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HomeProduct name listTOLAZAMIDE

TOLAZAMIDE

Synonym(s):1-(Hexahydro-1H-azepin-1-yl)-3-(p-toluenesulfonyl)urea

  • CAS NO.:1156-19-0
  • Empirical Formula: C14H21N3O3S
  • Molecular Weight: 311.4
  • MDL number: MFCD00083504
  • EINECS: 214-588-3
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-19 20:33:22
TOLAZAMIDE Structural

What is TOLAZAMIDE?

Absorption

Rapidly and well absorbed from the gastrointestinal tract.

Toxicity

Overdosage of sulfonylureas can produce hypoglycemia. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization.

Description

Tolazamide is a first generation sulfonylurea that inhibits sulfonylurea receptor 1 (SUR1) linked to the inwardly rectifying potassium channel (KIR6.2; IC50 = 4.2 μM in HEK293 cells transfected with the human receptor). It has no effect on glucose uptake in L6 rat skeletal muscle cells when used at a concentration of 0.6 mg/mL but enhances glucose uptake two-fold when used in combination with insulin. In vivo, tolazamide (128 mg/kg) reduces glomerulosclerosis and albumin excretion in a rat model of insulin-dependent diabetes induced by streptozotocin . Formulations containing tolazamide have been used in the treatment of type 2 diabetes.

Chemical properties

White Solid

Originator

Tolinase,Upjohn,Italy,1964

The Uses of TOLAZAMIDE

Labelled Tolazamide, an antidiabetic.

The Uses of TOLAZAMIDE

This drug is also a derivative of first generation of sulfonylurea, and it possesses stimulatory action on β-cells in pancreas, as well as the same range of action as all other drugs of the group of examined compounds. Tolazamide is used for non-insulin-dependent diabetes mellitus without expressed microvascular complications.

What are the applications of Application

Tolazamide is sulphonylurea hypoglycemic agent with actions and uses similar to those of chlorpropamide

Background

A sulphonylurea hypoglycemic agent with actions and uses similar to those of chlorpropamide.

Indications

For use as an adjunct to diet to lower the blood glucose in patients with non-insulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone.

Definition

ChEBI: An N-sulfonylurea that is 1-tosylurea in which a hydrogen attached to the nitrogen at position 3 is replaced by an azepan-1-yl group. A hypoglycemic agent, it is used for the treatment of type 2 diabetes mellitus.

Manufacturing Process

1-Nitrosohexamethyleneimine: A solution of 89.5 grams of hexamethyleneimine, 75 ml of concentrated hydrochloric acid and 36 ml of water was heated to 70°C on a steam bath. The solution was made acidic by adding 5 ml of 2 N hydrochloric acid. While maintaining the reaction mixture at 70° to 75°C, a solution of 67 grams of sodium nitrite in 95 ml of water was added with stirring over a period of 1 hour. The mixture was then stirred at 70°C for 2 hours, and then cooled. The upper oily layer was separated and the aqueous layer was then extracted with ether. The combined ether extract and oil was dried over anhydrous magnesium sulfate and concentrated to dryness. Upon distillation of the residue there was obtained 1- nitrosohexamethyleneimine as a yellow oil, boiling at 136° to 138°C/34 mm. 1-Aminohexamethyleneimine: To a mixture of 15.18 grams of lithium aluminum hydride and 400 ml of anhydrous ether was added about 10% of a solution of 51.27 grams of 1-nitrosohexamethyleneimine in 100 ml of anhydrous ether. The mixture was refluxed until the reaction started. The remainder of the solution was added at such a rate as to maintain gentle reflux. Refluxing was continued for 2 hours more, followed by the successive addition of 16 ml of water, 12 ml of 20% aqueous sodium hydroxide solution and 56 ml of water. The inorganic precipitate was removed by filtration and washed with ether. The filtrate and ether washes were dried and the ether was removed by evaporation. Upon distillation of the residue there was obtained 25.46 grams (56%) of 1-aminohexamethyleneimine as a colorless liquid boiling at 94° to 96°C/55 mm.
N-(4-Methylbenzenesulfonyl)-N'-Hexamethyleneiminourea Free Base: A mixture of 11.42 grams of 1-aminohexamethyleneimine and 24.33 grams of 4-methylbenzenesulfonylurethane was heated at 130°C (oil-bath temperature) for 2 hours. The resulting ethanol and unreacted amine were removed at 15 mm pressure for 2 hours while keeping the oil bath at 130°C. The residue was cooled and recrystallized from methanol, giving 16.73 grams (54%) of N-(4- methylbenzenesulfonyl)-N'-hexamethyleneiminourea free base melting at 163° to 166°C. After a second recrystallization from methanol, the melting point was 163.5° to 166.5°C.

Therapeutic Function

Oral hypoglycemic

General Description

White to off-white crystalline powder. Odorless or with a slight odor.

General Description

Tolazamide is N-[[(hexahydro-1H-azepin-1-yl)amino]carbonyl]-4-methylbenzenesulfonamide; or 1-(hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea; or 1-(4-methylphenylsulfonyl)-3-(hexahydro-1H-azepin-1-yl)urea (generic).Tolazamide incorporates a fully saturated azepine moietythat is but weakly basic, with a pKa of~3.32 The pKa of thesulfonylurea group lies within the typical range; thus, inareas of the duodenum wherein the pH falls within the rangeof 4 to 5, the uncharged form of the drug is the predominantspecies, and its lipophilicity lends to rapid absorption bypassive diffusion.

General Description

Tolazamide, 1-(hexahydro-1Hazepin-1-yl)-3-(p-tolylsulfonyl)urea (Tolinase), is an analogof tolbutamide and is reported to be effective, in general,under the same circumstances in which tolbutamide is useful.Tolazamide, however, appears to be more potent than tolbutamideand is nearly equal in potency to chlorpropamide. Instudies with radioactive tolazamide, investigators found that85% of an oral dose appeared in the urine as metabolites thatwere more soluble than tolazamide itself.

Air & Water Reactions

TOLAZAMIDE may be sensitive to prolonged exposure to air. Insoluble in water.

Reactivity Profile

TOLAZAMIDE is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx). TOLAZAMIDE is incompatible with acids. .

Fire Hazard

Flash point data for TOLAZAMIDE are not available; however, TOLAZAMIDE is probably combustible.

Pharmacokinetics

Tolazamide is an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide, may become unresponsive or poorly responsive over time. Alternatively, tolazamide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance.

Synthesis

Tolazamide is 1-hexahydro-1H-azepin-1-yl)-3-(p-toluenesulfonyl)urea (26.2.8). By maintaining structural similarities with first-generation drugs, this drug differs from the other drugs examined in that it has a semicarbazide group instead of a urea residue, and an azepine group instead of a cyclohexyl group. It is synthesized by reacting with ethyl-(p-toluenesulfonyl)carbamate (26.2.7), which is made from p-toluenesulfonamide and ethylchloroformate, with 1-aminoazepine.

Synthesis_1156-19-0

Metabolism

Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0 to 70%.

Properties of TOLAZAMIDE

Melting point: 162-164°C
Boiling point: 300°C (rough estimate)
Density  1.2228 (rough estimate)
refractive index  1.6740 (estimate)
storage temp.  Sealed in dry,Room Temperature
solubility  Very slightly soluble in water; freely soluble in chloroform; soluble in acetone; slightly soluble in ethanol (96%).
form  Solid
pka 3.6(at 25℃)
color  White to Off-White
Water Solubility  65.4mg/L(30 ºC)
CAS DataBase Reference 1156-19-0(CAS DataBase Reference)
EPA Substance Registry System Tolazamide (1156-19-0)

Safety information for TOLAZAMIDE

Computed Descriptors for TOLAZAMIDE

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