Mitotan Property

Melting point:

77-78 °C(lit.)

Boiling point:

405.59°C (rough estimate)

Density 

1.3118 (rough estimate)

refractive index 

1.6000 (estimate)

storage temp. 

Inert atmosphere,Room Temperature

solubility 

DMSO: soluble20mg/mL, clear

form 

powder

color 

white to beige

Water Solubility 

<0.1 g/100 mL at 24 ºC

Merck 

13,6237 / 13,6237

BRN 

2056007

InChI

InChI=1S/C14H10Cl4/c15-10-7-5-9(6-8-10)13(14(17)18)11-3-1-2-4-12(11)16/h1-8,13-14H

InChIKey

JWBOIMRXGHLCPP-UHFFFAOYSA-N

SMILES

C1(Cl)=CC=CC=C1C(C1=CC=C(Cl)C=C1)C(Cl)Cl

CAS DataBase Reference

53-19-0(CAS DataBase Reference)

NIST Chemistry Reference

Mitotane(53-19-0)

EPA Substance Registry System

o,p'-DDD (53-19-0)

Safety

Hazard Codes 

Xn

Risk Statements 

40

Safety Statements 

36/37

RIDADR 

3249

WGK Germany 

3

RTECS 

KH7880000

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

2903990002

Hazardous Substances Data

53-19-0(Hazardous Substances Data)

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H351Suspected of causing cancer

Precautionary statements

P280Wear protective gloves/protective clothing/eye protection/face protection.

Mitotan Chemical Properties,Usage,Production

Pharmacological effects

Mitotan is structurally similar with insecticide DDT and DDD and can selectively cause the atrophy and necrosis of adrenal cortex-zona fasciculata and reticularis cells but without affecting the zona, therefore the secretion of aldosterone will not affected. After the drug administration, the cortisol and its metabolites level in blood and urine decreased rapidly after treatment. At the same time, the in vivo adrenocorticotropic hormone and metabolite products level also decrease rapidly. It is suitable for the treatment of inoperable, functional and non-functional adrenal cortical carcinoma, adrenal tumor, adrenal hyperplasia-caused Klinefelter’s syndrome, adrenal hyperplasia, and the adjuvant therapy of postoperation cortical cancer and tumor-induced Cushing's syndrome.
After oral administration, about 40% of Mitotan is absorbed through the gastrointestinal tract with the remaining 60% of the prototype excreted together with the feces. At a dose of 5~10 g daily, the plasma concentration can be up to 10~90μg/ml, the concentration of metabolites can be up to 30~50μg/ml. At 6-9 weeks after discontinuation, it can be still detected of o-alkyl chloride in the plasma. Mitotan has a high fat-solubility and is mainly stored in fat. The water soluble metabolites discharged from the urine can account for about 25% of the administered dose.
The above information is edited by the chemicalbook of Dai Xiongfeng.

Chemical Properties

It appears as white crystals with the melting point being 76-78 ℃. It is soluble in ethanol and carbon tetrachloride.

Uses

It belongs to antineoplastic agents and can be used for the treatment of adrenal cortical carcinoma.

Production method

It can be prepared from O-bromo-chlorobenzene (see 05820) by the following steps.

Category

Toxic substances.

Toxicity grading

Poisoning.

Acute toxicity

Oral-rat; LD50> 5000 mg/kg; Oral-Mouse LD50> 4000 mg/kg.

Flammability and hazard properties

Thermal decomposition can release toxic chloride fume.

Storage characteristics

Low-temperature, dry and ventilated warehouse.

Extinguishing media

Water, carbon dioxide, foam, powder.

Description

Mitotane is an inhibitor of steroidogenesis that suppresses the growth of adrenocortical cells. It blocks the expression of several genes that encode proteins involved in steroidogenesis and disrupts mitochondrial respiratory chain activity in human adrenocortical cells. Mitotane has anti-neoplastic actions, alone or in combination with other compounds, and suppresses cortisol synthesis, although it also has significant toxicity in the gastrointestinal tract and nervous system. It is effective against adrenocortical carcinoma and Cushing’s Syndrome in clinical trials.

Chemical Properties

Crystalline Solid

Uses

insecticide, antineoplastic

Uses

Mitotane is an inhibitor of steroidogenesis that suppresses the growth of adrenocortical cells. It blocks the expression of several genes that encode proteins involved in steroidogenesis and disrupts mitochondrial respiratory chain activity in human adrenocortical cells. Mitotane has anti-neoplastic actions, alone or in combination with other compounds, and suppresses cortisol synthesis, although it also has significant toxicity in the gastrointestinal tract and nervous system. It is effective against adrenocortical carcinoma and Cushing’s Syndrome in clinical trials.

Uses

An Antineoplastic. Used as an adrenolytic agent

Uses

aminobiphoshphanate for treatment of osteoporosis and Paget's bone disease

Definition

ChEBI: Mitotane is a diarylmethane.

Indications

Mitotane (Lysodren) produces selective atrophy of the zona fasciculata and zona reticularis, which results in a decrease in the secretion of 17-hydroxycorticosteroids. Direct inhibition of cholesterol side-chain cleavage and 11/18-hydroxylase activities has also been demonstrated.

Indications

The observation that mitotane (Lysodren) could produce adrenocortical necrosis in animals led to its use in the palliation of inoperable adrenocortical adenocarcinomas. A reduction in both tumor size and adrenocortical hormone secretion can be achieved in about half of the patients taking the drug. Because normal adrenocortical cells also are affected, endogenous glucocorticoid production should be monitored and replacement therapy administered when appropriate.
Mitotane is incompletely absorbed from the gastrointestinal tract after oral administration. However, once absorbed, it tends to accumulate in adipose tissue. Mitotane is slowly excreted and will appear in the urine for several years.The major toxicities associated with its use are anorexia, nausea, diarrhea, lethargy, somnolence, dizziness, and dermatitis.

Manufacturing Process

From dichloroacetaldehyde and 2-chlorphenylmagnesiumbromide was prepared 1-(2-chlorphenyl-2,2-dichloroethanol. By action of H2SO4 on 1-(2- chlorphenyl)-2,2-dichloroethanol in chlorobenzene was prepared 1,1-dichloro- 2,2-bis(2,4'-dichlorophenyl)ethane.

brand name

Lysodren (Bristol-Myers Squibb).

Therapeutic Function

Antineoplastic

General Description

Colorless powder.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Mitotan dehydrohalogenates with strong alkalis. Simple aromatic halogenated organic compounds are very unreactive; halogenated aliphatic compounds are moderately or very reactive. For both subgroups, reactivity generally decreases with increased degree of substitution of halogen for hydrogen atoms. Materials in this group are incompatible with strong oxidizing and reducing agents. Also, they are incompatible with many amines, nitrides, azo/diazo compounds, alkali metals, and epoxides.

Fire Hazard

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

Pharmacology

Mitotane, a derivative of the insecticide DDT, quickly lowers the level of corticosteroids, and is metabolized in the blood and urine and used on non-operable metastatic prostate carcinomas. Synonyms of this drug are lysodren and others.

Clinical Use

Mitotane is the drug of choice for the treatment of primary adrenal carcinoma when surgery or radiation therapy is not feasible. Its effectiveness in curtailing adrenal activity is due to an action on adrenocortical mitochondria to impair cytochrome P450 steps in steroid biosynthesis. Mitotane requires metabolic transformation to exert its therapeutic action, and the differential ability of tumors to metabolize the drug may determine its clinical effectiveness. It is advised to measure serum mitotane levels and urinary free cortisol excretion to ensure adequate therapeutic concentrations. Mitotane increases circulating cholesterol by inhibiting cytochrome P450–mediated reactions and therefore contributes to the cardiovascular events that are a significant cause of mortality in untreated Cushing’s syndrome.
Mitotane, being closely related to the organochlorine insecticides, shares its inductive effects on the liver microsomal drug-metabolizing enzyme system, and its use may therefore alter the requirement for concomitantly administered drugs that are also metabolized by this pathway.

Side effects

Mitotane is capable of inducing remission of Cushing’s disease, but only after several weeks of therapy and at the price of severe gastrointestinal distress. Moreover, more than half of patients relapse following cessation of therapy. Other side effects include lethargy, mental confusion, skin rashes, and altered hepatic function. Being a lipid-soluble substance, mitotane remains stored in body tissues for extended periods. This may account for the marked patient-to-patient variability in its therapeutic and/or toxic effects.

Synthesis

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)ethane (30.5.8), is made by alkylating chlorobenzene with 1-(2-chlorophenyl)-2,2-dichloroethane (30.5.7) in the presence of sulfuric acid. The necessary 1-(2-chlorophenyl)-2,2-dichloroethanol (30.5.7) is in turn made from reacting 2-chlorophenylmagnesiumbromide with dichloroacetic aldehyde.

Veterinary Drugs and Treatments

In veterinary medicine, mitotane is used primarily for the medical treatment of pituitary-dependent hyperadrenocorticism (PDH), principally in the dog. It has also been used for the palliative treatment of adrenal carcinoma in humans and dogs.

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: possibly reduced anticoagulant effect of coumarins.
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
Diuretics: avoid with spironolactone.

Metabolism

Metabolised in the liver and other tissues and excreted as metabolites in urine and bile. From 10-25% of a dose has been recovered in the urine as a water-soluble metabolite and 1-17% in the faeces as metabolites

Purification Methods

Purify Mitotane by recrystallisation from pentane, MeOH or EtOH. It is soluble in isooctane and CCl4. [Haller et al. J Am Chem Soc 67 1600 1945, Beilstein 5 IV 1883.]