Synthesis and antifolate activity of 2,4‐diamino‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidine analogues of trimetrexate and piritrexim

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Abstract
2,4‐Diamino‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidines with di‐ and trimethoxyaralkyl substitution at the 6‐position were synthesized from theN6‐unsubstituted compound and appropriate aralkyl bromides inN,N‐dimethylformamide solution containing a catalytic amount of sodium iodide. An improved method of preparation of 2,4‐diamino‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidine from 2‐amino‐6‐benzyl‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidin‐4(3H)‐one was also developed, in whichN2was protected by reaction with pivalic anhydride and the resulting product was subjected consecutively to reaction with 4‐chlorophenylphosphorodichloridate and 1,2,4‐triazole, ammonolysis to replace the 4‐imidazolido group and remove theN2‐pivaloyl group, and catalytic hydrogenolysis to remove the 6‐benzyl group. In assays of the ability of the products to inhibit dihydrofolate reductase fromPneumocystis carinii, andToxoplasma gondii, and rat liver the most active of the compounds tested was 2,4‐diamino‐6‐(2′‐bromo‐3′,4′,5′‐trimethoxybenzyl)‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidine. The concentration of this compound needed to inhibit enzyme activity by 50% was 0.51 μMagainst theP. cariniienzyme, 0.09 μMagainst theT. gondii enzyme, and 0.35 μMagainst the rat enzyme. Thus, there was selectivity of binding toT. gondiienzyme, but notP. cariniienzyme, relative to rat enzyme. 2′,5′‐Dimethoxybenzyl analogues were less active than the corresponding 3′,4′,5′‐trimethoxybenzyl analogues, and compounds with a CH2CH2or CH2CH2CH2bridge were less active than those with a CH2bridge. 2,4‐Diamino‐6‐(2′‐bromo‐3′,4′,5′‐trimethoxybenzyl)‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidine showed greater selectivity than trimetrexate or piritrexim for theP. cariniiandT. gondiienzyme, but was less selective than trimethoprim or pyrimethamine. However its molar potency against both enzymes was greater than that of trimethoprim, the antifolate most commonly used, in combination with sulfamethoxazole, for initial treatment of opportunisticP. cariniiandT. gondiiinfections in patients with AIDS and other disorders of the immune system.

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