TOLAZAMIDE Chemical Properties

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%).

pka

3.6(at 25℃)

form 

Solid

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

Hazard Codes 

Xn

Risk Statements 

22

Safety Statements 

36

WGK Germany 

3

RTECS 

YT4400000

HS Code 

2935904000

Hazardous Substances Data

1156-19-0(Hazardous Substances Data)

Toxicity

LD50 in rats, mice (mg/kg): >5000 orally, 2239 i.p. (Dulin)

MSDS

• Language:English Provider:SigmaAldrich

TOLAZAMIDE Usage And Synthesis

Description

Tolazamide is a first generation sulfonylurea that inhibits sulfonylurea receptor 1 (SUR1) linked to the inwardly rectifying potassium channel (K_IR6.2; 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

Uses

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.

Uses

Labelled Tolazamide, an antidiabetic.

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

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.

General Description

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

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.

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.

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