- A Practical Synthesis of (S)-HPMPC
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Synthesis of the title nucleotide was accomplished in high yield starting from (S)-tritylglycidol (5) and N-benzoylcytosine (9).
- Brodfuehrer, Paul R.,Howell, Henry G.,Sapino, Chester Jr.,Vemishetti, Purushotham
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- Method for synthesizing antiviral drugs cidofovir and buciclovir
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The invention relates to a method for synthesizing antiviral drugs, i.e., cidofovir and buciclovir, belonging to the field of asymmetric synthesis in organic chemistry. According to the invention, pyrimidine with position 1 substituted by an allyl group or purine with position 9 substituted by a butenyl group are used as raw materials and subjected to asymmetric dihydroxylation so as to obtain a key chiral intermediate of cidofovir or buciclovir, and then a multi-step reaction is carried out so as to obtain cidofovir or buciclovir. With such a route in the invention, the reaction raw materialsare easily available, stereoselectivity is high, and the chiral dihydroxynucleoside intermediates are obtained after the reaction, and the cidofovir and buciclovir can be smoothly obtained after multiple steps of transformation.
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- EGFR inhibitor and antiviral agent for simultaneous, separate or sequential use in the treatment and/or prevention and/or palliation of cancer
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The application relates to a combination of biologically active compounds comprising at least one antiviral agent and at least one EGFR antagonist, for simultaneous, separate or sequential use in the treatment and/or prevention and/or palliation of malignant or pre-malignant neoplasms, preferably of solid malignant or pre-malignant neoplasms.
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- Puromycin-sensitive aminopeptidase: An antiviral prodrug activating enzyme
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Cidofovir (HPMPC) is a broad-spectrum antiviral agent, currently used to treat AIDS-related human cytomegalovirus retinitis. Cidofovir has recognized therapeutic potential for orthopox virus infections, although its use is hampered by its inherent low oral bioavailability. Val-Ser-cyclic HPMPC (Val-Ser-cHPMPC) is a promising peptide prodrug which has previously been shown by us to improve the permeability and bioavailability of the parent compound in rodent models (Eriksson et al., 2008. Molecular Pharmaceutics 5, 598-609). Puromycin-sensitive aminopeptidase was partially purified from Caco-2 cell homogenates and identified as a prodrug activating enzyme for Val-Ser-cHPMPC. The prodrug activation process initially involves an enzymatic step where the l-Valine residue is removed by puromycin-sensitive aminopeptidase, a step that is bestatin-sensitive. Subsequent chemical hydrolysis results in the generation of cHPMPC. A recombinant puromycin-sensitive aminopeptidase was generated and its substrate specificity investigated. The kcat for Val-pNA was significantly lower than that for Ala-pNA, suggesting that some amino acids are preferred over others. Furthermore, the three-fold higher kcat for Val-Ser-cHPMPC as compared to Val-pNA suggests that the leaving group may play an important role in determining hydrolytic activity. In addition to its ability to hydrolyze a variety of substrates, these observations strongly suggest that puromycin-sensitive aminopeptidase is an important enzyme for activating Val-Ser-cHPMPC in vivo. Taken together, our data suggest that puromycin-sensitive aminopeptidase makes an attractive target for future prodrug design.
- Tehler, Ulrika,Nelson, Cara H.,Peterson, Larryn W.,Provoda, Chester J.,Hilfinger, John M.,Lee, Kyung-Dall,McKenna, Charles E.,Amidon, Gordon L.
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experimental part
p. 482 - 489
(2010/12/19)
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- CIDOFOVIR PEPTIDE CONJUGATES AS PRODRUGS
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Cidofovir-based compounds having an amino acid, dipeptide or tripeptide attached to a cidofovir or cyclic cidofovir framework. The compounds show enhanced oral bioavailability and increased binding to the PepT1 transporter. The present invention also provides compositions and methods for treating virus infections, and a method of preparing cidofovir.
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Page/Page column 11; figure 3
(2008/06/13)
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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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- SYNTHESES OF ENANTIOMERIC N-(3-HYDROXY-2-PHOSPHONOMETHOXYPROPYL)DERIVATIVES OF PURINE AND PYRIMIDINE BASES
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Methods of preparation of N-(3-hydroxy-2-phosphonomethoxypropyl) (HPMP) derivatives of (2S)- and (2R)-configuration compounds I and XXVII, respectively are described.The general method starts from the corresponding N-(2,3-dihydroxypropyl) derivatives which were converted either into the (R)-enantiomers XIII by reaction of the base with (R)-glycidol butyrate (XII) in the presence of cesium carbonate and subsequent methanolysis, or into the (S)-enantiomers XI by alkylation of the base with (R)-2,2-dimethyl-4-tosyloxymethyl-1,3-dioxolane (V) in the presence of the same reagent.The amino groups on the heterocyclic base in compounds XI and XIII were benzoylated by silylation followed by reaction with benzoyl chloride and the obtained N-benzoates XV and XVII on reaction with trityl chloride afforded the corresponding 3'-O-trityl derivatives XVI and XVIII.These compounds were condensed with bis(2-propyl)-p-toluenesulfonyloxymethanephosphonate (XXIII) in dimethylformamide in the presence of sodium hydride to give the fully protected diesters XXIV and XXVIII.These compounds could be selectively acid-hydrolyzed to remove the trityl group only under formation of compounds XXXV, or methanolyzed and then acid-hydrolyzed to remove the trityl and N-benzoyl groups and lead to compounds XXVI and XXX, or treated with bromotrimethylsilane to remove the trityl and 2-propyl group to give phosphonates of the type XXVI.All the three types of compounds were then converted into free phosphonates of the (S)-series (I) and (R)-series (XXVII).Derivatives of cytosine (Ia, XXVIIa), adenine (Ib, XXVIIb), 2,6-diaminopurine (Ic, XXVIIc) and guanine (Id, XXVIId) were prepared.Condensation of the partially blocked adenine derivative XXXV with the tosyl derivative XXIII and subsequent deprotection afforded 9-(S)-(2,3-diphosphonomethoxypropyl)adenine (XLIII).Reaction of the same compound XXXV or its (R)-enantiomer XXXVIII with diethyl chlorophosphonate, followed by deblocking, afforded 3'-O-phosphoryl derivatives (S)-HPMPA (XXXVII) and (R)-HPMPA (XL).
- Holy, Antonin
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p. 649 - 674
(2007/10/02)
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- GENERAL METHOD OF PREPARATION OF N- DERIVATIVES OF HETEROCYCLIC BASES
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Reaction of (R)-1-O-p-toluenesulfonyl-1,2,3-propanetriol (IV) with N-trimethylacetylimidazole (II) afforded (R)-1-O-p-toluenesulfonyl-3-O-trimethylacetyl-1,2,3-propanetriol (V) which was reacted with dimethoxymethane in the presence of phosphorus pentoxide to give (R)-2-O-methoxymethyl-1-O-p-toluenesulfonyl-3-O-trimethylacetyl-1,2,3-propanetriol (VI).Compound VI was treated with acetic anhydride and boron trifluoride etherate and the obtained 2-acetoxy derivative VII reacted with bromotrimethylsilane to give the intermediary bromomethyl ether VIII.Compound VIII on reaction with tris(2-propyl) phosphite afforded (R)-2-O-bis(2-propyl)phosphonomethyl-1-O-p-toluenesulfonyl-3-O-trimethylacetyl-1,2,3-propanetriol (IX).Condensation of synthon IX with sodium salts of adenine, 2,6-diaminopurine, or with cytosine, 6-azacytozine or 2-chloroadenine in the presence of cesium carbonate, afforded fully protected diesters X and XIIIb which on methanolysis and reaction with bromotrimethylsilane gave N- derivatives of adenine (XIa), 2-chloroadenine (XIb), 2,6-diaminopurine (XIc), cytosine (XIVa) and 6-azacytosine (XIVb).In an analogous reaction, sodium salt of 4-methoxy-2-pyrimidone reacted with compound IX to give an intermediate XIIIa which on treatment with methanolic ammonia and subsequent deblocking under the same conditions also afforded the cytosine derivative XIVa.Sodium salt of 2-amino-6-chloropurine was in this way converted into the corresponding 2-aminopurine derivative XVIII.Deprotection of this compound gave 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)-2-aminopurine (XIX).
- Alexander, Petr,Holy, Antonin
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p. 1151 - 1163
(2007/10/02)
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- Synthesis and antiviral activity of the nucleotide analogue (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cystosine
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The acyclic nucleotide analogue (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (2, HPMPC) was prepared on a multigram scale in 18% overall yield starting from (R)-2,3-O-isopropylideneglycerol. The key step in the nine-step synthetic route is coupling of cytosine with the side-chain derivative 8 which bears a protected phosphonylmethyl ether group. In vitro data showed that HPMPC has good activity against herpes simplex virus types 1 and 2, although it was 10-fold less potent that acyclovir [ACV, 9-[(2-hydroxyethoxy)methyl]guanine]. By comparison, HPMPC exhibited greater activity than ACV against a thymidine kinase deficient strain of HSV 1 and was more potent than ganciclovir [DHPG, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine] against human cytomegalovirus. In vivo, HPMPC showed exceptional potency against HSV 1 systemic infection in mice, having an ED50 of 0.1 mg/kg per day (ip) compared with 50 mg/kg per day for ACV. HPMPc was also more efficacious than ACV in the topical treatment of HSV 1 induced cutaneous lesions in guinea pigs.
- Bronson,Ghazzouli,Hitchcock,Webb II,Martin
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p. 1457 - 1463
(2007/10/02)
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