Aminoglutethimide Chemical Properties

Melting point:

152-154 °C(lit.)

Boiling point:

374.44°C (rough estimate)

Density 

1.1099 (rough estimate)

refractive index 

1.6450 (estimate)

storage temp. 

2-8°C

solubility 

H₂O: 0.2 mg/mL, slightly soluble

pka

11.60±0.40(Predicted)

form 

Solid

color 

white

Water Solubility 

Soluble in water (2 mg/ml at 20°C), methanol (50 mg/ml), ethanol (7 mg/ml at 25°C), DMSO (20 mg/ml at 25°C), and chloroform.

Merck 

14,440

CAS DataBase Reference

125-84-8(CAS DataBase Reference)

NIST Chemistry Reference

Aminoglutethimide(125-84-8)

EPA Substance Registry System

Aminoglutethimide (125-84-8)

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

26-36

RIDADR 

3249

WGK Germany 

3

RTECS 

MA4026950

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

2925190100

Hazardous Substances Data

125-84-8(Hazardous Substances Data)

MSDS

• Language:English Provider:3-(4-Aminophenyl)-3-ethyl-2,6-Piperidinedione
• Language:English Provider:SigmaAldrich

Aminoglutethimide Usage And Synthesis

Description

Aminoglutethimide is an aromatase inhibitor (IC₅₀ = 7.5 μM). Aromatase inhibitors, including aminoglutethimide, inhibit estrogen synthesis via aromatase, suppressing estrogen levels in post-menopausal women. Formulations containing aromatase inhibitors have been used to treat estrogen receptor-positive breast cancer in post-menopausal women.

Chemical Properties

White Solid

Originator

Ellipten,Ciba,US,1960

Uses

Aminoglutethimide is used to decrease the production of sex hormones and suppress the growth of tumors that need sex hormones to grow. It blocks the production of steroids derived from cholesterol and is clinically used in the treatment of Cushing's syndrome and metastatic breast cancer. It is also a drug of abuse by body builders.

Uses

An aromatase inhibitor. Also blocks adrenal steroidogenesis

Uses

aromatase inhibitor, antineoplastic, testosterone suppressant

Definition

ChEBI: A dicarboximide that is a six-membered cyclic compound having ethyl and 4-aminophenyl substituents at the 3-position.

Indications

Aminoglutethimide (Cytadren) is a competitive inhibitor of desmolase, the enzyme that catalyzes the conversion of cholesterol to pregnenolone; it also inhibits 11-hydroxylase activity.This drug also reduces estrogen production by inhibiting the aromatase enzyme complex in peripheral (skin, muscle, fat) and steroid target tissues.

Manufacturing Process

The α-(p-nitrophenyl)-α-ethyl-glutarimide starting material can be prepared as follows: 217 g of α-phenyl-α-ethyl-glutarimide are dissolved in 800 g of concentrated sulfuric acid with subsequent cooling to about -10°C and nitration is carried out at -10°C to +10°C by slow addition of a mixed acid consisting of 110 g of concentrated sulfuric acid and 110 g of 63% nitric acid. The nitration solution is stirred into ice, the separated nitro compound taken up in methylene or ethylene chloride, the solution washed with water and sodium carbonate solution until neutral and the solvent evaporated under vacuum. The residue is crystallized from methanol or ethyl acetate, whereby a yellowish crystal powder of MP 128-136°C is obtained in a yield of about 85% which consists for the most part of α-(p-nitrophenyl)-α-ethyl-glutarimide. By recrystallization from methanol the pure p-nitrophenyl compound is obtained of MP 137-139°C. From the residues of the mother liquors a small quantity of the isomeric α-(o-nitrophenyl)-α-ethyl-glutarimide of MP 170-172°C can be obtained.
26.2 g of α-(p-nitrophenyl)-α-ethyl-glutarimide of MP 137-139°C dissolved in ethyl acetate, are reduced in the presence of nickel with hydrogen in a shaking flask at 50-70°C until the absorption of hydrogen falls off. The catalyst is then filtered off with suction and the solution concentrated and cooled, as a result of which colorless crystals of MP 146-149°C are obtained. Recrystallization from methanol gives pure α-(p-aminophenyl)-α-ethylglutarimide of MP 149-150°C (yield 97%).
Instead of ethyl acetate another solvent can be used in the above reduction, such as methanol or ethanol.
The hydrochloride of MP 223-225°C is obtained by dissolving the base with alcohol and the corresponding quantity of hydrochloric acid gas in the hot with subsequent cooling of the solution. Colorless crystals are formed of MP 223- 225°C, which are easily soluble in water.

brand name

Cytadren (Novartis);C-16038-ba;Crytraden;Doredin;Mamomit;Ormeten.

Therapeutic Function

Cytostatic

World Health Organization (WHO)

Aminoglutethimide, a weak anticonvulsant, was introduced in 1960 for use in the treatment of epilepsy. However, its adrenocortical suppressant activity gave rise to serious adverse effects. The FDA decision in 1966 was taken in respect of a preparation indicated in epilepsy. In 1980 preparations containing aminoglutethimide were reintroduced in the USA exclusively for the treatment of Cushing's disease. In 1986 they were also registered in Saudi Arabia for use in Cushing's syndrome and for the treatment of breast cancer. In some other countries these preparations are additionally approved for carcinoma of the prostate.

General Description

Aminoglutethimide, 3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione, is mainly usedto treat Cushing syndrome, a condition of adrenal steroidexcess, a use in which the P450_scc inhibition of thiscompound is exploited rather than its aromatase inhibition.Aminoglutethimide is a weak inhibitor of aromataseand has been used successfully in the treatment of estrogen-dependent breast cancer. Because of the developmentof more selective aromatase inhibitors, the use ofaminoglutethimide for its ability to inhibit aromatase is notsupported.

Mechanism of action

This drug blocks the transformation of cholesterol into pregnenolone, and androgens into estrogens in the adrenal glands, thus completely suppressing the production of all steroid hormones. Aminoglutethimide is used for palliative treatment of prostate carcinomas and post-menopausal breast carcinomas. Synonyms of aminoglutethimide are orimeten, citadren and others.

Clinical Use

Aminoglutethimide is suitable for use in Cushing’s syndrome that results from adrenal carcinoma and in congenital adrenal hyperplasia, in which it protects the patient from excessive secretion of endogenous androgens. The drug is not curative, and relapse occurs when treatment is terminated. Since aminoglutethimide therapy is frequently associated with mineralocorticoid deficiency, mineralocorticoid supplements may be needed. Aminoglutethimide and metyrapone are frequently used in combination at lower doses of both drugs as an adjunct to radiation or surgical therapy.

Side effects

Such a medical adrenalectomy is an efficacious treatment for metastatic breast and prostate cancer, since it diminishes the levels of circulating sex hormones. Glucocorticoids are administered concomitantly to suppress enhanced corticotrophin release. Cortisol is preferable to dexamethasone in this situation because aminoglutethimide markedly enhances the hepatic microsomal metabolism of dexamethasone. Hepatic enzyme induction may be responsible for the development of tolerance to the side effects of aminoglutethimide, such as ataxia, lethargy, dizziness, and rashes.

Synthesis

Aminoglutethimide, (±)-2-(4-aminophenyl)-2-ethylglutarimide (30.5.4), is made by two methods, the first of which begins with glutethimide (4.3.6), which is nitrated to form 2-(4-nitrophenyl)-2-ethylglutarimide (30.5.3). Reducing the nitro group with hydrogen over a nickel catalyst gives the desired aminoglutethimide (30.5.4).

The second method starts with 2-phenylbutyronitrile, which is nitrated under analogous conditions, forming 2-(4-nitrophenyl)butyronitrile (30.5.5). The last, in Michael addition reaction conditions, in the presence of benzyltrimethylammonia hydroxide is added to methylacrylate, and the obtained product undergoes acidic hydrolysis by a mixture of acetic and sulfuric acids, during which a cyclyzation to 2-(4-nitrophenyl)-2-ethylglutarimide (30.5.3) occurs, and this product is reduced by hydrogen by the analogy to that described above, to give the desired product aminoglutethimide (30.5.4) .

Metabolic pathway

Following administration of a single oral dose of 14C- aminoglutethimide to rats, guinea pigs, rabbits, and man, more than 89% of the dose is excreted in urine and feces within 72h, and dogs eliminate only 51% in this time. Extensive metabolism occurs in all species, with N-acetylaminoglutethimide being the major metabolite except for dogs and man. In the latter two species, the unchanged drug is the main product excreted. As shown in the pathways, it appears that aminoglutethimide is metabolized by several pathways in man and, of the ten metabolites, only two are present in any quantity, namely N-acetylaminoglutethimide and N-hydroxyaminoglutethimide, the latter increasing during the course of treatment.

Aminoglutethimide(125-84-8)Related Product Information

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