Trimethoprim

Trimethoprim (Proloprim, Trimpex) interferes with the bacterial folic acid pathway by inhibiting the dihydrofolate reductase enzyme in susceptible bacteria (see Fig. 33-2). This enzyme converts dihydrofolic acid to tetrahydrofolic acid during the biosynthesis of folic acid cofactors. By inhibiting this enzyme, trimethoprim directly interferes with the production of folic acid cofactors, and subsequent production of vital bacterial nucleic acids is impaired. 

The subject of trimethoprim-induced hypersensitivities is not straightforward in that the literature leaves one with the impression that the real situation may not be in full view. From the authors  

Studies have been few but the diagnostic procedures applied so far for trimethoprim and sulfamethoxazole, and the immunochemical defliution of the drug allergenic determinants, have provided a firm basis for the clinician to confidently diagnose and distinguish immediate allergic reactions to these two drugs. 

IgE antibodies to trimethoprim were first demonstrated in the mid-1980s. Immunochemical investigations employing bimethoprim covalently coupled via a spacer arm to Sepharose in quantitative hapten inhibition experiments with carefully selected analogs provided insights into the precise structures of the drug recognized by 

Reproduced from Pham NH et al. Clin Exp Allergy 1996-,26 1155 with permission 

Model showing distinct IgE4nnding determinant stmctnres (green, yeBow or bbie) recognized by different groups of allergic subjects 

Chemical Name 5-[(3,4,5-trimethoxyphenyl)methyl] -2,4-pyrimidinediamine Common Name — 

Trade Name Manufacturer Country Year Introduced 

20 grams of the above product was added to 30 ml of 3 N aqueous sulfuric acid at 60°C under stirring. The solution was chilled under stirring to 5° to 10°C. The crystalline sulfate was collected by vacuum filtration and washed on the filter twice with 10 ml of cold 3N aqueous sulfuric acid each time. From the filtrate there was recovered 1.3 grams. (6.5%) of discolored material melting at 195° to 196°C and which can be added to subsequent purification batches. 

The sulfate on the filter was dissolved in 200 ml of hot water, the solution charcoaled hot, and the product precipitated from the clear colorless filtrate by the gradual addition of a 

Other names 2,4-Diamino-5-(3,4,5-trimethoxybenzyl) Pyrimidine, 2,4-Diamino-5-(3,4,5 -trimethoxybenzyl) pyrimidine) 

Solubility Very soluble in HCl, slightly soluble in water, sparingly soluble in alkalies. 

Synthesis of trimethoprim from 3,4,5-TMBA based on the conventional process would proceed as follows  

Bishomologation of the benzaldehyde (by reduction to the alcohol, conversion to the chloride and then malonic ester CH2(COOC2H5)2 synthesis to hydro-cinnamic acid. 

Formylation with ethyl formate HCOOC2H5 and base gives hydroxy methylene derivative. Condensation of that intermediate with guanidine (H2N)2 C = NH gives pyrimidine. 

Trade Name Manufacturer Cou ntry Year introduced 

6 grams (0.26 mol) sodium was dissolved in 300 ml methanol under stirring and refluxing. 

28 grams (91% of the theory). The material showed the correct melting point of 199° to 200°C and was, however, yellowish discolored. 

6 grams (0.26 moi) sodium was dissoived in 300 mi methanoi under stirring and refiuxing. 

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Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

A monograph (1) covers the pioneering period of sulfa dmg development and describes over 5000 sulfanilamide derivatives, their preparation, properties, trade names, and biological testing. This review is remarkably complete through 1944. Several thousand additional derivatives have been made since, but no comparable coverage is available. A definitive account of medical appHcations up to 1960 has been pubHshed (2), and a review of experimental antibacterial aspects has been made (3). Chapters on general aspects of sulfonamides and sulfones have appeared (4,5). A review of the clinical efficacy of trimethoprim—sulfamethoxazole has been pubHshed (6). 

The sulfa dmgs are stiH important as antimicrobials, although they have been replaced in many systemic infections by the natural and semisynthetic antibiotics. They are of great value in third world countries where problems of storage and lack of medical personnel make appropriate use of antibiotics difficult. They are especially useful in urinary tract infections, particularly the combination of sulfamethoxazole with trimethoprim. Their effectiveness has been enhanced by co-adniinistration with dihydrofolate reductase inhibitors, and the combination of sulfamethoxazole with trimethoprim is of value in treatment of a number of specific microbial infections. The introduction of this combination (cotrimoxazole) in the late 1960s (1973 in the United States) resulted in increased use of sulfonamides. 

Sulfonamides in combination with dihydrofolate reductase inhibitors are of continuing value. Pyrimethamine [58-14-0] (5) in combination with sulfonamides is employed for toxoplasmosis (7), and a trimethoprim (6)-sulfamethoxa2ole preparation is used not only for urinary tract infections but also for bmceUosis, cholera, and malaria. 

Table 3. Representative Minimum Inhibitory Concentrations for Urinary Tract Organisms by Sulfamethoxazole (SMX), Trimethoprim (TMP), and Their Combination...

Other Infections. The slowly excreted sulfonamides (eg, sulfamethoxypyrida2ine, sulfadimethoxine) are used for treatment of minor infections such as sinusitis or otitis, or for prolonged maintenance therapy. Soluble sulfonamides are sometimes used for proto2oal infections in combination with other agents. Pyrimethamine, combined with sulfonamides, has been used for toxoplasmosis or leishmaniasis, and trimethoprim with sulfonamides has been used in some types of malaria. In nocardiosis, sulfonamides have been used with cycloserine [68-41-7] (17). 

L-Dopa and Trimethoprim are two other dmgs that can be made from vanillin. u-Dopa is used for the treatment of Parkinson s disease Trimethoprim is an antiinfective agent used mainly for urinary tract infections and certain venereal diseases. Also, Mebeverine, an antispasmodic agent, and Verazide, a generic antitubercular agent, are dmgs that can be made from vanillin or its derivatives. 

C22H24N2O, or trimethoprim [738-70-5] These preparations may also contain an antiinflammatory corticoid such as hydrocortisone... 

Diaveridine (1044) is a close relative of trimethoprim (Section 2.13.4.2.3) and is made by an analogous Principal Synthesis. It is used prophylactically against coccidiosis in poultry and in combination with sulfaquinoxaline as a curative agent for the same disease similar mixtures are also effective (64MI21305). 

We proposed using MLC for assay of azithromycin in tablets and capsules. As alternative conventional reversed-phase HPLC method MLC was used for analysis of Biseptol (sulfamethoxazole and trimethoprim) tablets and injection. The MLC was proposed to assay of triprolydine hydrochloride and pseudoephedrine hydrochloride in tablets as alternative normal-phase HPLC method described in USP phamiacopoeia. 

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