RNA ligase deoxyribozyme is engineered to accept a small-molecule NTP substrate in a multiple-turnover fashion. Selective binding is enforced by hydrogen bonding, and structural preorganization within the NTP itself is important for its efficient utilization as a substrate. This study points the way toward a broader use of small-molecule substrates with nucleic acid enzymes. (Figure Presented)
- Hoebartner, Claudia,Silverman, Scott K.
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p. 7420 - 7424
(2008/09/18)
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- Compositions and methods for enhancing drug delivery across and into ocular tissues
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This invention provides compositions and methods for enhancing delivery of drugs and other agents across epithelial tissues, including into and across ocular tissues and the like. The compositions and methods are also useful for delivery across endothelial tissues, including the blood brain barrier. The compositions and methods employ a delivery enhancing transporter that has sufficient guanidino or amidino sidechain moieties to enhance delivery of a compound conjugated to the reagent across one or more layers of the tissue, compared to the non-conjugated compound. The delivery-enhancing polymers include, for example, poly-arginine molecules that are preferably between about 6 and 25 residues in length.
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- Specific lipid conjugates to nucleoside diphosphates and their use as drugs
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The present invention concerns new phospholipid derivatives of nucleosides of the general formula (I) in which R1represents a straight-chained or branched, saturated or unsaturated aliphatic residue with 9-14 carbon atoms which can optionally be substituted once or several times; R2can represent a straight-chained or branched, saturated or unsaturated aliphatic residue with 8-12 carbon atoms which can optionally be substituted once or several times; m is 2 or 3; A can represent a methylene group or an oxygen; Nuc can be a nucleoside or a residue derived from a nucleoside derivative; and tautomers thereof and their physiologically tolerated salts of inorganic and organic acids and bases as well as pharmaceutical preparations containing these compounds.
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- Pharmaceutical composition comprising a suspension for the active ingredient
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A pharmaceutical formulation may be prepared by a method comprising providing the active ingredient in solution in a pharmacologically-acceptable base and mixing the resulting solution with a pharmacologically-acceptable acid in an amount such that the formulation attains a pH in the range of from about 3.5 to about 8.5 to thereby precipitate out the active ingredients, a viscosity-enhancing agent having been incorporated in the formulation prior to or during the mixing with acid. The formulation is suitable for administration of a pharmacologically active ingredient which is sparingly soluble in water at a pH acceptable for administration, for example to the eye of the patient.
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- Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir
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The objective of this work was to improve nasal absorption of relatively impermeable small drug molecules via an amino acid prodrug approach. Acyclovir was selected as a model drug. L-Aspartate β-ester, L-lysyl, and L-phenylalanyl esters of acyclovir were synthesized to investigate their effectiveness in enhancing nasal absorption of acyclovir. A stability study was conducted in phosphate buffer under various pH conditions at 25 and 37°C. Enzymatic hydrolysis in rat nasal washings and plasma was conducted at 37°C. A rat in situ nasal perfusion technique was utilized in this investigation to examine the rate and extent of nasal absorption of amino acid prodrugs. The remaining analyte concentrations in the nasal perfusate were quantitated by reversed-phase high-performance liquid chromatography. The results revealed that the L-lysyl and L-phenylalanyl esters were less stable than L-aspartate β-ester. The stability of all three esters decreased with increasing pH and temperature. L-phenylalanyl ester is highly susceptible to plasma esterases, with an in vitro half-life 1.33 min. The rat in situ nasal perfusion study revealed that the extent of nasal absorption of acyclovir, L-lysyl and L-phenylalanyl esters was not significant (p 1%). L-Aspartate β-ester was absorbed to the extent of ～8% over 90 min of perfusion at an initial drug concentration of 100 μM. Nasal absorption of L-aspartate β-ester of acyclovir was inhibited by L-asparagine but not by a dipeptide glycylsarcosine (Gly-Sar). The enhancement of acyclovir nasal absorption from the L-aspartate β-ester prodrug suggests that nasal uptake of this prodrug probably involves an active transport system.
- Yang, Chun,Gao, Hongwu,Mitra, Ashim K.
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p. 617 - 624
(2007/10/03)
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- PROCESS FOR THE PREPARATION OF 9- (2-HYDROXYETHOXY)METHYL]GUANINE
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There is described a process for the preparation of acyclovir by hydrolysis of N-acetyl-9-(2-acetoxyethoxymethyl)guanine with monoethanolamine and isolation of acyclovir by neutralization with an acid and filtration. There is furthermore described a method for the purification of acyclovir by transformation of it into one of its alkali metal salts and neutralization of the alkali metal salt thus obtained.
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- Regioselective synthesis of acyclovir and its various prodrugs
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High-yield regioselective synthesis of 9-[(2-hydroxyethoxy)methyl]guanine (Acyclovir 1, Scheme 1) was achieved from guanine via trisilylated guanine. N2-acylacyclovir 9a-9b were prepared from N2, O-diacylacyclovir (4, 8b-8d) using regioselective deacylation procedure. N2-Acylacyclovir 11 and 13 were prepared via protection of primary hydroxyl groups. Three amino acid esters of acyclovir were synthesized as water-soluble prodrugs, which form protonated cations in pH 7.4 phosphate buffer. Two water-soluble ester prodrugs with free carboxylic acids, which form anionic species in pH 7.4 phosphate buffer, were also synthesized.
- Gao,Mitra
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p. 1399 - 1419
(2007/10/03)
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- Azetidinone derivatives for the treatment of HCMV infections
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A compound of formula 1: wherein Y is S or O; R1is C1-6alkyl; (C0-6alkyl)aryl; (C0-6alkyl)Het; or R1is an amino acid analog or dipeptide analog of the formula: wherein R2is H, C1-10alkyl; or an amide or ester group; A is C6-10aryl, Het or CH—R3wherein R3is C1-6alkyl or (C0-4alkyl)aryl; and Z is H, C1-6alkyl, or an acyl; R4is hydrogen, lower alkyl, methoxy, ethoxy, or benzyloxy; and R5is alkyl, cycloalkyl, carboxyl group; an aryl; Het or Het(lower alkyl); or R4and R5together with the nitrogen atom to which they are attached form a nitrogen containing ring optionally substituted with phenyl or C(O)OCH2-phenyl, said phenyl ring optionally mono- or di-substituted with among others C(O)OR7wherein R7is lower alkyl or phenyl(lower alkyl); or a therapeutically acceptable acid addition salt thereof which compounds are useful in the treatment of HCMV infections.
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- Transport of acyclovir ester prodrugs through rabbit cornea and SIRC-rabbit corneal epithelial cell line
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The purpose of this study is to assess the permeability of acyclovir (ACV) prodrugs through the rabbit corneal cell line (SIRC) as well as the cornea, and characterize the SIRC cell line for transport and metabolism studies of ester prodrugs. Prodrug derivatization of an acycloguanosine antiviral agent, acyclovir, was employed to improve its permeability across the cornea. New Zealand albino rabbits were used as an animal model for corneal studies. The SIRC cell line grown on polyester membranes was used for transport of these prodrugs. SIRC cells grown on the membrane support for 10 days developed four to six layers of epithelial cells, and this is comparable to the normal rabbit corneal epithelial layer. Transport experiments were conducted across the rabbit cornea and confluent SIRC cells using side-by-side diffusion-cell apparatus. Enzymatic hydrolysis of these compounds was evaluated in SIRC cell lysates. Appropriate reversed phase HPLC method(s) were employed for quantitation of both the prodrug and ACV simultaneously. Corneal permeabilities of some of these prodrugs (Malonyl ACV and Acetyl ACV) were higher relative to ACV. The SIRC cell line permeability values of all the prodrugs were higher compared to that of the intact cornea. The total amount of ACV-prodrugs transported, i.e., unhydrolyzed prodrugs and regenerated ACV, across the SIRC cell line was more relative to ACV. Hydrolytic studies in the SIRC cell line homogenate demonstrated the bioreversion potential of the prodrugs and the presence of enzymes, particularly the cholinesterase in the SIRC cell line. It may be concluded that the SIRC cell line is leakier compared to the cornea. Keeping in mind the limitations, the SIRC cell line after further characterization may be used for transport and metabolism studies of ester prodrugs.
- Tak, Rahul V.,Pal, Dhananjay,Gao, Hongwu,Dey, Surajit,Mitra, Ashim K.
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p. 1505 - 1515
(2007/10/03)
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- Acyclovir transdermal delivery system
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A transdermal formulation for providing antiviral effect in dermis or epidermis, wherein comprising (a) 0.01 to 30 weight percent of antiviral drug; (b) 0.05 to 20 weight percent of a Chinese medicine enhancer; and (c) a pharmaceutical acceptable vehicles. The antiviral drug is selected from the group consisting of ACV(Acyclovir), Carbovir, DDA(2',3'-Dideoxyadnosine), HPMPA(1-(3-Hydroxy-2-phosphonylmethoxylpropyl)-adenosine), DHPG(Ganciclovir), Desciclovir, IDC (5-Iodo-2'-deoxy-cytidine), Vidarabine(Ara-A), DDI(2',3'-Dideoxyinosine), Cordycepin, Cytarabine, Deoxyguanosine, d4T(2',3'-Didehydro-3'-deoxythymidine), FIAC(2'-Fluoro-5-iodoaracytosine), AZT(ZDV, Zidovudine), Ara-T(1- beta -D-Ara-binofuranosylthymine), Deoxythymidine, Ribavirin, EDU(5-Ethyl-2'-deoxy-uridine), Enviroxime, Amantadine, Arildone, HPMPC(9-(3-Hydroxy-2-phosphonyl-methoxyl-propyl)cytidine), Riboxamide, Rimantidine, Tromantadine, Foscamet sodium, Moroxydine, F3T(5-Trifluoro-methyl-2'-deoxy-uridine), BVDU (Bromovinyldeoxyuridine). Preferably, the Chinese medicine enhancer is oleanolic acid, and the pharmaceutical acceptable vehicles is polyethylene glycols.
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- Process for the preparation of 9-(2-hydroxy)-ethoxymethyl-guanine
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A process for the preparation of acyclovir by alkylation of N2 -formylguanine with 2-oxa-1,4-diacyloxybutane and hydrolysis of the resulting intermediate is described.
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- Process for producing acyclic nucleosides and process for separating purine nucleosides
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Herein is disclosed a novel and industrially advantageous process for synthesizing acyclic nucleosides such as acyclovir and ganciclovir from ribonucleosides, which process comprises adding an acid catalyst and an acid anhydride to a solution of a ribonucleoside such as guanosine and an ester derivative of an acyclic sugar, and heating the mixture, whereby a transglycosilation reaction takes place between the ribose moiety of the ribonucleoside and the ester derivative of the acyclic sugar. Herein is also disclosed an industrially favorable method for the separation of 9-substituted purine nucleosides which are important intermediates for the synthesis of acyclic nucleosides such as acyclovir, ganciclovir, and the like from ribonucleosides, which method comprises crystallizing only the 9-isomer from a solution or suspension containing both a 9-substituted purine nucleoside and a 7-substituted purine nucleoside by cooling the solution or/and by adding a crystallizing solvent thereto.
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- Oxidative Cleavage of the Tricyclic Derivatives of 9-Substituted Guanines
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Iodine in methanol was found to be a simple and effective reagent for the removal of prop-1-ene-1,2-diyl bridge from the tricyclic derivatives of 9-substituted guanines exemplified by 1b-1d.The transformation proceeds via cleavage of the N8-C7 bond of the tricyclic system with formation of N2-guanine derivatives 2b-2d; compounds 2b-2d were isolated and their structure assigned on the basis of 1H and 13C NMR spectra.Treatment of 2b-2d with aq. ammonia resulted in parent 9-substituted guanines 3b-3d.
- Boryski, Jerzy,Ostrowski, Tomasz,Baranowski, Daniel,Goslinski, Tomasz,Golankiewicz, Bozenna
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p. S38 - S41
(2007/10/03)
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- Preparation of acyclovir using 1,3 dioxolane
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A process for the preparation of acyclovir includes contacting an at least partially silylated guanine or mixture of at least partially silylated guanines with 1,3-dioxolane in the presence of a selective alkylation catalyst selected from the group consisting of trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, and bistrimethylsilyl sulfonate, and hydrolyzing the product thus formed.
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- Process for the synthesis of 9-(2-hydroxyethoxy methyl) guanine
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A process for the synthesis of 9-(2-hydroxyethoxy methyl) guanine in which guanine, or its salts, is reacted with 2-4 moles of hexamethyldisilazane, in the presence of an aprotic solvent and of ammonium sulfate. Thereafter, the trimethylsilyl derivative, without being isolated, is reacted with a stoichiometric quantity of an acyloxyethoxy methyl halide and hydrolyzed with aqueous sodium acetate or sodium hydroxyde to give 9-(2-hydroxyethyoxy methyl) guanine.
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- Preparation of N-9 substituted guanine compounds
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The invention relates to efficient and selective processes for the synthesis of the antiviral N-9 substituted guanine compounds acyclovir and ganciclovir.
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- Syntheses of acyclic guanine nucleosides
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A method is provided for the synthesis of synthesis of acyclic purine nucleosides, particularly 9-(2-hydroxyethoxymethyl)-guanine (acyclovir) and 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine ("DHPG") where the N2,N9 -diprotected guanine is reacted with CH3 C(O)OCH2 O(CH2)2)OC(O)CH3 or diacetoxypropane, respectively, in the presence of a mixture of an acid and acetic anhydride, or in the presence of an acid, where the acid can be phosphoric acid or polyphosphoric acid.
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- Nucleic acid related compounds. 93. A solution for the historic problem of regioselective sugar-base coupling to produce 9-glycosylguanines or 7-glycosylguanines
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Per(trimethylsilyl)-2-N-acylguanine derivatives and tetra-O-acylpentofuranoses were coupled [tin(IV) chloride or titanium(IV) chloride catalysis] to give predominant formation of 7-glycosylguanines. With TiCl4, a fortuitous organic/aqueous partitioning allowed isolation of 7-glycosylguanines from the 7/9 isomer mixtures. Per(trimethylsilyl)-2-N-acyl-6-O-(diphenylcarbamoyl)guanine derivatives and tetra-O-acylpentofuranoses underwent regioselective coupling (trimethylsilyl trifluoromethanesulfonate catalysis) to give 9-glycosylguanines. The 6-O-(diphenylcarbamoyl)peracyl-9-β-D-ribofuranosyl isomer was shown to be both the xinetic and thermodynamic coupling product. Deprotection of all of the peracyl coupling products was effected under mild conditions to give good to high yields of guanine nucleoside analogues. These methodologies provide solutions for the regioselective synthesis of 7- and 9-glycosylguanine nucleosides.
- Robins, Morris J.,Zou, Ruiming,Guo, Zhiqiang,Wnuk, Stanislaw F.
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p. 9207 - 9212
(2007/10/03)
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- Process for the synthesis of 9(2-hydroxyethoxy methyl) guanine
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The subject of the present invention is a new process for the synthesis of 9-(2-hydroxyethoxy methyl) guanine (acyclovir) (I), carried out starting from guanine, without intermediate isolation.
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- Conversion of guanosine into acyclovir and its 6-deoxy derivative
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2-amino-6-(4-chlorophenylthio)-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl) purine 11, which is readily prepared by allowing the corresponding 6-chloro-compound 10 to react with 4-chloro(thiophenol) and triethylamine in methanol solution at room temperature, reacts with boron trifluoride diethyl etherate in boiling dichloromethane solution to give 2-amino-6-(4-chlorophenylthio)-9H-purine 12 in high isolated yield. 9-[(2-acetoxyethoxy)methyl]-2-amino-6-(4-chlorophenylthio)-9H-purine 13, prepared from the latter aglycone 12 in good yield, is converted by a four-step process into acyclovir 1 and by a two-step process into 6-deoxyacyclovir 2.
- Buck, Ildiko M.,Eleuteri, Alessandra,Reese, Colin B.
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p. 9195 - 9206
(2007/10/02)
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- Transglycosilation process for producing acyclic nucleosides
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Herein is disclosed a novel and industrially advantageous process for synthesizing acyclic nucleosides such as acyclovir and ganciclovir from ribonucleosides, which process comprises adding an acid catalyst and an acid anhydride to a solution of a ribonucleoside such as guanosine and an ester derivative of an acyclic sugar, and heating the mixture, whereby a transglycosilation reaction takes place between the ribose moiety of the ribonucleoside and the ester derivative of the acyclic sugar.
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- Anti-virals
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Anti-virals wherein a linoleyl, gamma-linolenyl or other unsaturated long chain fatty acyl group is borne directly on a hydroxy or amino group of the sugar/sugar analogue or heterocyclic moiety of a nucleoside or nucleoside analogue.
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- Process for preparing 9-(2-hydroxyethoxymethyl)-guanine
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There is disclosed a process for preparing 9-(2-hydroxyethoxymethyl)-guanine (acyclovir) of the formula IV STR1 wherein a novel compound of the formula I STR2 wherein R and R' may be the same or different and represent hydrogen, (C1 -C8)acyl or benzyl and R1 represents (C1 -C8)acyl, is hydrolyzed basic conditions. Also disclosed is the novel compound of the formula I, a process for the preparation thereof by condensing a novel compound of the formula II STR3 with a compound A--CH2 --O--CH2 CH2 --OR' (A is a leaving group, Q is hydrogen or a leaving group), the novel compound of the formula II and a process for the preparation thereof by means of condensing glyoxal hydrate and a compound of the formula V STR4
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- An Efficient Regioselective Synthesis of Substituted Purine Analogues of Guanosine and Inosine
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Condensation of 2-bromo-6-(4-nitrophenylethoxy)purine as the trimethylsilyl derivative (5a) with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose, 1-O-acetyl-2,3-di-O-benzoyl-5-deoxy-5-diethoxy-phosphinyl-β-D-ribofuranose, and (2-acetoxyethoxy)methyl bromide resulted in N9-regioselective alkylation to give (6a-c), which were then converted to guanine and hypoxanthine nucleosides, nucleotides, and Acyclovir analogues, respectively.
- Raju, Natarajan,Robins, Roland K.,Vaghefi, Morteza M.
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p. 1769 - 1770
(2007/10/02)
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- Methods and compositions for treating viral infections and guanine acyclic nucleosides
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9-Hydroxyethoxymethyl (and related) derivatives of certain 6-, and 2,6-substituted purines have been discovered to have potent anti-viral activities. Novel compounds and their pharmaceutically acceptable salts, pharmaceutical formulation containing the compounds of this invention, and the treatment of viral infections with these formulations are all disclosed. 9-(2-hydroxyethoxymethyl) guanine and 2-amino-9-(2-hydroxyethoxymethyl)adenine are examples of especially active compounds of this invention.
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- A direct method for the preparation of 2-hydroxyethoxymethyl derivatives of guanine, adenine, and cytosine
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Alkylation of 2-chloro-6-iodopurine with iodomethyl [(trimethylsilyl)oxy]ethyl ether at -63°C and subsequent treatment of the 9-substituted chloroiodopurine with K2CO3 in aqueous dioxane at 25°C and then with NH3 under pressure at 150°C provided 9-[(2-hydroxyethoxy)methyl]guanine (1a), a potent antiviral agent against Herpes simplex virus type 1, in excellent yield. Its monophosphate (1g), which is enzymatically produced from 1a in the virus-infected cell, was also synthesized. 6-Chloropurine and 4-(methylthio)pyrimidin-2-one anions were similarly alkylated with iodomethyl [(trimethylsilyl)oxy]ethyl ether, and the products were transformed by treatment with methanolic NH3 at 110°C into 9-[(2-hydroxyethoxy)methyl]adenine and 1-[(2-hydroxyethoxy)methyl]cytosine respectively. The synthesis of these analogues, heretofore difficult to prepare by a simple procedure, has been conveniently accomplished.
- Barrio,Bryant,Keyser
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p. 572 - 574
(2007/10/02)
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- 2-Amido-9-(2-acyloxyethoxymethyl)hypoxanthines
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Method of preparing 9-(2-hydroxyethoxymethyl)guanine which comprises preparing the compound STR1 wherein R and R1 are hydrogen, lower alkyl and phenyl and then hydrolyzing same. 9-(2-hydroxyethoxymethyl)guanine is useful as an antiviral.
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