6-Mercaptopurines

Similarly, 6-mercaptopurine in alkaline medium adds across the triple bond in 3,3,3-trifluoropropyne to form the carbon-sulfur bond to the carbon more remote from the trifluoromethyl group In trifluoromethyl-ferf-butyldiacetylene, the bond is formed to the carbon adjacent to the trifluoromethyl group [5] (equation 6)... 

Several synthetic pyrimidines and purines are useful drugs. Acyclovir was the first effective antiviral compound and is used to treat herpes infections. 6-Mercaptopurine is one of the drugs used to treat childhood leukemia, which has become a very treatable fonn of cancer with a cure rate approaching 80%. 

N,N -dimethyloxaldiamide is reacted with PCI5 to give 4-chloro-1-methyl imidazole. This is nitrated with HNO3 to give 5-nitro-1-methyl-4-chloroimidazole. Then, a mixture of 4.6 grams of anhydrous 6-mercaptopurine, 5 grams of 1-methyl-4-chloro-5-nitroimidazole and 2.5 grams of anhydrous sodium acetate in 100 ml of dry dimethyl sulfoxide was heated at 100°C for 7 hours. 

To B20 mg of 7-amino-thiazolo (5,4-d) pyrimidine was added 2.5 cc of 2 N sodium hydroxide. The water was removed under reduced pressure. The sodium salt was then heated at 240°C for one hour, during which time it melted, gave off water and resolidified. The sodium salt of 6-mercaptopurine was dissolved in 15 ml of water and acidified to pH 5 with acetic acid. Yellow crystals of 6-mercaptopurine hydrate precipitated, according to U.S. Patent 2,933,49B. 

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

In vivo azathioprine is rapidly converted into its active metabolite 6-mercaptopurine by the enzyme thiopurine methyltransferase (TPMT). The active agent inhibits IMPDH function. Furthermore, it also acts as antimetabolite of the RNA and DNA synthesis particularly in T-lymphocytes leading to cell death. Due to genetic polymorphism of TPMT, therapy may fail, thus it is currently discussed whether individual patients should be monitored before the use of azathioprine. 

Thiopurine S methyltransferase Low activity in about 10% of Caucasians and deficient activity in about 0.4%. High incidence of severe adverse events from azathioprine and 6-mercaptopurine in carriers of low activity. 

Thiopurine S-methyltransferase is an enzyme which inactivates the anticancer drug 6-mercaptopurine by S-methylation. 

The carbons added in reactions 4 and 5 of Figure 34-2 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, which are rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction 5, Figure 34—2), diazanorleucine (reaction 2), 6-mercaptopurine (reactions 13 and 14), and mycophenofic acid (reaction 14). 

Maintenance of remission of ulcerative colitis may be achieved with oral or topical aminosalicylates. Immunosuppressants such as azathioprine or 6-mercaptopurine can be used for unresponsive patients or those who develop corticosteroid dependency. 

Maintenance of remission of Crohn s disease may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 16-3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-associated GI inflammation. They are most useful for maintaining remission of IBD or reducing the need for long-term use of corticosteroids. Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions resulting in pancreatitis, fever, rash, hepatitis, and leukopenia.25,26... 

Immunosuppressants such as azathioprine or 6-mercaptopurine can be used for unresponsive patients or those who develop corticosteroid dependency. Remission may be maintained in up to 58% of patients after 5 years of treatment.1,25 Intermittent infliximab dosing (5 mg/kg IV every 8 weeks) may be used to maintain disease remission and reduce the need for corticosteroids in patients with moderate to severe UC. Colectomy is an option for patients with progressive disease who cannot be maintained on drug therapy alone. 

Patients with CD are at high risk for disease relapse after induction of remission. Within 2 years, up to 80% of patients suffer a relapse therefore, most patients should be evaluated for indefinite maintenance therapy. Maintenance of remission of CD may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

There are several important drug-drug interactions with allopurinol. The effects of both theophylline and warfarin may be potentiated by allopurinol. Azathioprine and 6-mercaptopurine are purines whose metabolism is inhibited... 

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. 

However, when a bi-dentate site is available as in 6-mercaptopurine the following product is formed with the m-isomer... 

Thiopurine (6-mercaptopurine) gives rise to three pH-dependent voltam-metric oxidation peaks at the PGE (Table 1) 6S>. The first, least positive peak is an adsorption pre-peak due to the one-electron oxidation of 6-thiopurine (I, Fig. 18) to an adsorbed layer of product, bis (6-purinyl) disulfide (III,... 

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