December 20, 2021 4:18 am
ALLUPURINOL
1H-Pyrazolo(3,4-d)pyrimidin-4-ol
2,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
206-250-9[EINECS], 315-30-0[RN]
4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1,5-dihydro-, radical ion(1+)
4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1,7-dihydro-
691008-24-9[RN]
7H-Pyrazolo[3,4-d]pyrimidin-4-ol
Allopurinol is a medication used to decrease high blood uric acid levels.[2] It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy.[3][4] It is taken by mouth or injected into a vein.[4]
Common side effects when used by mouth include itchiness and rash.[4] Common side effects when used by injection include vomiting and kidney problems.[4] While not recommended historically, starting allopurinol during an attack of gout appears to be safe.[5][6] In those already on the medication, it should be continued even during an acute gout attack.[5][3] While use during pregnancy does not appear to result in harm, this use has not been well studied.[1] Allopurinol is in the xanthine oxidase inhibitor family of medications.[4]
Allopurinol was approved for medical use in the United States in 1966.[4] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[7] Allopurinol is available as a generic medication.[4] In 2019, it was the 43rd most commonly prescribed medication in the United States, with more than 15 million prescriptions.[8][9]
ALLUPRINOLCAS Registry Number: 315-30-0
CAS Name: 1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Additional Names: 1H-pyrazolo[3,4-d]pyrimidin-4-ol; 4-hydroxypyrazolo[3,4-d]pyrimidine; HPP
Manufacturers’ Codes: BW-56158
Trademarks: Adenock (Mitsubishi); Allurit (Aventis); Aloral (Lagap); Alositol (Tanabe); Allo-Puren (Isis); Allozym (Sawai); Allural (Rovi); Anoprolin (Azwell); Anzief (Nippon Chemiphar); Apulonga (Dorsch); Apurol (Siegfried); Apurin (GEA); Bleminol (Gepepharm); Caplenal (Teva); Cellidrin (Hennig); Cosuric (DDSA); Dabroson (Hoyer); Embarin (Merckle); Epidropal (Teofarma); Foligan (DESMA); Gichtex (Gerot); Hamarin (Roche); Hexanurat (Durascan); Ketanrift (Ohta); Lopurin (Abbott); Lysuron (Roche); Miniplanor (Galen); Monarch (SS Pharm.); Remid (TAD); Riball (Schering AG); Sigapurol (Siegfried); Suspendol (Merckle); Takanarumin (Takata); Uricemil (Molteni); Uripurinol (Azupharma); Urosin (Roche); Urtias (Novartis); Zyloprim (GSK); Zyloric (GSK)
Molecular Formula: C5H4N4O, Molecular Weight: 136.11
Percent Composition: C 44.12%, H 2.96%, N 41.16%, O 11.75%
Literature References: Xanthine oxidase inhibitor; decreases uric acid production. Prepn: Robins, J. Am. Chem. Soc.78, 784 (1956); Schmidt, Druey, Helv. Chim. Acta39, 986 (1956); Druey, Schmidt, US2868803 (1959 to Ciba); GB798646 (1958 to Wellcome Found.); Hitchings, Falco, US3474098 (1969 to Burroughs Wellcome). Physiological and biochemical studies: Hitchings, in Biochem. Aspects Antimetab. Drug Hydroxylation, D. Shugar, Ed. (Academic Press, London, 1969) pp 11-22, C.A.75, 3531h (1971). Clinical trial in treatment of renal calculi: M. J. V. Smith, J. Urol.117, 690 (1977); B. Ettinger et al.,N. Engl. J. Med.315, 1386 (1986). Use in hyperuricemia and gout: G. R. Boss, J. E. Seegmiller, ibid.300, 1459 (1977). Effect on renal function in treatment of gout: T. Gibson, Ann. Rheum. Dis.41, 59 (1982). Comprehensive description: S. A. Benezra, T. R. Bennett, Anal. Profiles Drug Subs.7, 1-17 (1978).
Properties: Crystals, mp above 350°. uv max (0.1N NaOH): 257 nm (e 7200); (0.1N HCl): 250 nm (e 7600); (methanol): 252 nm (e 7600). Soly in mg/ml at 25°: water 0.48; n-octanol <0.01; chloroform 0.60; ethanol 0.30; DMSO 4.6. pKa 10.2.
Melting point: mp above 350°
pKa: pKa 10.2
Absorption maximum: uv max (0.1N NaOH): 257 nm (e 7200); (0.1N HCl): 250 nm (e 7600); (methanol): 252 nm (e 7600)
Derivative Type: Sodium salt
CAS Registry Number: 17795-21-0
Trademarks: Aloprim (Nabi)
Molecular Formula: C5H3N4NaO, Molecular Weight: 158.09Percent Composition: C 37.99%, H 1.91%, N 35.44%, Na 14.54%, O 10.12%
Properties: White amorphous mass. pKa 9.31.
pKa: pKa 9.31
Therap-Cat: Treatment of hyperuricemia and chronic gout. Antiurolithic.
Keywords: Antigout; Antiurolithic; Xanthine Oxidase Inhibitor.
Synthesis ReferenceDruey, J. and Schmidt, P.; US. Patent 2868,803; January 13,1959; assigned to Ciba Pharmaceutical Products Inc. Hitchings, G.H. and Falco, EA.; U.S. Patent 3,474,098; October 21,1969; assigned to Bur- roughs Wellcome & Co. Cresswell, R.M.and Mentha, J.W.; US.Patent4,146,713; March27,1979; assigned to Bur- roughs Wellcome & Co.
SYN
SYN
http://drugsynthesis.blogspot.co.uk/2011/11/laboratory-synthesis-of-allopurinol.html
Reference(s):
Similar process:
Alternative syntheses:
SYNCondensation of hydrazine with ethoxymethylenemalononitrile (I) leads to 3-amino-4-cyanopyrazole (II), which, by hydrolysis with sulphuric acid, gives the corresponding amide (III); heating III with formamide in excess results in allopurinol (IV). The synthesis of allopurinol can be illustrated as below:
SYN
Synthesis
IR
https://www.sciencedirect.com/science/article/abs/pii/S0099542808600878
Infrared Spectrum The infrared spectrum of allopurinol is shown in Figure 1 . in KBr with a Perkin Elmer model 457 infrared spectrophotometer. with the structure of allopurinol . It was taken as a 0.2% dispersion of allopurinol Table I gives the infrareg assignments consistent Table I Infrared Spectral Assignments for Allopurinol Frequency (cm-l) Assignment
3060 CH stretching vibrations of the pyrimidine ring
1700 CO stretching vibration of the keto form of the 4-hydroxy tautomer 1
590 ring vibrations
1245 CH in-plane deformation
NMR
| Clinical data | |
|---|---|
| Trade names | Zyloprim, Caplenal, Zyloric, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682673 |
| License data | US DailyMed: Allopurinol |
| Pregnancy category | AU: B2[1] |
| Routes of administration | By mouth (tablet), intravenous |
| ATC code | M04AA01 (WHO) |
| Legal status | |
| Legal status | AU: S4 (Prescription only)UK: POM (Prescription only)US: ℞-only |
| Pharmacokinetic data | |
| Bioavailability | 78±20% |
| Protein binding | Negligible |
| Metabolism | liver (80% oxipurinol, 10% allopurinol ribosides) |
| Elimination half-life | 2 h (oxipurinol 18–30 h) |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 315-30-0 |
| PubChem CID | 135401907 |
| IUPHAR/BPS | 6795 |
| DrugBank | DB00437 |
| ChemSpider | 2010 |
| UNII | 63CZ7GJN5I |
| KEGG | D00224 |
| ChEBI | CHEBI:40279 |
| ChEMBL | ChEMBL1467 |
| CompTox Dashboard (EPA) | DTXSID4022573 |
| ECHA InfoCard | 100.005.684 |
| Chemical and physical data | |
| Formula | C5H4N4O |
| Molar mass | 136.114 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
| (verify) |
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Allopurinol is used to reduce urate formation in conditions where urate deposition has already occurred or is predictable. The specific diseases and conditions where it is used include gouty arthritis, skin tophi, kidney stones, idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase, including Lesch–Nyhan syndrome; glucose 6-phosphatase including glycogen storage disease; phosphoribosyl pyrophosphate synthetase, phosphoribosyl pyrophosphate amidotransferase; adenine phosphoribosyltransferase.
It is also used to treat kidney stones caused by deficient activity of adenine phosphoribosyltransferase.
Allopurinol was also commonly used to treat tumor lysis syndrome in chemotherapeutic treatments, as these regimens can rapidly produce severe acute hyperuricemia;[10] however, it has gradually been replaced by urate oxidase therapy.[11] Intravenous formulations are used in this indication when people cannot take medicine by mouth.[12]
Allopurinol cotherapy is used to improve outcomes for people with inflammatory bowel disease and Crohn’s disease who do not respond to thiopurine monotherapy.[13][14] Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD.[15] Cotherapy invariably requires dose reduction of the thiopurine, usually to one-third of the standard dose depending upon the patient’s genetic status for thiopurine methyltransferase.[16]
Allopurinol has been tested as an augmentation strategy for the treatment of mania in bipolar disorder. Meta-analytic evidence showed that adjunctive allopurinol was superior to placebo for acute mania (both with and without mixed features).[17] Its efficacy was not influenced by dosage, follow-up duration, or concurrent standard treatment.[17]
Because allopurinol is not a uricosuric, it can be used in people with poor kidney function. However, for people with impaired kidney function, allopurinol has two disadvantages. First, its dosing is complex.[18] Second, some people are hypersensitive to the drug; therefore, its use requires careful monitoring.[19][20]
Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, eosinophilia, hepatitis, and worsened renal function, collectively referred to as DRESS syndrome.[19] Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome and toxic epidermal necrolysis, two life-threatening dermatological conditions.[19] More common is a less-serious rash that leads to discontinuing this drug.[19]
More rarely, allopurinol can also result in the depression of bone marrow elements, leading to cytopenias, as well as aplastic anemia. Moreover, allopurinol can also cause peripheral neuritis in some patients, although this is a rare side effect. Another side effect of allopurinol is interstitial nephritis.[21]
Allopurinol should not be given to people who are allergic to it.[10]
Drug interactions are extensive, and are as follows:[10]
Allopurinol may also increase the activity or half-life of the following drugs, in order of seriousness and certainty of the interaction:[10]
Co-administration of the following drugs may make allopurinol less active or decrease its half-life:[10]
Co-administration of the following drugs may cause hypersensitivity or skin rash:[10]
A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by aldehyde oxidase.[22] The active metabolite of allopurinol is oxipurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxipurinol within two hours of oral administration, whereas oxipurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxipurinol is believed responsible for the majority of allopurinol’s effect.[23]
Allopurinol is a purine analog; it is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an inhibitor of the enzyme xanthine oxidase.[2] Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine, resulting in the production of uric acid, the product of human purine metabolism.[2] In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides may cause feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.[24]
The HLA-B*5801 allele is a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).[25][26] The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively.[27] The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity.[25][26] As of 2011 the FDA-approved drug label for allopurinol did not contain any information regarding the HLA-B*5801 allele, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced SJS and TEN.[28] However, the American College of Rheumatology recommends screening for HLA-B*5801 in high-risk populations (e.g. Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug.[29] The Clinical Pharmacogenetics Implementation Consortium guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.[30][31]
Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for antineoplastic agents.[2][32] Because allopurinol inhibits the breakdown (catabolism) of the thiopurine drug mercaptopurine, and it was later tested by Wayne Rundles, in collaboration with Gertrude Elion‘s lab at Wellcome Research Laboratories to see if it could improve treatment of acute lymphoblastic leukemia by enhancing the action of mercaptopurine.[2][33] However, no improvement in leukemia response was noted with mercaptopurine-allopurinol co-therapy, so that work turned to other compounds and the team then started testing allopurinol as a potential for gout.[34] Allopurinol was first marketed as a treatment for gout in 1966.[33]
Pure allopurinol is a white powder.
Allopurinol is sold as an injection for intravenous use[12] and as a tablet.[10]
Allopurinol has been marketed in the United States since 19 August 1966, when it was first approved by FDA under the trade name Zyloprim.[35] Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.[36]
Acute interstitial nephritis has also been reported associated with by the administration of allopurinol.
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