50-60-2 Usage
Description
Phentolamine is a synthetic imidazoline that functions as a competitive alpha-adrenergic antagonist. It is a short-acting, effective α-blocker that exhibits direct α-adrenoblocking, muscle-relaxant effects on smooth muscle, as well as cholinomimetic, histamine, and sympathomimetic effects. Phentolamine is approved by the U.S. Food and Drug Administration (FDA) and is also known by the brand name Regitine (Novartis).
Uses
Used in Medical Applications:
Phentolamine is used as a diagnostic agent for pheochromocytoma, a rare tumor of the adrenal gland that causes high blood pressure. It is also used for the treatment of hypertension in patients with pheochromocytoma and to control or prevent paroxysmal hypertension during pheochromocytomectomy.
Phentolamine is used to treat hypertensive crises resulting from interactions between MAO inhibitors and sympathomimetic amines, as well as rebound hypertension upon withdrawal of clonidine, propranolol, or other antihypertensive agents.
Used in Peripheral Blood Circulation Disorders:
Phentolamine is utilized for the treatment of peripheral blood circulation disorders, particularly in the early stages of gangrene. It is also used for the treatment of trophic ulcers of the extremities, bedsores, and frostbite.
Used in Anti-adrenergic Applications:
Phentolamine is employed to prevent or control hypertensive episodes in patients with pheochromocytoma. It has also been used in combination with papaverine to treat impotence (erectile dysfunction).
Used in Tissue Protection:
Phentolamine is used for the prevention of tissue necrosis after norepinephrine extravasation, which can occur during medical procedures involving the administration of norepinephrine.
Pharmacology
Analogues of the imidazoline adrenergic amines were among the first synthetic adrenergic blocking agents to be identified. Phentolamine is the only compound from this class that is still clinically available.
Phentolamine is a competitive non-selective α1- and α2-adrenergic receptor blocker of relatively short duration of action. It causes vasodilatation and a fall in blood pressure resulting from the blockade of both post-junctional vascular α1- and α2-adrenoceptors. It also antagonises the vasoconstrictor response to noradrenaline and adrenaline infusions. Enhanced neural release of noradrenaline due to presynaptic α2-blockade may contribute to the positive inotropic and chronotropic effects of Regitine on cardiac muscle.
clinical use
The clinical effects of phentolamine include peripheral vasodilation and tachycardia.Vasodilation results from both direct relaxation of vascular smooth muscle and a blockade. The drug produces positive inotropic and chronotropic effects,leading to an increase in cardiac output.In smaller doses, the positive inotropic effect can predominate and raise blood pressure; in larger doses, peripheral vasodilation can mask the inotropic effect and lower blood pressure.These actions make phentolamine useful in treating hypertension caused by increased circulating levels of epinephrine and norepinephrine, as occurs in pheochromocytoma.
The effects of phentolamine in treating impotence are mediated by α-adrenergic blockade in penile blood vessels. Actions of the drug cause relaxation of the trabecular cavernous smooth muscles and dilation of the penile arteries; this increases arterial blood flow into the corpus cavernosa and subsequently causes an erection. Phentolamine is administered IV or IM but can be injected subcutaneously to prevent local tissue necrosis when vasoconstrictor drugs extravasate. The pharmacokinetics of phentolamine is largely unknown;10% of a parenteral dose is excreted in the urine unchanged.
Carcinogenicity / mutagenicity
Experimental data have established that phentolamine lacks mutagenic potential in bacteria, and does not induce chromosomal aberrations in mammalian somatic cells in vivo. Long-term carcinogenicity studies have not been conducted with phentolamine.
Overdosage
No deaths due to acute poisoning with phentolamine have been reported.
Overdosage with parenterally administered phentolamine is characterized chiefly by cardiovascular disturbances, such as arrhythmias, tachycardia, hypotension, and possibly shock. In addition, the following might occur: excitation, headache, sweating, pupillary contraction, visual disturbances, nausea, vomiting, diarrhea, or hypoglycemia.
There is no specific antidote; treatment consists of appropriate monitoring and supportive care. Substantial decreases in blood pressure or other evidence of shock-like conditions should be treated vigorously and promptly.
Originator
Regitine, Ciba, US ,1952
Indications
Human erectile tissue has a population of membrane
receptors that are predominantly of the -adrenoceptor
subtype. Phentolamine (Vasomax) is a nonselective -
adrenoceptor blocking agent (see Chapter 11), and like
other such agents, it has been used to treat ED.
Nonselective adrenoceptor antagonists may provoke a
reflex that increases both sympathetic outflow and the
release of norepinephrine.
Manufacturing Process
199.24 parts of N-(p-methylphenyl)-m'-hydroxyphenylamine and 77.52 parts of 2-chloromethylimidazoline hydrochloride are heated for sixteen hours in an oil bath having a temperature of 150°C, while stirring and introducing a current of nitrogen. The viscous contents of the flask are then cooled to about 100°C, mixed with 400 parts by volume of hot water, and stirred for a short time.After further cooling to about 60°C, 200 parts by volume of water and 500 parts by volume of ethyl acetate at 60°C are added, and the aqueous layer is separated. The excess of starting material may be recovered from the ethyl acetate.The aqueous portion is chilled in a cooling chamber at -10°C, whereupon the hydrochloride of 2-[N-(p-methylphenyl)-N-(m'-hydroxyphenyl)-aminomethyl]imidazoline crystallizes. Upon being concentrated and cooled the mother liquor yields a further quantity of the hydrochloride. The combined quantities of hydrochloride are treated with a small quantity of cold water, dried with care, and washed with ethyl acetate. The product is then crystallized from a mixture of alcohol and ethyl acetate, and there is obtained a hydrochloride melting at 239°-240°C.
Therapeutic Function
Adrenergic blocker
Mechanism of action
Its mechanism of action is as an α-adrenergic antagonist of both α1- and α2-receptors, causing vasodilation and reduction in peripheral resistance. When administered by intracavernosal injection, it is thought to cause relaxation of the cavernous smooth muscles and vasodilation of the penile arteries. This results in increased arterial blood flow into the corpus cavernosa as well as swelling and elongation of the penis. Venous outflow also is reduced, possibly as a result of increased venous resistance. Phentolamine is slowly released into venous circulation with minimal, if any, systemic effects. Time to peak effect is within 10 minutes, and duration of action when used with papaverine is 1 to 6 hours.
Clinical Use
Phentolamine has been used orally and intracavernosally
in the treatment of ED. Following oral administration,
phentolamine has a plasma half-life of about 30
minutes and a duration of action of 2 to 4 hours. An intracavernosal
injection of phentolamine results in the
drug reaching maximum serum levels in about 20 to 30
minutes. It is rapidly metabolized.
Phentolamine has been used in combination with
papaverine, chlorpromazine, and vasoactive peptides in
the treatment of ED.
Side effects
Side effects of phentolamine are dose related. It
may cause orthostatic hypotension, reflex tachycardia,
cardiac arrhythmias, and rarely, myocardial infarction.
Phentolamine also may reduce sperm motility in vitro.
Safety Profile
Poison by subcutaneous, intravenous, and intraperitoneal routes. Moderately toxic by ingestion. Experimental reproductive effects. When heated to decomposition it emits toxic fumes of NOx.
Synthesis
Phentolamine, 2-[[N-(3′-hydroxyphenyl)-para-toluidion]methyl]-2-
imidazoline (12.2.8), is synthesized by alkylation of 3-(4-methylanilino)phenol using
2-chloromethylimidazoline [36, 37].
Check Digit Verification of cas no
The CAS Registry Mumber 50-60-2 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 0 respectively; the second part has 2 digits, 6 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 50-60:
(4*5)+(3*0)+(2*6)+(1*0)=32
32 % 10 = 2
So 50-60-2 is a valid CAS Registry Number.
InChI:InChI=1/C17H19N3O/c1-13-5-7-15(8-6-13)20(11-14-10-18-12-19-14)16-3-2-4-17(21)9-16/h2-9,18,21H,10-12H2,1H3
50-60-2Relevant articles and documents
Continuous Synthesis of Aryl Amines from Phenols Utilizing Integrated Packed-Bed Flow Systems
Ichitsuka, Tomohiro,Kobayashi, Shū,Koumura, Nagatoshi,Sato, Kazuhiko,Takahashi, Ikko
, p. 15891 - 15896 (2020/07/13)
Aryl amines are important pharmaceutical intermediates among other numerous applications. Herein, an environmentally benign route and novel approach to aryl amine synthesis using dehydrative amination of phenols with amines and styrene under continuous-flow conditions was developed. Inexpensive and readily available phenols were efficiently converted into the corresponding aryl amines, with small amounts of easily removable co-products (i.e., H2O and alkanes), in multistep continuous-flow reactors in the presence of heterogeneous Pd catalysts. The high product selectivity and functional-group tolerance of this method allowed aryl amines with diverse functional groups to be selectively obtained in high yields over a continuous operation time of one week.
