2-Thiouracils synthesis

Uracils can be prepared via reaction of primary amines with 3-ethoxyacryloyl isocyanate this method is particularly suitable for complex amines and has found much use in recent years in the synthesis of, for example, carbocyclic nucleoside analogues as potential anti-viral agents. The immediate product of amine/ isocyanate interaction can be cyclised under either acidic or basic conditions and the method can also be applied to thiouracil synthesis. 

The primary synthesis of alkoxypyrimidines is exemplified in the condensation of dimethyl malonate with O-methylurea in methanolic sodium methoxide at room temperature to give the 2-methoxypyrimidine (854) (64M207) in the condensation of diethyl phenoxymalonate with formamidine in ethanolic sodium methoxide to give the 5-phenoxypyrimidine (855) (64ZOB1321) and in the condensation of butyl 2,4-dimethoxyacetoacetate with thiourea to give 5-methoxy-6-methoxymethyl-2-thiouracil (856) (58JA1664). 

Hyperthyroidism may be treated in several ways. One of these is interference with the synthesis of the thyroid hormones, possibly by removal of iodine. Thiourea and cyclic thioureas have this effect and of such cyclic compounds, thiouracil (1030 R = H), its 6-alkyl derivatives (1030 R = Me or Pr) and thiobarbital (1031) are effective thyroid drugs. Today only propylthiouracil (1030 R = Pr) is widely used, probably because it has fewer side effects than the others (71MI21302). The thiouracils are made by the Principal Synthesis from a /3-oxo ester (1032 R = H, Me, Pr, etc.) and thiourea (45JA2197) their fine structures are experimentally based (64AF1004). 

Progressive departure from the fundamental structure of the lead agent cimetidine led to the anti ulcer agent oxmetidine (47). The synthesis involves -methylation (CH3I) of the 2-thiouracil intermediate and is followed by an addition-elimination reaction with 2-(5-methyl-4-imidazolylmethylthio) ethylamine to give oxmetidine (47). ... 

Solid-phase synthesis of dihydropteridinones has been achieved from 4,6-dichloro-5-nitropyrimidine <00TL8177>. A series of ethyl 7-aminopteridine-6-carboxylate derivatives has been prepared in one step from the reaction of vicinal diamines as 13-dialky 1-5,6-diamino-2-thiouracils with diethyl ( )-2,3-dicyanobutenedioate <99JHC1317>. The relative binding affinities to human dihydrofolate reductase of new 2,4-diaminopteridine derivatives... 

Agents which inhibit hormone synthesis Propyl thiouracil 50-100 mg/day (initial) and maintained at 20-30 mg/day... 

Botta and coworkers recently developed an Oxone cleavage methodology for the solid-phase synthesis of substituted uracils (equation 57)165. Whereas some common methods of thioether cleavage, such as reduction with Na/NH3, acid catalyzed hydrolysis, heavy metal ions followed by treatment with hydrogen sulfide and iodotrimethylsilane proved to be unsuccessful for this reduction, Oxone was shown to be an efficient and selective reagent for cleavage of polymer bound thiouracils. 

A small group of cyclic thioureas have been used in the treatment of excessive thyroid function. They include 6-n-propylthiouracil (176 R1 = H, R2 = Prn), 5-iodo-2-thiouracil (176 R1 = I, R2 = H), l-methyl-2-mercaptoimidazole (methimazole) and its ethoxycarbonyl derivative carbimazole (177), which lacks the bitter taste of the unacylated compound. These compounds block the synthesis of thyroxin by inhibiting the oxidation of iodide to iodine and the oxidative coupling of iodotyrosine residues. 

Synthesis of 5-iodo-2-thiouracil (ITU) (343) labelled with 123/, 125/ and131 /... 

On the basis of experience derived from previous successful syntheses of 1-substituted 5-cyano-2-thiouracils,236 Shaw and coworkers233 synthesized 5 -cyano-2 -thiouridine. This synthesis was accomplished, interestingly enough, from the 1,3-thiazine (LXXIV) which, when reacted with the tribenzoate ester of D-ribofuranosylamine (LXX), proceeded by way of the acyclic compound LXXV (not isolated) to afford the tribenzoate ester of LXXVI (R = D-ribofuranosyl). Removal of the benzoyl groups yielded 5 -cyano-2 -thiouridine. 

The imidazoles methimazole [60-56-0] (MMI) (12) and Carbimazole [22232-54-8] (13) act by inhibiting intrathyroidal hormone synthesis, whereas the thiouracils (10) [51-52-5] and (11) [56-04-2] also inhibit the peripheral deiodination of T4 to T3. Thus, the latter are preferred in the treatment of thyroid storm (thyrotoxic crisis) where a quick drop in circulating T3 is desired (2,9). In general, the imidazoles are 10 times as active as the thiouracils. 

PURPOSE AND RATIONALE Propyl-thiouracil (PTU) and a wide spectrum of drugs may inhibit thyroid hormone synthesis. Some of these drugs can be used for treatment of thyrotoxicosis. As consequence of thyroid peroxidase inhibition, the iodine uptake and content of the thyroid is decreased. This phenomenon is dose-dependent and may occur at lower doses than those increasing thyroid weight in rats (McGinty and Bywater 1945). The historical parameter of iodine content was replaced by measuring uptake and release of radio-iodine (131-1). 

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