125-84-8 Usage
Description
Aminoglutethimide, also known as 3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione, is an aromatase inhibitor primarily used to treat Cushing's syndrome, a condition characterized by adrenal steroid excess. It is a white solid with the chemical formula C12H16N2O2 and is known by various brand names, including Cytadren (Novartis), C-16038-ba, Crytraden, Doredin, Mamomit, and Ormeten. Aminoglutethimide works by decreasing the production of sex hormones and suppressing the growth of tumors that require sex hormones to grow. It also blocks the production of steroids derived from cholesterol and has been used successfully in the treatment of estrogen-dependent breast cancer.
Uses
1. Used in Oncology:
Aminoglutethimide is used as an antineoplastic agent for the treatment of metastatic breast cancer. It functions as a testosterone suppressant and an aromatase inhibitor, blocking the production of estrogen, which is essential for the growth of certain tumors.
2. Used in Endocrinology:
Aminoglutethimide is used as a treatment for Cushing's syndrome, a condition resulting from adrenal steroid excess. It inhibits the enzyme P450scc, which is involved in the production of steroid hormones from cholesterol.
3. Used in Bodybuilding:
Although not a medical use, Aminoglutethimide is a drug of abuse by some bodybuilders who utilize it to suppress the production of sex hormones, potentially leading to muscle growth and fat loss.
Originator
Ellipten,Ciba,US,1960
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.
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.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 125-84-8 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 1,2 and 5 respectively; the second part has 2 digits, 8 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 125-84:
(5*1)+(4*2)+(3*5)+(2*8)+(1*4)=48
48 % 10 = 8
So 125-84-8 is a valid CAS Registry Number.
InChI:InChI=1/C13H16N2O2/c1-2-13(8-7-11(16)15-12(13)17)9-3-5-10(14)6-4-9/h3-6H,2,7-8,14H2,1H3,(H,15,16,17)
125-84-8Relevant articles and documents
Divergent and Chemoselective Transformations of Thioamides with Designed Carbene Equivalents
Saito, Masato,Kobayashi, Yusuke,Takemoto, Yoshiji
, p. 10314 - 10318 (2019)
The reactions of thioamides with ortho-nitro-substituted iodonium ylides proceeded under mild conditions to give enaminones or thiazoles, depending on the iodonium ylide used. This protocol allowed the use of protic solvents, including aqueous solutions, and therefore coupling reactions with complex molecules such as peptides or steroids were possible. A mild and efficient method for the synthesis of various iodonium ylides was established. DFT calculations suggested that the halogen bonding between a thioamide and iodonium ylide was important in this chemoselective coupling reaction. The potential use of enaminones conjugated with pharmaceuticals as prodrugs was also demonstrated.
Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
-
, (2008/06/13)
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A mild preparation of 2,6-piperidinediones
Zhu, Jiarong,Chuong, Pham Huy,Lemoine, Pascale,Tomas, Alain,Galons, Herve
, p. 1923 - 1926 (2007/10/03)
Substituted glutaric acids reacted with alkyloxyamines in the presence of M-ethyl-N-dimethylaminopropylcarbodiimide hydrochloride to form 1-alkyloxy-2,6-piperidinediones. The protecting group on the nitrogen was easily removed in high yield. This process is exemplified by the preparation of aminoglutethimide.