Preparation of Phosphonomethyl Ethers Derived from 2-Phenylethanol and Its Amino Derivatives

1995 ◽  
Vol 60 (4) ◽  
pp. 659-669
Author(s):  
Marcela Krečmerová ◽  
Antonín Holý
Keyword(s):  
Antiviral Activity ◽  
Cell Cultures ◽  
Sodium Hydride ◽  
Amino Group ◽  
Lithium Aluminium Hydride ◽  
Adenine Ring ◽  
Lithium Aluminium ◽  
Amino Derivatives ◽  
Acyclic Nucleoside

A series of compounds derived from the acyclic nucleoside antiviral 9-(2-phosphonomethoxyethyl)adenine (PMEA), in which the adenine ring is replaced by phenyl, 4-aminophenyl, 3-aminophenyl or 3,5-diaminophenyl group, has been prepared starting from the corresponding phenethyl alcohols. 2-(3-Aminophenyl)ethanol was prepared from 3-nitrobenzoyl chloride using the Arndt-Eistert reaction. The primarily formed diazoketone Ia was converted into ethyl 3-nitrophenylacetate (IIa) which on catalytic hydrogenation afforded ethyl 3-aminophenylacetate (IIIa). Compound IIIa was reduced with lithium aluminium hydride to give 2-(3-aminophenyl)ethanol (IVa). 2-(3,5-Diaminophenyl)ethanol (IVb) was prepared analogously from 3,5-dinitrobenzoyl chloride. After protection of the amino group with dimethylaminomethylene group, the alcohol IVa was converted to diisopropyl 2-(3-aminophenyl)ethoxymethylphosphonate (XII) by reaction with sodium hydride and diisopropyl p-toluenesulfonyloxymethanephosphonate, followed by deprotection of the amino group by treatment with ammonia. Reaction of diisopropyl ester XII with bromotrimethylsilane gave free 2-(3-aminophenyl)ethoxymethylphosphonic acid (XVII). The same procedure, applied to the corresponding aminophenethyl alcohols, afforded: 2-(4-aminophenyl)ethoxymethylphosphonic acid (XVI) and 2-(3,5-diamino phenyl)ethoxymethylphosphonic acid (XVIII). The synthesized compounds were tested in vitro on cell cultures for the cytostatic and antiviral activity (HSV-1, HSV-2, VSV, VZV, CMV). No antiviral activity has been found for any of the compounds.

Pyrimidine Acyclic Nucleotide Analogues with Aromatic Substituents in C-5 Position

2007 ◽  
Vol 72 (7) ◽  
pp. 927-951 ◽  
Author(s):  
Marcela Krečmerová ◽  
Antonín Holý ◽  
Milena Masojídková
Keyword(s):  
Antiviral Activity ◽  
Cell Cultures ◽  
Inhibitory Activity ◽  
Thymidine Phosphorylase ◽  
Sodium Hydride ◽  
Phosphonic Acids ◽  
Nucleotide Analogues ◽  
Varicella Zoster ◽  
Subsequent Hydrolysis ◽  
Phosphonate Esters

NH2-protected 5-phenylcytosine and its derivatives 2a-2d were treated with (2S)-2-[(trityloxy)methyl]oxirane (3) followed by etherification with diisopropyl [(tosyloxy)methyl]phosphonate (5) in the presence of sodium hydride. The intermediary phosphonate esters 6 were debenzoylated and subsequently transformed to free phosphonic acids, i.e. (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-phenylcytosine (5-phenyl-HPMPC) derivatives (8a-8d) by the action of bromotrimethylsilane and subsequent hydrolysis. Deamination of these compounds with 3-methylbutyl nitrite afforded corresponding (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-phenyluracil (5-phenyl-HPMPU) derivatives (9a-9d). R-Enantiomers 14 and 15 were prepared analogously starting from (2R)-2-[(trityloxy)methyl]oxirane. 5-Benzyl-, 5-[(1-naphthyl)methyl]- and 5-[(2-naphthyl)methyl]HPMPU (24a-24c) and -HPMPC (25a-25c) were synthesized from appropriate 5-arylmethyl-4-methoxypyrimidin-2(1H)-ones similarly as described for 5-phenyl derivatives. Antiviral activity was found for (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-phenyluracil (9a) (HSV-1 and HSV-2) and (R)-1-[3-hydroxy2-(phosphonomethoxy)propyl]-5-phenylcytosine (14) (cytomegalovirus and varicella-zoster virus), both tested in cell cultures. Some of the 5-phenyluracil derivatives possessed inhibitory activity against thymidine phosphorylase from SD-lymphoma.

Antiviral Activity of Some Hydroxycoumarin Derivatives

1996 ◽  
Vol 51 (7-8) ◽  
pp. 558-562 ◽  
Author(s):  
Angel S. Galabov ◽  
Tanya Iosifova ◽  
Elka Vassileva ◽  
Ivanka Kostova
Keyword(s):  
Antiviral Activity ◽  
Newcastle Disease Virus ◽  
Disease Virus ◽  
Virus Replication ◽  
Cell Cultures ◽  
Newcastle Disease ◽  
Inhibitory Effect ◽  
Marked Inhibitory Effect ◽  
Herpès Virus

Abstract Esculetin (6,7-dihydroxycoumarin) and its diacetate exhibited a marked inhibitory effect on Newcastle disease virus replication in cell cultures at concentrations of 36 jam and 62 jam, respectively. These compounds were selected from ten hydroxycoumarin derivatives through an in vitro antiviral screen involving viruses of the picorna-, orthomyxo-, paramyxo-, and herpes virus families.

New in vitro method for evaluating antiviral activity of acyclic nucleoside phosphonates against plant viruses

2010 ◽  
Vol 88 (3) ◽  
pp. 296-303 ◽  
Author(s):  
J. Špak ◽  
A. Holý ◽  
D. Pavingerová ◽  
I. Votruba ◽  
V. Špaková ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Plant Viruses ◽  
In Vitro Method ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside

Phosphonium salts. II. The reaction of bis-phosphonium salts with metal hydrides

1969 ◽  
Vol 22 (7) ◽  
pp. 1399 ◽  
Author(s):  
JJ Brophy ◽  
MJ Gallagher
Keyword(s):  
Alkaline Hydrolysis ◽  
Metal Hydrides ◽  
Sodium Hydride ◽  
Lithium Aluminium Hydride ◽  
Phosphonium Salts ◽  
Lithium Aluminium

Ethane-1,2-bis-phosphonium salts are cleaved by sodium hydride to phos- phines in 55-80% yields with loss of the two-carbon bridge. The reaction is independent of the substituents at the phosphorus atoms. The same reaction is observed with an ethene-1,2-bis-salt and with but- 2-ene-1,4-bis(triphenylphosphonium) dibromide. It is suggested that a phosphorane is formed which subsequently fragments in a manner analogous to alkaline hydrolysis. ��� Lithium aluminium .hydride behaves similarly but loss of the bridge is competitive with loss of benzyl groups, and yields are generally better (> 70%).

scholarly journals Antiviral Activities of Novel 5-Phosphono-Pent-2-en-1-yl Nucleosides and Their Alkoxyalkyl Phosphonoesters

2006 ◽  
Vol 51 (2) ◽  
pp. 611-615 ◽  
Author(s):  
Hyunah Choo ◽  
James R. Beadle ◽  
Earl R. Kern ◽  
Mark N. Prichard ◽  
Kathy A. Keith ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Oral Bioavailability ◽  
Dna Viruses ◽  
B Virus ◽  
Acyclic Nucleoside Phosphonates ◽  
Antiviral Activities ◽  
Acyclic Nucleoside

ABSTRACT Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegalovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread). This important antiviral class inhibits viral polymerases after cellular uptake and conversion to their diphosphates, bypassing the first phosphorylation, which is required for conventional nucleoside antivirals. Small chemical alterations in the acyclic side chain lead to marked differences in antiviral activity and the spectrum of activity of acyclic nucleoside phosphonates against various classes of viral agents. We synthesized a new class of acyclic nucleoside phosphonates based on a 5-phosphono-pent-2-en-1-yl base motif in which the oxygen heteroatom usually present in acyclic nucleoside phosphonates has been replaced with a double bond. Since the intrinsic phosphonate moiety leads to low oral bioavailability and impaired cellular penetration, we also prepared the hexadecyloxypropyl esters of the 5-phosphono-pent-2-en-1-yl nucleosides. Our earlier work showed that this markedly increases antiviral activity and oral bioavailability. Although the 5-phosphono-pent-2-en-1-yl nucleosides themselves were not active, the hexadecyloxypropyl esters were active against DNA viruses and hepatitis B virus, in vitro. Notably, the hexadecyloxypropyl ester of 9-(5-phosphono-pent-2-en-1-yl)-adenine was active against hepatitis B virus mutants resistant to lamivudine, emtricitabine, and adefovir.

Transannular reactions in the dibenzo[a,d]cycloheptene series. III. Preparation of 11-substituted-10,11-dihydro-10,5-(iminomethano)-5H-dibenzo[a,d]cycloheptenes

1968 ◽  
Vol 46 (21) ◽  
pp. 3391-3397
Author(s):  
T. A. Dobson ◽  
M. A. Davis ◽  
A. M. Hartung
Keyword(s):  
Sodium Hydride ◽  
Ammonium Hydroxide ◽  
Grignard Reagents ◽  
Lithium Aluminium Hydride ◽  
Tertiary Alcohols ◽  
Lithium Aluminium

Treatment of the syn-epoxyamide 3 with either ammonium hydroxide or sodium hydride gives 10,11-dihydro-anti-11-hydroxy-10,5-(iminomethano)-5H-dibenzo[a,d]cyclohepten-13-one (1a). This compound is readily converted to the syn-epimer 1c by oxidation to 1b and subsequent hydrogenation. The ketone 1b reacts with Grignard reagents to give the tertiary alcohols 1k,l which undergo hydrogenolysis to give the 11-substituted lactams 1q,r. Reduction of the lactams with lithium aluminium hydride gives the corresponding amines.

1-(4-Cyclopentylphenyl)piperazine and its 4-substituted derivatives; Synthesis and biological screening

1987 ◽  
Vol 52 (7) ◽  
pp. 1834-1840 ◽  
Author(s):  
Zdeněk Vejdělek ◽  
Miroslav Protiva
Keyword(s):  
Antimicrobial Activity ◽  
Benzyl Chloride ◽  
Addition Reaction ◽  
Anthelmintic Activity ◽  
Ethyl Formate ◽  
Lithium Aluminium Hydride ◽  
Biological Screening ◽  
Acyl Chlorides ◽  
Lithium Aluminium

Heating the hydrochlorides of 4-cyclopentylaniline and diethanolamine to 250 °C gave 1-(4-cyclopentylphenyl)piperazine (I). Acylation of I with ethyl formate and the corresponding acyl chlorides gave the amides II, VI, and VII which were reduced with lithium aluminium hydride to the piperazines III, VIII, and IX. Treatment of I with benzyl chloride and with 4-chloro-1-(4-fluorophenyl)butan-1-one under different conditions led to compounds IX and XI. Addition reaction of I to 1,2-epoxybutane resulted in the amino alcohol V. The products showed marginal tranquillizing activity (especially compound VIII), some antimicrobial activity in vitro and some anthelmintic activity.

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