104227-87-4 Usage
Description
Famciclovir, an effective oral prodrug of the antiviral penciclovir, was launched in
the UK and shortly after in the U.S.A. for the treatment of shingles (herpes
zoster). As the diacetyl ester of the 6-deoxy- penciclovir, famciclovir has
significantly improved oral absorption. It is converted to penciclovir in vivo with a
bioavailability of 41 % in rats. Penciclovir is phosphorylated, and hence activated
onty in herpesvirus infected cells. This stable metabolite, penciclovir-triphosphate,
is a strong inhibitor of herpesvirus DNA polymerases and of viral DNA synthesis with
long lasting effects. The high selectivity of famciclovir/penciclovir to herpes family
of viruses and their rather low toxicity may make this agent superior to other existing
drugs.
Chemical Properties
Off-White Powder
Originator
SmlthKline Beecham (United Kingdom)
Uses
Different sources of media describe the Uses of 104227-87-4 differently. You can refer to the following data:
1. Used as an antiviral. Prodrug of Penciclovir (P221500).
2. sterol absorption inhibitor.
Famciclovir (Famvir) a synthetic acyclic purine analog derived from guanine. It is the diacetyl ester (prodrug) of penciclovir, which exhibits no antiviral activity until hydrolyzed to penciclovir and its active metabolites. It is indicated for the management of acute herpes zoster infections. It has been shown to relieve acute symptoms as well as to shorten the duration of postherpetic neuralgia. It is also used for the treatment or suppression of recurrent episodes of genital herpes in immunocompetent patients and in the treatment of recurrent herpes simplex types 1 and 2 infections in patients with human immunodeficiency virus.
3. These Secondary Standards are qualified as Certified Reference Materials. These are suitable for use in several analytical applications including but not limited to pharma release testing, pharma method development for qualitative and quantitative analyses, food and beverage quality control testing, and other calibration requirements.
Definition
ChEBI: 2-Amino-9H-purine in which the hydrogen at position 9 is substituted by a 4-acetoxy-3-(acetoxymethyl)but-1-yl group. A prodrug of the antiviral penciclovir, it is used for the treatment of acute herpes zoster (shingles), for the treatmen
or suppression of recurrent genital herpes in immunocompetent patients and for the treatment of recurrent mucocutaneous herpes simplex infections in HIV infected patients.
Indications
Famciclovir (Famvir) is the diacetyl ester prodrug of the
acyclic guanosine analogue 6-deoxypenciclovir (Denavir).
Manufacturing Process
A suspension 1.0 mmol of 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-
chloropurine (was synthesized from 2-amino-6-chloropurine and acetic acid 2-
acetoxymethyl-4-hydroxybutyl ester) and 400 mmol 10% palladium-oncharcoal
in methanol containing ammonium formate was heated under reflux
for 30 min. The mixture was allowed to cool, filtered and the solvent removed.
The residue was taken up in water and solution extracted twice with
chloroform. The organic layers were combined, dried (magnesium sulfate) and
the solvent removed to afford 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-
amino-6-purine, yield 90%, m.p. 102-104°C.
Brand name
Famvir (Novartis);Famvlr.
Therapeutic Function
Antiviral
General Description
Famciclovir is a diacetyl prodrug of penciclovir.As a prodrug,it lacks antiviral activity. Penciclovir, 9-[4-hydroxy-3-hydroxymethylbut-1-yl] guanine, is an acyclic guanine nucleoside analog. The structure is similar to that of acyclovir,except in penciclovir, a side chain oxygen has beenreplaced by a carbon atom and an extra hydroxymethylgroup is present.VSV-infected cells, penciclovir is first phosphorylated byviral thymidine kinase41 and then further elaborated to thetriphosphate by host cell kinases. Penciclovir triphosphate isa competitive inhibitor of viral DNA polymerase. The pharmacokineticparameters of penciclovir are quite different fromthose of acyclovir. Although penciclovir triphosphate is about100-fold less potent in inhibiting viral DNA polymerase thanacyclovir triphosphate, it is present in the tissues for longerperiods and in much higher concentrations than acyclovir.
Biological Activity
Famciclovir has much greater oral bioavailability (77%) than its active metabolite, penciclovir (5%). Upon oral administration of famciclovir, rapid, extensive, and consistent absorption occurs in the wall of the upper intestine. The consistent absorption is in part due to the drug’s prolonged stability in duodenal contents. Famciclovir undergoes first-pass metabolism by the intestinal wall and liver, where deacetylation and oxidation occur, subsequently forming the major active metabolite, penciclovir. In healthy male subjects the plasma elimination half-life of penciclovir is approximately 2 hours following both intravenous doses of penciclovir and an oral dose of famciclovir (125, 250, 500, or 750 mg). Over the concentration range of 0.1–20 mg/ml, penciclovir is o20% bound to plasma proteins.
Biochem/physiol Actions
Famciclovir is an antiretroviral guanosine analog used to treat herpesvirus infections and hepatitis B. Famciclovir is rapidly converted to penciclovir. Viral thymidine kinase phosphorylates penciclovir to a monophosphate form that celular kinases convert in turn to penciclovir triphosphate. Penciclovir triphosphate competitively inhibits viral DNA polymerase and thus viral replication. Prolonged administration can lead to resistance; it is often manifested as selection of pre-existing resistant strains with mutations in the reverse transcriptase domain of the DNA polymerase gene.
Mechanism of action
Different sources of media describe the Mechanism of action of 104227-87-4 differently. You can refer to the following data:
1. Famciclovir is an oral prodrug of the antiviral agent penciclovir (diacetyl 6-deoxy analog of penciclovir). It is effectively metabolized in the liver and the intestinal wall, where two acetyl groups are removed to give 6-deoxy-penciclovir, which is then oxidized at the 6-position of the purine ring to form penciclovir. The mode of action of penciclovir is broadly similar to that of aciclovir. Like aciclovir, the affinity of penciclovir for viral DNA polymerases is markedly higher than for host cell DNA polymerases. In herpesvirusinfected cells the virus-specific TK enzyme efficiently converts penciclovir to penciclovir monophospate, which is then converted to penciclovir triphosphate (the active metabolite) by host cell enzymes. Penciclovir triphosphate inhibits viral replication through competitive inhibition of viral DNA polymerase with the natural substrate deoxyguanosine triphosphate (dGTP).
2. Famciclovir is a synthetic purine nucleoside analogue related to guanine. It is the
diacetyl 6-deoxy ester of penciclovir, which is structurally related to ganciclovir. Its pharmacological and
microbiological activities are similar to those of acyclovir. Famciclovir is a prodrug of penciclovir, which
is formed in vivo by hydrolysis of the acetyl groups and oxidation at the 6-position by mixed function
oxidases. Penciclovir and its metabolite penciclovir triphosphate possess antiviral activity resulting from
inhibition of viral DNA polymerase.
Pharmacology
Famciclovir (Famvir) undergoes extensive first-pass metabolism to penciclovir
after oral administration. Penciclovir is another nucleoside analog that has a
mechanism of action similar to that of acyclovir. Compared with oral acyclovir,
famciclovir has improved bioavailability as well as a significantly prolonged
intracellular half-life, allowing for less frequent dosing.
Valacyclovir and famciclovir
are similar in their high absorption, bioavailability, renal elimination,
minimal drug interaction profiles, safety profiles, and efficacy.
Pharmacokinetics
Famciclovir can be given with or without food. The most common adverse effects are headache and GI
disturbances. Concomitant use of famciclovir with probenecid results in increased plasma concentrations
of penciclovir. The recommended dose of famciclovir is 500 mg every 8 hours for 7 days. The absolute
bioavailability of famciclovir is 77%, and the area under plasma concentration–time curve (AUC) is 86
μg/mL. Famciclovir with digoxin increased plasma concentration of digoxin to 19% as compared to digoxin
given alone.
Clinical Use
Different sources of media describe the Clinical Use of 104227-87-4 differently. You can refer to the following data:
1. Famciclovir is indicated for the treatment of acute
herpes zoster (shingles); it is at least as effective in reducing
pain and healing time. Famciclovir is generally as
effective as acyclovir in the treatment of HSV. In immunocompetent
patients, famciclovir is approved for
the treatment and prophylaxis of recurrent genital herpes.
For HIV-infected individuals, famciclovir is approved
for the treatment of all recurrent mucocutaneous
HSV infections.
2. Famciclovir is utilized in the treatment and suppression of herpes simplex infections, as well as in the treatment of zoster (secondary, dermatomal infection with VZV). In addition to these FDA-approved indications, it has also shown very limited activity in the treatment of HBV infections, but it is not recommended for this indication.
Side effects
Famciclovir may interact with probenecid or other
drugs eliminated by renal tubular secretion. This interaction
may result in increased blood levels of penciclovir
or other agents.
Veterinary Drugs and Treatments
Famciclovir may be of benefit in treating feline herpes infections.
Drug interactions
Potentially hazardous interactions with other drugs
Probenecid: decreased excretion of famciclovir.
Increased famciclovir levels reported with
mycophenolate mofetil.
Metabolism
Famciclovir is a pro-drug; it is rapidly converted to
penciclovir; virtually no famciclovir is detectable in the
plasma or urine. Bioavailability of penciclovir is reported
to be 77%.Famciclovir is mainly excreted in the urine (partly by
renal tubular secretion) as penciclovir and its 6-deoxy
precursor. No unchanged famciclovir has been detected
in urine.
references
[1] hodge r a v, sutton d, boyd m r, et al. selection of an oral prodrug (brl 42810; famciclovir) for the antiherpesvirus agent brl 39123 [9-(4-hydroxy-3-hydroxymethylbut-l-yl) guanine; penciclovir]. antimicrobial agents and chemotherapy, 1989, 33(10): 1765-1773.[2] sáez-llorens x, yogev r, arguedas a, et al. pharmacokinetics and safety of famciclovir in children with herpes simplex or varicella-zoster virus infection. antimicrobial agents and chemotherapy, 2009, 53(5): 1912-1920.
Check Digit Verification of cas no
The CAS Registry Mumber 104227-87-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,4,2,2 and 7 respectively; the second part has 2 digits, 8 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 104227-87:
(8*1)+(7*0)+(6*4)+(5*2)+(4*2)+(3*7)+(2*8)+(1*7)=94
94 % 10 = 4
So 104227-87-4 is a valid CAS Registry Number.
InChI:InChI=1/C14H19N5O4/c1-9(20)22-6-11(7-23-10(2)21)3-4-19-8-17-12-5-16-14(15)18-13(12)19/h5,8,11H,3-4,6-7H2,1-2H3,(H2,15,16,18)
104227-87-4Relevant articles and documents
A new route to famciclovir via palladium catalysed allylation
Freer, Richard,Geen, Graham R.,Ramsay, Thomas W.,Share, Andrew C.,Slater, Graham R.,Smith, Neil M.
, p. 4589 - 4595 (2000)
An efficient route to the acyclic nucleoside analogue famciclovir has been developed based on a palladium(0) catalysed coupling of 2-amino-6- chloropurine and an allylic carbonate sidechain derived from 2,2-dimethyl- 1,3-dioxan-5-one. The reaction proceeds via a highly N-9 regioselective purine allylation step involving a novel palladium mediated N-7 to N-9 rearrangement. (C) 2000 Elsevier Science Ltd.
Method for synthesizing famciclovir by using microchannel reactor
-
Paragraph 0054-0068, (2021/06/22)
The invention discloses a preparation method for synthesizing famciclovir by using a microchannel reactor, which comprises the following steps: mixing and dispersing 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbutyl) purine serving as a raw material and a palladium-carbon catalyst in a solvent, feeding by using a slurry pump, and performing dechlorination reaction with hydrogen in a microchannel continuous flow reactor to obtain reaction liquid, filtering the obtained reaction liquid, respectively inputting the filteringed reaction liquid and an acetic anhydride solution into the microchannel continuous flow reactor by using a diaphragm feeding pump, and carrying out esterification reaction in the microchannel reactor to obtain famciclovir. Compared with the prior art, the method has the advantages that the process safety can be greatly improved by carrying out hydrogenation reaction in the micro-channel continuous flow reactor; as the microchannel continuous flow reactor has the characteristic of high-efficiency mass and heat transfer, the reaction time can be effectively shortened, the use amount of raw materials is reduced, and the discharge of three wastes is reduced; and the route of first hydrogenation and then esterification is adopted, so that hydrolysis of ester bonds during first esterification and then hydrogenation can be effectively avoided, and the product purity is improved.
Preparation method of famciclovir
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Paragraph 0037-0042, (2019/03/28)
The invention relates to a preparation method of famciclovir. The preparation method comprises the following steps of: adopting guanidine nitrate and diethyl malonate as raw materials, carrying out ring-closing reaction under an alkaline condition to obtain 2-amino-4,6-pyrimidinediol, then obtaining 2-amino-4,6-dichloropyrimidine by hydroxyl chlorination, reacting with 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl-1-amine to generate 6-chloro-N(i)4(/i)-(2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl)pyrimidine-2,4-diamine, then reacting with sodium nitrite under the acidic condition to obtain 2-(2-((2-amino-6-chloro-5-nitrosopyrimidin-4-yl)amino)ethyl)propane-1,3-diol, and finally carrying out reduction/dechloridation, ring-closing and esterification reaction to obtain the famciclovir. The preparation method has the beneficial effects that the problems of poor N-alkylation reaction selectivity and need of additional purification of reaction intermediates and the like in the current process are solved.
