Sulphonylurea derivatives

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Chapter: Medicinal Chemistry : Oral Hypogylcaemic Drugs

Sulphonylurea derivatives : a. First-generation drugs i. Tolbutamide (Orinase) ii. Chloropropamide (Diabenese) iii. Tolazamide (Tolamide, Tolinase) iv. Acetohexamide b. Second-generation drugs i. Glibenclamide (Glyburide) ii. Glipizide (Dibizide, Glucolip, Glynase) iii. Gliclazide


SYNTHESIS AND DRUG PROFILE

Sulphonylurea derivatives

a. First-generation drugs

Mode of action: They target on the specific receptors in the β cells of islets of Langerhans called sulphonylurea receptors, and cause depolarization by reducing the conductance of ATP sensitive K+ channels. This enhances the Ca2+ influx and produces degranulation, leading to the secretion of insulin.

The sulphonylureas may be represented by the following general structure


All members of this group are urea derivatives with an aryl sulphonyl group in the 1st position and an aliphatic group at the 3rd position. The R group on the aromatic ring primarily influences the duration of action of the compound.

 

i. Tolbutamide (Orinase)


Properties and uses: Tolbutamide is a white crystalline powder, practically insoluble in water, soluble in acetone, alcohol, and dilute solutions of alkali hydroxides. It is useful in the treatment of selected cases of diabetes mellitus, namely, mild and uncomplicated, stable diabetes of adult.

Assay: Dissolve the sample in a mixture of water and alcohol (1:2) and titrate against 0.1 M sodium hydroxide using phenolphthalein as indicator.

Synthesis

Route I. From: 4-Methylbenzene sulphonamide


Route II. From: Toluene


Dose: The usual dosage is 250 and 500 mg with an initial dose of 500 mg.

Dosage forms: Tolbutamide tablets B.P.

 

ii. Chloropropamide (Diabenese)


Synthesis

Route I. From: 4-Chlorobenzenesulphonamide


Ruote II. From: Chlorobenzene


Metabolism: It is metabolized by ω or ω-1 hydroxylation of the propyl group. This reaction is slow and significant amount of the drug is excreted unchanged in urine.

Properties and uses: Chloropropamide is a white crystalline powder, practically insoluble in water, soluble in acetone, methylene chloride, alcohol, and dilute solutions of alkali hydroxides. Used in the treatment of diabetes mellitus.

Assay: Dissolve the sample in alcohol and add water. Titrate against 0.1 M sodium hydroxide using phenolphthalein as indicator until a pink colour is obtained.

Dose: The usual dose is 100–250 mg per day.

 

iii. Tolazamide (Tolamide, Tolinase)


Metabolism of tolbutamide and tolazamide: They undergo a more rapid benzylic oxidation, leading to an inactive benzoic acid derivative. An alternative hydroxylation of the aliphatic ring of tolazamide becomes active and results in a metabolite of prolonged duration of action.


Synthesisp


Properties and uses: Tolazmide is a white crystalline powder, very slightly soluble in water, soluble in chloroform and acetone, slightly soluble in ethanol. Used as an oral hypoglycaemic agent with action and uses similar to Tolbutamide.

Assay: Dissolve the sample in butan-2-one with the aid of gentle heat. Allow to cool, add 30 ml of ethanol and titrate with 0.1 M sodium hydroxide using phenolphthalein as indicator.

Dose: The dose is 100–250 mg daily.

Dosage forms: Tolazamide tablets B.P.

 

iv. Acetohexamide


Synthesis


Metabolism: The major metabolite of acetohexamide is a reduced product of the keto group, forming an alcohol. The hydroxy metabolite exhibits 2.5 times the hypoglycaemic activity of the parent molecule.

Properties and uses: It is a white, odourless crystalline powder, soluble in alcohol and chloroform, but insoluble in water or ether. It is an orally active hypoglycaemic drug.

 

b. Second-generation drugs


i. Glibenclamide (Glyburide)


Synthesis

Route I. From: 5-Chloro-2-methoxybenzoylchloride


Route II.

Step I: Synthesis of 5-chloro-2-methoxybenzoyl chloride


Step II: Synthesis of 4-(Aminoethyl)-1-cyclohexylamino carbonyl benzene sulphonamide


Step III: Condensation of product of Step I and Step II


Properties and uses: Glibenclamide is a white crystalline powder, practically insoluble in water, sparingly soluble in methylene chloride, slightly soluble in alcohol and methanol. Used in the treatment of mild uncomplicated NIDDM unresponsive to diet alone.

Assay: Dissolve the sample in alcohol by heating and titrate against 0.1 M sodium hydroxide, using phenolphthalein as indicator, until a pink colour is obtained.

Dose: The dose is 2.5–5 mg per day to be taken with breakfast.

Dosage forms: Glibenclamide tablets B.P.

 

ii. Glipizide (Dibizide, Glucolip, Glynase)


Synthesis


Metabolism: It is extensively metabolized to less active or inactive metabolites. Its metabolites are excreted primarily in the urine.


Properties and uses: Glipizide is a white crystalline powder, practically insoluble in water and ethanol, very slightly soluble in methylene chloride and acetone, soluble in dilute solutions of alkali hydroxides. It is an orally active hypoglycaemic drug.

Assay: Dissolve the sample in dimethylformamide and titrate against 0.1 M lithium methoxide add quinaldine red as indicator, until the colour changes from red to colourless.

Dose: The dosage is 25–50 mg once a day or in divided doses.

Dosage forms: Glipizide tablets B.P.

 

iii. Gliclazide


Properties and uses: Gliclazide is a white powder, practically insoluble in water, soluble in methylene chloride, sparingly soluble in acetone, and slightly soluble in alcohol. It is an orally active hypoglycaemic drug.

Assay: Dissolve the sample in anhydrous acetic acid and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically.

Dosage forms: Gliclazide tablets B.P.

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