Allopurinol, synthesis

Allomaltol, methyl — see Pyran-4-one, 5-methoxy-2-methyl-Allopurinol applications, 5, 343 metabolism, 1, 237 synthesis, 5, 316, 340 tautomerism, 5, 308 xanthine oxidase inhibition by, 1, 173 Allopurinol, oxy-applications, 5, 343 synthesis, 5, 316 Alloxan... 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Allopurinol, in contrast to the uricosuric drugs, reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate reabsorption. This action is accomplished by inhibiting xanthine oxidase, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid. After enzyme inhibition, the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of the more soluble uric acid precursors, xanthine and hypoxanthine. 

The literature on these ring systems in the last 10 years is vast. An Internet search alone provides 3500 citations for sildenafil (60a, Viagra). Not only Viagra is of medical interest allopurinol (ALP) 61, the classical treatment of gout arthritis, is still of interest, and pyrazolopyridazines and thiazolopyridazines have also been shown to be of biological importance. These activities extend beyond an interest in the synthesis and chemistry of these compounds indicated by the large number of patented potential applications. 

Bundgaard, H. andE. Falch. 1985a. Allopurinol prodrugs. II. Synthesis, hydrolysis kinetics and physicochemical properties of varioufeJ-acyloxymethyl allopurinol derivativeint. J. Pharm24 307-325. 

On the other hand, drugs may inhibit the metabolism of other drugs. For example, allopurinol (a xanthine oxidase inhibitor that inhibits the synthesis of uric acid) increases the effectiveness of anticoagulants by inhibiting their metabolism. Chloramphenicol (a potent inhibitor of microsomal protein synthesis) and cimetidine (an H2-receptor blocker used in acid-pepsin disease) have similar properties. In addition, drugs may compete with each other in metabolic reactions. In methyl alcohol (methanol) poisoning, ethyl alcohol may be given intravenously to avert methanol-induced blindness and minimize the severe acidosis. Ethyl alcohol competes with methyl alcohol for... 

If left untreated, the hyperuricemic state may precipitate an acute attack of gout, which first appears in metatarsal phalangeal joints. Ultimately, tophaceous deposits form in the joints and soft tissues such as the kidneys. The hyperuricemic state may be corrected either by inhibiting the synthesis of uric acid by allopurinol or by enhancing the elimination of uric acid by uricosuric agents. 

Allopurinol (Zyloprim) reduces the synthesis of uric acid by inhibiting the activity of xanthine oxidase, according to the scheme shown in Figure 24.2. The reduction in the uric acid pool occurs slowly. Because xanthine and hypoxanthine are more soluble than uric acid, they are easily excreted. 

In a pathological condition that causes pain, drugs may be used either to care for the acute attack of pain or as prophylaxis to prevent the occurrence of pain. For example, colchicine is used during an acute attack of gout, and after the pain has subsided initially, the patient is switched to uricosuric agents such as probenecid or an inhibitor of uric acid synthesis such as allopurinol. 

An alternative to increasing uric acid excretion in the treatment of gout is to reduce its synthesis by inhibiting xanthine oxidase with allopurinol. 

Xanthine oxidase is able to bind allopurinol and catalyze one oxidation, converting it to a compound that is similar to xanthine. However, after that conversion, the enzyme is trapped in an inactive oxidation state and can t carry out its normal function of forming uric acid. Additionally, allopurinol inhibits the de novo ( new, from other compounds not recycled) synthesis of purines, further decreasing the amount of uric acid formed in the blood. 

The reaction of 5-aminopyrazole-4-carboxylates with amides affords pyrazolo[3,4-d]pyrimidines <79AP(312)703, 87MI 712-02). The synthesis of allopurinol (53) by reaction of ethyl ethoxymethyl-enecyanoacetate, hydrazine, and formamide probably proceeds via intermediacy of ethyl 5-amino-1 //-pyrazole-4-carboxylate which then condenses with formamide to yield intermediate (318) which readily cyclizes to allopurinol (53) <74NEP7507554>. 

Chronic gout can be caused by (1) a genetic defect, for example, one resulting in an increase in the rate of purine synthesis, (2) renal deficiency, (3) Lesch-Nyhan Syndrome,4 or (4) excessive synthesis of uric acid associated with cancer chemotherapy. Treatment strategies for chronic gout include the use of uricosuric drugs that increase the excretion of uric acid, thereby reducing its concentration in plasma, and the use of allopurinol, which is a selective inhibitor of the terminal steps in the biosynthesis of uric acid. 

The yield is only about 50%, but what does that matter in such a simple process By counting atoms we can guess that four molecules of aldehyde and one of ammonia react, but exactly how is a triumph of thermodynamics over mechanism. Much more complex molecules can sometimes be made very easily too. Take allopurinol, for example. One synthesis of this gout remedy goes like this. 

Treatment involves a low-protein diet (0.5-0.7 g/kg BW/day) with a sufficient supply of calories. Substitution of essential amino acids (in about the same quantity) is required. The administration of benzoate (0.1-0.25 g/kg BW/day), arginine hydrochloride (1 mmol/kg BW/day) or sodium phenylacetate (0.3-0.5 g/ kg BW/day) (phenylbutyrate tends to be more effective) facilitates nitrogen excretion via other metabolic pathways. (168-170) With an enhanced excretion of orotate or other metabolites of pyrimidine synthesis, the administration of allopurinol leads to an increase in the excretion of nitrogen via metabolites from pyrimidine synthesis. Ammonia and urea precursors are eliminated by haemodialysis. In individual cases, liver transplantation is indicated. (I7l)... 

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