Antithyroid Drugs: Thioureylenes - Synthesis and Drug Profile

Antithyroid Drugs (Drugs Acting On Endocrine System)

SYNTHESIS AND DRUG PROFILE

I. Thioureylenes

Mode of action: Thiourea and thiouracil derivatives are among the primary drugs to treat thyroid hyperactivity. Methyl and propylthiouracil derivatives are effective drugs in the treatment of thyroidrelated problems. They prevent iodine incorporation into the organic form perhaps by antagonizing the iodide oxidation by peroxidase. They are also found to prevent coupling of iodotyrosines to form iodothyronines.

The 2-thiouracil derivatives, that is, 4-keto-2-thio pyrimidines, are undoubtedly tautomeric compounds and can be represented as follows:

Some 300-related structures have been evaluated for antithyroid activity, but, of these, only the 6-allyl-2thio uracil and closely related structure possess useful clinical activity. The most serious adverse effect of thiouracil therapy is agranulocytosis.

i. Propylthiouracil (Tietil)

Synthesis

Properties and uses: It is a white powdery crystalline substance with bitter taste, soluble in water, alcohol, chloroform, and ether. Used in the management of hyperthyroidism.

Dose: For hyperthyroidism, the dose for adults initially is 200–300 mg per day in divided doses. When the patient attains normal basal metabolic rate (euthyroidism), the dose is usually reduced to a maintenance dose of 50–75 mg per day in two to three divided doses. In children, over 10 years old, initial dose is 150–300 mg per day in four divided doses until the child becomes euthyroid, then, usually, 100 mg daily is given in two divided doses, for maintenance.

ii. Methimazole (Tapazele)

Synthesis

Properties and uses: It exists as white to pale-buff colour solid with characteristic odour and soluble in water. The drug is more potent, more prompt, and has more prolonged action than propylthiouracil. It is indicated in the treatment of hyperthyroidism.

Dose: Usual initial dose is 5–20 mg every 8 h. When condition is stabilized (1–2 months), the dose is reduced to a maintenance dose of 5–15 mg per day. For children, the initial dose is 400 μg/kg body weight per day in divided doses.

iii. Carbimazole

Synthesis

Route I: From: Methimazole

Route II. From: N-methylamino acetal