59-52-9

Description

Dimercaprol (INN) or British anti - Lewisite (abbreviated BAL), is a compound developed by British biochemists at Oxford University during World War II . It was developed secretly as an antidote for lewisite, the now - obsolete arsenic - based chemical warfare agent . Today, it is used medically in treatment of arsenic, mercury , gold, lead, antimony, and other toxic metal poisoning . In addition , it has in the past been used for the treatment of Wilson's disease, a genetic disorder in which the body tends to retain copper.

Chemical Properties

colourless oily liquid with a typically offensive mercaptan smell

Originator

Bal,Hynson/Westcott,US,1944

Uses

chelating agent (As, Au, Hg antidote)

Definition

ChEBI: A dithiol that is propane-1,2-dithiol in which one of the methyl hydrogens is replaced by a hydroxy group. a chelating agent originally developed during World War II as an experimental antidote against the arsenic-based poison gas Lewisite, it has been use clinically since 1949 for the treatment of poisoning by arsenic, mercury and gold. It can also be used for treatment of poisoning by antimony, bismuth and possibly thallium, and (with sodium calcium edetate) in cases of acute leaad poisoning. Administrati n is by (painful) intramuscular injection of a suspension of dimercaprol in peanut oil, typically every 4 hours for 2-10 days depending on the toxicity. In the past, dimercaprol was also used for the treatment of Wilson's disease, a severely debilitating g netic disorder in which the body tends to retain copper, with resultant liver and brain injury.

Manufacturing Process

1,2-Dithioglycerol is prepared in the following manner: 1,537 parts of sodium monosulfide nonahydrate and 411 parts of powdered sulfur are dissolved with stirring in 1,345 parts of water. Magnesium hydroxide is precipitated in the stirred sodium trisulfide solution by adding successively 97 parts of sodium hydroxide dissolved in 180 parts of water and then slowly 246 parts of magnesium chloride hexahydrate dissolved in 180 parts of water. The magnesium hydroxide serves as a dispersing agent to maintain the resulting sulfide polymer in finely divided condition. The mixture is heated and stirred at 50°C while 1,329 parts of glycerol 1,2-dibromohydrin is added continuously during a period of 1.5 hours. The reaction is exothermic and external cooling is employed to maintain the temperature within the range of 50°-55°C. After the addition of the dibromohydrin is complete, the mixture is stirred and heated at 75°C for 6 hours.The finely divided yellow sulfide polymer formed is then allowed to settle and the reaction liquor is separated by decantation. The product is washed by decantation five times with water and finally filtered by suction. The moist cake of polymer is then air dried. The yield is 988 parts including approximately 75 parts of magnesium hydroxide.Thirty-two hundred fifty parts of the hydroxypropylene trisulfide containing magnesium hydroxide is charged into a steel autoclave equipped with a mechanical agitator. There is also charged into the autoclave 2,550 parts of dry dioxane and 350 parts of cobalt trisulfide catalyst pasted with 700 parts of dioxane. Hydrogen is charged into the autoclave to a pressure of 1,000 lb/in2 and the autoclave is heated to a temperature of 125°C during 1.5 hours, agitation being employed during this operation. When the temperature reaches about 110°C the pressure commences to drop and is kept between the limits of 1,000 and 1,300 lb/in2 by the addition of hydrogen. When the temperature reaches 125°C the pressure is raised to 1,700 lb/in2 with hydrogen. The rate of hydrogenation increases as the temperature rises and the process is about complete when a temperature of 125°C is reached.After the hydrogen absorption ceases, the autoclave is cooled, vented, and the reaction mixture is filtered to separate the catalyst. The filtrate is then heated on a steam bath at 60-80 mm pressure to remove the dioxane. The less volatile residue consists of 1,933 parts of crude dithioglycerol, a viscous oil.1,2-Dithioglycerol is isolated from the oil by distillation from an oil heated pot through a short still. The distillation is carried out at a pressure of less than 1mm and at a bath temperature of 120°-175°C, the dithioglycerol distilling over at a head temperature of 60°-65°C/0.2 mm or 75°-80°C/0.8 mm. Starting from 550 parts of crude dithioglycerol, 340 parts of distillate is obtained which contains 53% of mercapto sulfur and is nearly pure 1,2- dithioglycerol. The overall yield of dithioglycerol from the glycerol dibromohydrin is 48% of theoretical.

Brand name

Bal (Akorn).

Biological Functions

Arsenic and some other heavy metals act by chemically reacting with adjacent thiol residues on metabolic enzymes, creating a chelate complex that inhibits the affected enzyme's activity. Dimercaprol competes with the thiol groups for binding the metal ion, which is then excreted in the urine . Dimercaprol is itself toxic, with a narrow therapeutic range and a tendency to concentrate arsenic in some organs. Other drawbacks include the need to administer it by painful intramuscular injection. Serious side effects include nephrotoxicity and hypertension. Dimercaprol has been found to form stable chelates in vivo with many other toxic metals including inorganic mercury, antimony, bismuth, cadmium, chromium, cobalt, gold, and nickel. However, it is not necessarily the treatment of choice for toxicity to these metals. Dimercaprol has been used as an adjunct in the treatment of the acute encephalopathy of lead toxicity. It is a potentially toxic drug, and its use may be accompanied by multiple side effects. Although treatment with dimercaprol will increase the excretion of cadmium, there is a concomitant increase in renal cadmium concentration, so that its use in case of cadmium toxicity is to be avoided. It does, however, remove inorganic mercury from the kidneys; but is not useful in the treatment of alkylmercury or phenyl mercury toxicity. Dimercaprol also enhances the toxicity of selenium and tellurium, so it is not to be used to remove these elements from the body.

General Description

Clear colorless viscous liquid with a pungent offensive odor of mercaptans. Used as a medicine and an antidote to the chemical warfare agent LEWISITE.

Air & Water Reactions

Moderately soluble in water with decomposition [Hawley].

Reactivity Profile

2,3-Dimercapto-1-propanol forms highly stable chelates with a variety of metal ions. Organosulfides are incompatible with acids, diazo and azo compounds, halocarbons, isocyanates, aldehydes, alkali metals, nitrides, hydrides, and other strong reducing agents. Reactions with these materials generate heat and in many cases hydrogen gas. Many of these compounds may liberate hydrogen sulfide upon decomposition or reaction with an acid.

Fire Hazard

2,3-Dimercapto-1-propanol is probably combustible.

Pharmaceutical Applications

Dimercaprol (BAL) is a chelating agent used as an antidote for arsenic, antimony, bismuth, gold and mercury poisoning. It has the chemical name 2,3-dimercapto-1-propanol and is a clear, colourless or slightly yellow liquid.

Clinical Use

2,3-Dimercapto-1-propanol, BAL, or dithioglycerol is afoul-smelling, colorless liquid. It is soluble in water (1:20)and alcohol. It was developed by the British during WorldWar II as an antidote for “Lewisite,” hence the name Britishanti-Lewisite or BAL. Dimercaprol is effective topicallyand systematically as an antidote for poisoning caused byarsenic, antimony, mercury, gold, and lead. It can, therefore,also be used to treat arsenic and antimony toxicity associatedwith overdose or accidental ingestion of organoarsenicalsor organoantimonials.The antidotal properties of BAL are associated with theproperty of heavy metals to react with sulfhydryl (SH)groups in proteins (e.g., the enzyme pyruvate oxidase) andinterfere with their normal function. 1,2-Dithiol compoundssuch as BAL compete effectively with such proteins for themetal by reversibly forming metal ring compounds.These are relatively nontoxic, metabolically conjugated(as glucuronides), and rapidly excreted.BAL may be applied topically as an ointment or injectedintramuscularly as a 5% or 10% solution in peanut oil.

Safety Profile

Poison via ingestion, intramuscular, parenteral, intraperitoneal, and intravenous routes. Experimental teratogenic effects. Human systemic effects by intramuscular route: hemorrhage and dermatitis. Human blood and systemic skin effects by intramuscular route. It causes redness and swelling when applied locally to the skin, but does not produce blisters or ulcers. Intensely irritating to eyes and mucous membranes. Systemic symptoms are caused by injection. When heated to decomposition, it emits toxic fumes of SO,. Used as an antidote to arsenic, gold, and mercury poisoning.

Environmental Fate

BAL is believed to compete with tissue sulfhydryl groups and interferes with cellular respiration. It also competes with metallic cofactors of metabolic enzyme systems and increases capillary permeability. Metabolic degradation and excretion are essentially complete within 4 h. BAL not excreted as dimercaprol– metal complex is quickly metabolized by the liver and excreted as an inactive product in the urine. Because it is a lipophilic drug, it penetrates rapidly the intracellular spaces. The highest concentrations are found in the liver, kidneys, brain, and small intestine. Due to its lipophilic characteristic, the complexes formed with mercury and other metals may be redistributed into sensitive cells in the brain following dimercaprol treatment.

Purification Methods

Precipitate BAL as the Hg mercaptide [see Bj.berg Chem Ber 75 13 1942], regenerate with H2S, and distil it under a vacuum [Rosenblatt & Jean Anal Chem 951 1955]. It is an antidote for heavy metal (As, Hg, Au etc) poisoning. [Beilstein 1 IV 2770.]

Toxicity evaluation

BAL is a colorless or slightly yellowish viscous oily liquid and has a pungent odor. The molecular weight, melting point, boiling point, vapor pressure, and the octanol–water partition coefficient (log Kow) are 124.23, 77°C, 120°Cat 15 mm Hg, 4.36×103 mm Hg at 25°C, and 0.16, respectively. The Henry’s law constant is 9.39×109 atmm3 mol-1 at 25°C. BAL is soluble in ethanol and ether, and slightly soluble in chloroform and vegetable oils. Water solubility is 8.7 g/100 ml. BAL should be protected from light and should be stored at temperatures between 2 and 10°C in small vials.