TOLBUTAMIDE Chemical Properties

Melting point:

128-130°C

Density 

1.2450

refractive index 

1.6360 (estimate)

storage temp. 

Sealed in dry,Room Temperature

solubility 

Soluble in chloroform.

pka

pKa 5.32(H2O t = 37) (Uncertain)

color 

White to Off-White

Water Solubility 

0.14g/L(25 ºC)

Merck 

14,9507

BRN 

1984428

Specific Activity

50-60 mCi/mmol

Concentration

0.1 mCi/ml

Solvent

Ethanol

Stability:

Stable. Combustible.

CAS DataBase Reference

64-77-7(CAS DataBase Reference)

EPA Substance Registry System

Tolbutamide (64-77-7)

Safety Information

Hazard Codes 

F,Xn

Risk Statements 

20/21/22-40-43-36-11

Safety Statements 

26-36/37/39-36/37-16-24/25

WGK Germany 

2

RTECS 

YS4550000

TSCA 

Yes

HS Code 

29350090

Hazardous Substances Data

64-77-7(Hazardous Substances Data)

Toxicity

LD50 oral in rat: 2490mg/kg

MSDS

• Language:English Provider:SigmaAldrich
• Language:English Provider:ALFA

TOLBUTAMIDE Usage And Synthesis

Chemical Properties

White or almost white, crystalline powder.

Originator

Dolipol,Hoechst,France,1956

Uses

Tolbutamide, have been used in a cDNA microarray assay to probe changes in gene expression in HepG2 cells upon their administration. It has been utilized to counteract insulin activity in a patch-clamp investigation of ATP sensitive K+ channels in mouse pancreatic β-cells. The activity of various biotransformation enzymes in cultured primary rat proximal tubular cells in the presence of tolbutamide and other compounds has been studied.

Uses

An antidiabetic, used as a hypoglycemic agent in veterinary medicine.

Uses

It is used for type II diabetes mellitus of medium severity with no expressed microvascular complications.

Definition

ChEBI: An N-sulfonylurea that consists of 1-butylurea having a tosyl group attached at the 3-position.

Manufacturing Process

50 grams of n-butyl isocyanate are stirred at room temperature into a suspension of 96 grams of sodium 4-methyl-benzenesulfonamide in 120 cc of dry nitrobenzene and the whole is then heated for 7 hours at 100°C. After being cooled, the reaction mixture, which is a thick magma, is diluted with methylene chloride or ethyl acetate and the sodium salt of the sulfonylurea formed is separated by centrifuging. The centrifuged crystalline residue freed from organic solvents is dissolved in 500 to 600 cc of water heated at 50°C and decolorized with animal charcoal.
The precipitate obtained by acidification with dilute hydrochloric acid is dissolved in an equivalent quantity of dilute ammonia solution (about 1:20), again treated with animal charcoal and reprecipitated with dilute hydrochloric acid. In this manner N-4-methylbenzenesulfonyl-N'-n-butyl-urea is obtained in analytically pure form in a yield of 70 to 80% of theory. It melts at 125° to 127°C (with decomposition).

Therapeutic Function

Oral hypoglycemic

General Description

Tolbutamide is N-[(butylamino)carbonyl]-4-methylbenzenesulfonamide;or 1-butyl-3-(p-tolylsulfonyl)urea (Orinase,generic). Orinase Diagnostic was the sodium salt, which isfreely soluble in water for injection, but this product was discontinuedc. 2000.

General Description

Tolbutamide, 1-butyl-3-(p-tolylsulfonyl)urea (Orinase), occurs as a white, crystalline powderthat is insoluble in water and soluble in alcohol or aqueousalkali. It is stable in air.
Tolbutamide is absorbed rapidly in responsive diabetic patients.The blood sugar level reaches a minimum after 5 to8 hours. It is oxidized rapidly in vivo to 1-butyl-3-(p-carboxyphenyl)sulfonylurea, which is inactive. The metabolite isfreely soluble at urinary pH; if the urine is strongly acidified,however, as in the use of sulfosalicylic acid as a protein precipitant,a white precipitate of the free acid may be formed.

General Description

White crystals.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

TOLBUTAMIDE 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). TOLBUTAMIDE is incompatible with acids. .

Fire Hazard

Flash point data for TOLBUTAMIDE are not available. TOLBUTAMIDE is probably combustible.

Biological Activity

tolbutamide is a potent inhibitor of camp with an ic50 value of 4mm [1].tolbutamide has been reported to inhibit both the basal and the cyclic amp-stimulated protein kinase activites with an ic50 value of 4mm for cyclic amp-dependent kinase activity. in addition, tolbutamide has been revealed to inhibit both soluble and membrane-bound protein kinase from canine heart. moreover, the tolbutamide inhibition of adipose tissue cyclic amp- dependent protein kinase is explanation for antilipolytic effects [1]. besides, tolbutamide and dbcamp has been exhibited to increase about four-fold levels of cx43 mrna and decrease about 80% the expression of ki-67 [2].

Mechanism of action

Tolbutamide is one of the most widely used antidiabetic agents. Its action is preferably connected with stimulatory action of β-cells in the pancreas, which results in intensive insulin secretion.

Clinical Use

Tolbutamide should be used only when the diabetic patientis an adult or shows adult-onset diabetes, and the patientshould adhere to dietary restrictions.

Safety Profile

Moderately toxic by ingestion and several other routes. A human teratogen. Human reproductive effects by ingestion and possibly other routes: stillbirth, developmental abnormalities of the cardlovascular (circulatory) system and urogenital system, and unspecified neonatal effects. Human systemic effects by ingestion: nausea or vomiting, hypoglycemia. Other experimental teratogenic and reproductive effects. Mutation data reported. Implicated in aplastic anemia. When heated to decomposition it emits very toxic fumes of NO, and SOx.

Synthesis

Tolbutamide, 1-butyl-3-p-toluenesulfonylurea (26.2.2), is made in a single step reaction by interaction of p-toluenesulfonylamide (in the form of sodium salt) with butylisocyanate.

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: effects enhanced by NSAIDs - avoid with azapropazone.
Antibacterials: effects enhanced by chloramphenicol, sulphonamides, tetracyclines and trimethoprim; effect reduced by rifamycins.
Anticoagulants: effect possibly enhanced by coumarins; also possibly changes to INR.
Antifungals: concentration increased by fluconazole and miconazole, and possibly voriconazole.
Lipid-regulating drugs: possibly additive hypoglycaemic effect with fibrates.
Sulfinpyrazone: enhanced effect of sulphonylureas.

Metabolism

Tolbutamide is metabolised in the liver by hydroxylation mediated by the cytochrome P450 isoenzyme CYP2C9. It is excreted in the urine chiefly as inactive metabolites.

References

[1] wray hl, harris aw. adenosine 3', 5'-monophosphate-dependent protein kinase in adipose tissue: inhibition by tolbutamide. biochem biophys res commun. 1973 jul 2;53(1):291-4.
[2] sánchez-alvarez r1, paíno t, herrero-gonzález s, medina jm, tabernero a. tolbutamide reduces glioma cell proliferation by increasing connexin43, which promotes the up-regulation of p21 and p27 and subsequent changes in retinoblastoma phosphorylation. glia. 2006 aug 1;54(2):125-34.

TOLBUTAMIDE(64-77-7)Related Product Information

• HYDROXY TOLBUTAMIDE
• alpha-Toluenesulfonyl chloride
• CHLORPROPAMIDE
• Repaglinide
• Glimepiride
• Tolbutamide-d9
• 4-Carboxytolbutamide Methyl Ester
• TOLAZAMIDE
• Tolbutamide 4-Carboxy Ethyl Ester
• Tolbutamide Impurity 5
• Sulfanilamide
• tolbutamide sodium
• HYDROXY TOLBUTAMIDE-D9
• Tolbutamide-d9 Carboxylic Acid
• Tetracaine-d6 Hydrochloride
• Tolbutamide Carboxylic Acid
• Tolbutamide, substrate for Cytochrome P450 2C9
• [RING-U-14C]TOLBUTAMIDE