39809-25-1 Usage
Description
2-Amino-9-[4-hydroxy-3-(hydroxymethyl)butyl]-3,9-dihydropurin-6-one, also known as Vectavir, is a white crystalline solid that belongs to the class of 2-aminopurines. It is a guanine derivative with a 4-hydroxy-3-(hydroxymethyl)but-1-yl group substituted at the 9th position. This antiviral drug is used topically for the treatment of herpes labialis and is a metabolic product of famciclovir, which is used for oral administration.
Uses
Used in Antiviral Applications:
2-Amino-9-[4-hydroxy-3-(hydroxymethyl)butyl]-3,9-dihydropurin-6-one is used as an antiviral agent for the treatment of herpes labialis. It acts as a competitive inhibitor of DNA polymerase, preferentially phosphorylated by viral-infected cells over normal cells. The triphosphate form has low activity against cellular DNA polymerase, which may contribute to its low toxicity. Its spectrum of activity is similar to acyclovir, but it is longer-acting due to the increased stability of its triphosphate form.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, 2-Amino-9-[4-hydroxy-3-(hydroxymethyl)butyl]-3,9-dihydropurin-6-one is used as an active pharmaceutical ingredient for the development of antiviral medications. It is marketed under the brand name Denavir (SmithKline Beecham) and is available in topical formulations for the treatment of herpes labialis.
Used in Research and Development:
2-Amino-9-[4-hydroxy-3-(hydroxymethyl)butyl]-3,9-dihydropurin-6-one is also used in research and development for the study of antiviral mechanisms and the development of new antiviral drugs. Its unique properties and activity against various herpes viruses make it a valuable compound for further investigation and potential applications in the field of virology and drug development.
Indications
Penciclovir has activity against HSV-1, HSV-2,
VZV, and HBV. After oral administration, famciclovir is
converted to penciclovir by first-pass metabolism.
Penciclovir has a mechanism of action similar to that of
acyclovir. It is first monophosphorylated by viral thymidine
kinase; then it is converted to a triphosphate by
cellular kinases.
Manufacturing Process
To a suspension of lithium aluminum hydride (2.87 g, 76 mmol) in tetrahydrofuran (125 ml), a solution of triethyl 1,1,2-ethanetricarboxylate (9.2 ml, 9.85 g, 40 mmol) in tetrahydrofuran (25 ml) was added dropwise with stirring over 2 hours. The inorganic salts were filtered off and washed with ethanol (100 ml). The filtrate and washings were combined and the solvent was evaporated under reduced pressure to afford a colourless oil (4.85 g). To a suspension of this oil in acetone (100 ml) 2,2-dimethoxypropane (25 ml) and p-toluenesulphonic acid monohydrate (2.3 g, 12 mmol) were added. The mixture was stirred for 1 hour. The resulting solution was neutralised with Amberlite IR 45 (methanol washed), filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with chloroform-methanol mixtures (40:1 and 25:1) to afford 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan as a colourless liquid (3.01 g, 47%).
To an ice-cooled solution of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan (1.92 g, 12 mmol) and carbon tetrabromide (7.96 g, 24 mmol) in dimethylformamide (100 ml) triphenylphosphine (6.30 g, 24 mmol) was added and the solution was left at 4°C overnight. To this solution methanol (20 ml) was added and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-acetone (12:1) to afford 5-(2-bromoethyl)-2,2-dimethyl1,3-dioxan as a clear colourless liquid (0.89 g, 40%).
To a solution of 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan (0.75 g, 3.7 mmol) in dry dimethylformamide (12 ml) 2-amino-6-chloropurine (0.68 g, 4.0 mmol) and then anhydrous potassium carbonate (0.83, 6.0 mmol) were added. The solution was stirred at room temperature for 5 hours and left at 4°C
overnight. The solution was filtered and the solvent removed. The residue was purified by column chromatography on silica gel, eluting with chloroformmethanol mixtures (80:1 and 60:1) to afford 2-amino-6-chloro-9-[2-(2,2dimethyl-1,3-dioxan-5-yl)ethyl]purine as a white crystalline solid (0.74 g, 64%), melting point 125°-126°C.
2-Amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)-ethyl]purine (0.59 g, 1.9 mmol) in hydrochloric acid (1.0 M, 4 ml) was stirred at 60°C for 24 hours. The solution was diluted with water and neutralised with Amberlite IR 45. The mixture was filtered, the resin washed with water and the solvent evaporated under reduced pressure. The residue was recrystallised from water to afford 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (238 mg, 49%), melting point 275°-277°C.
Therapeutic Function
Antiviral
Acquired resistance
Penciclovir is inactive against thymidine kinase-deficient
strains of HSV.
Pharmaceutical Applications
A synthetic acyclic purine nucleoside analog, usually administered
orally as the diacetyl ester, famciclovir, which acts as
a prodrug undergoing rapid first-pass metabolism to release
the active compound in vivo. The parent compound has
virtually no oral bioavailability, but is supplied as a topical
formulation.
Pharmacokinetics
Oral absorption, penciclovir： 5%
famciclovir： 77%
Cmax famciclovir 250 mg oral： 1.6 mg/L after 0.5–1.5 h
famciclovir 500 mg oral： 3.3 mg/L after 0.5–1.5 h
famciclovir 750 mg oral： 5.1 mg/L after 0.5–1.5 h
Plasma half-life： 2.1–2.7 h
Volume of distribution： c. 1.5 L/kg
Plasma protein binding： <20%
Following absorption famciclovir is converted rapidly by
enzyme-mediated deacetylation and oxidation to penciclovir.
Food does not lead to any significant change in the availability
or elimination.
The pharmacokinetics in elderly subjects are similar to
those seen in younger subjects, although small increases in
AUC and plasma half-lives were seen, consistent with slightly
decreased renal clearance.
Renal excretion is the major route of elimination, 50–60%
of an oral dose being recovered in the urine. After intravenous
infusion, about 70% is excreted unchanged in the urine.
After oral administration of famciclovir, penciclovir accounts
for 82% of urinary drug-related material. The remainder
includes metabolites, of which the largest is the 6-deoxy precursor
of penciclovir. Renal clearance exceeds glomerular filtration,
indicating renal tubular secretion.
Clinical Use
Herpes zoster and genital herpes
Orolabial herpes (topical)
Clinical Use
Penciclovir is approved as a topical formulation for the
treatment of herpes labialis. In immunocompetent individuals,
penciclovir shortens the duration of lesion presence
and pain by approximately half a day when it is initiated
within an hour of lesion development and applied
every 2 hours during waking hours for 4 days.
Side effects
In clinical trials the incidence of adverse events after famciclovir,
aciclovir and placebo were similar, the most common
adverse events being headache and nausea.
references
[1] boyd m r, bacon t h, sutton d, et al. antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl) guanine (brl 39123) in cell culture. antimicrobial agents and chemotherapy, 1987, 31(8): 1238-1242.[2] hodge r a, perkins r m. mode of action of 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine (brl 39123) against herpes simplex virus in mrc-5 cells. antimicrobial agents and chemotherapy, 1989, 33(2): 223-229.
Check Digit Verification of cas no
The CAS Registry Mumber 39809-25-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 3,9,8,0 and 9 respectively; the second part has 2 digits, 2 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 39809-25:
(7*3)+(6*9)+(5*8)+(4*0)+(3*9)+(2*2)+(1*5)=151
151 % 10 = 1
So 39809-25-1 is a valid CAS Registry Number.
InChI:InChI=1/C10H15N5O3/c11-10-13-8-7(9(18)14-10)12-5-15(8)2-1-6(3-16)4-17/h5-6,16-17H,1-4H2,(H3,11,13,14,18)
39809-25-1Relevant articles and documents
Penciclovir crystal form and preparation method thereof
-
Paragraph 0034-0043, (2020/07/24)
The invention provides a penciclovir crystal form and a preparation method thereof. In the X-ray powder diffraction of the crystal form, characteristic peaks exist at 2theta diffraction angles of 7.526 +/- 0.2 degrees, 20.399 +/- 0.2 degrees, 22.001 +/- 0.2 degrees, 23.250 +/- 0.2 degrees, 27.991 +/- 0.2 degrees and 33.898 +/- 0.2 degrees. Compared with the prior art, the penciclovir crystal formis smaller in particle size, higher in purity and better in stability, and particularly, the stability of the penciclovir crystal form is remarkably improved under the illumination condition. Moreover, the preparation method disclosed by the invention is high in yield, simple in purification, simple and convenient to operate and suitable for industrial production.
Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutylguanine derivatives
Mohammed, Anber F.,Andrei, Graciela,Hayallah, Alaa M.,Abdel-Moty, Samia G.,Snoeck, Robert,Simons, Claire
, p. 1023 - 1033 (2019/02/09)
A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against her
Practical syntheses of penciclovir and famciclovir from N2-acetyl-7-benzylguanine
Torii, Takayoshi,Shiragami, Hiroshi,Yamashita, Keizo,Suzuki, Yumiko,Hijiya, Toyoto,Kashiwagi, Tatsuki,Izawa, Kunisuke
, p. 5709 - 5716 (2007/10/03)
We have established practical methods for the synthesis of penciclovir (PCV) and famciclovir (FCV) from readily available guanosine via N2-acetyl-7-benzylguanine. The alkylation of N2-acetyl-7-benzylguanine proceeded selectively at the N9 position to give the desired alkylated product in good yield in salt form. After conventional catalytic hydrogenolysis of the benzyl group and hydrolysis of the resulting acetate, pure PCV was obtained without the need for chromatography. As a side chain precursor, the mesylate was selected rather than a halide since the corresponding halides gave several impurities under the same reaction conditions. Two procedures for the synthesis of FCV from PCV and a derivative are also reported.
