Amoxapine
Synonym(s):2-Chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine;Amoxapine
- CAS NO.:14028-44-5
- Empirical Formula: C17H16ClN3O
- Molecular Weight: 313.78
- MDL number: MFCD00069210
- EINECS: 237-867-1
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-11 20:33:26
What is Amoxapine?
Absorption
Rapidly and almost completely absorbed from the GI tract. Peak plasma concentrations occur within 1-2 hours of oral administration of a single dose.
Toxicity
Toxic manifestations of amoxapine overdosage differ significantly from those of other tricyclic antidepressants. Serious cardiovascular effects are seldom if ever observed. However, CNS effects, particularly grand mal convulsions, occur frequently, and treatment should be directed primarily toward prevention or control of seizures. Status epilepticus may develop and constitutes a neurologic emergency. Coma and acidosis are other serious complications of substantial amoxapine overdosage in some cases. Renal failure may develop two to five days after toxic overdose in patients who may appear otherwise recovered. Acute tubular necrosis with rhabdomuolysis and myolobinurla is the most common renal complication in such cases. This reaction probably occurs in less than 5% of overdose cases, and typically in those who have experienced multiple seizures.
Description
Amoxapine is a tetracyclic antidepressant with a wide range of pharmacological effects. It inhibits norepinephrine and serotonin reuptake, binding the respective transporters with Kd values of 16 and 58 nM. It has also been shown to act as either an antagonist or inverse agonist at serotonin 5-HT2A, 2B, 2C, 3, 6, 7 (Kis = 1 and 2 nM for 5-HT2A and 5-HT2C, respectively), dopamine D2, 3, 4 (Kd = 160 nM for D2), α1-adrenergic (Kd = 50 nM), and histamine H1 (Kd = 25 nM) receptors.
Chemical properties
Crystalline Solid
Originator
Asendin,Lederle,US,1980
The Uses of Amoxapine
Amoxapine is intended more for relieving symptoms in patients with neurotic or situational depression. It has a number of serious side effects.
The Uses of Amoxapine
A tricyclic norepinephrine uptake inhibitor
The Uses of Amoxapine
antidepressant, inhibits norepinephrine uptake
What are the applications of Application
Amoxapine is a strong norepinephrine reuptake inhibitor and weak serotonin reuptake inhibitor
Background
Amoxapine, the N-demethylated derivative of the antipsychotic agent loxapine, is a dibenzoxazepine-derivative tricyclic antidepressant (TCA). TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, amoxapine does not affect mood or arousal, but may cause sedation. In depressed individuals, amoxapine exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. In addition, TCAs down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine H1 receptors, α1-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. See toxicity section below for a complete listing of side effects. Amoxapine may be used to treat neurotic and reactive depressive disorders, endogenous and psychotic depression, and mixed symptoms of depression and anxiety or agitation.
Indications
For the relief of symptoms of depression in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions. May also be used to treat depression accompanied by anxiety or agitation.
Definition
ChEBI: A dibenzooxazepine compound having a chloro substituent at the 2-position and a piperazin-1-yl group at the 11-position.
Manufacturing Process
A mixture of 125 g of o-(p-chlorophenoxy)aniline hydrochloride and 100 ml of
dry pyridine is treated cautiously with a solution of 90 ml of ethyl
chlorocarbonate in 150 ml of ether. The mixture is kept at room temperature
for 3 days, diluted with about 500 ml of water and extracted with 300 ml of
ether, The ethereal extract is washed with 300 ml of water, dried over calcium
chloride, filtered and concentrated. The resulting ethyl o-(pchlorophenoxy)
carbanilate is obtained in a viscous oil suitable for use in the
next step without further purification.
A solution of 70 g of ethyl o-(p-chlorophenoxy)carbanilate and 120 g of Ncarbethoxypiperazine
in 100 ml of benzene containing a little sodium
methoxide is heated on a steam bath for about 5 days. The solvent is
removed by distillation and the residue is triturated with water. The resulting
solid is dissolved in ether and dried over sodium sulfate. Filtration and
concentration then yields ethyl 4-[[o-(p-chlorophenoxy)phenyl]carbamoyl]-1-
piperazinecarboxylate, melting at 89°C to 91°C, and suitable for cyclization.
A mixture of 10 g of the above piperazine carboxylate ester, 8 g of
phosphorus pentoxide and 20 ml of phosphorus oxychloride is heated under
reflux for about 1 day, diluted with 100 ml each of chloroform and benzene
and quenched with 200 g of ice. The mixture is made basic with 10% sodium
hydroxide. The organic layer is isolated and extracted with 150 ml of dilute
hydrochloric acid. The product is precipitated from the aqueous layer by
addition of 10% sodium hydroxide, extracted with benzene and dried over
potassium carbonate. Recrystallization from benzene-petroleum ether gives 2-
chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine which melts at 175°C to
176°C.
brand name
Asendin (Lederle).
Therapeutic Function
Antidepressant
General Description
Consideration of the structure of amoxapine, 2-chloro-11-(1-piperazinyl)dibenz-[b,f] [1,4]oxazepine (Asendin), reinforcesthe fact that many antidepressants are very closelyrelated to antipsychotics. Indeed, some, including amoxapine,have significant effects at D2 receptors. The Nmethyl–substituted relative of amoxapine is the antipsychoticloxapine (Loxitane). The 8-hydroxy metabolite ofamoxapine is reportedly active as an antidepressant and asa D2 receptor blocker.
Mechanism of action
Additionally, it is the N-desmethyl metabolite of the antipsychotic loxapine. Amoxapine differs structurally from the other secondary TCAs in that it has both a nitrogen and an oxygen atom in its 7-membered central ring and a piperazinyl ring rather than a propylamino side chain attached to the central ring.Amoxapine is a less potent inhibitor of neuronal NE reuptake compared with the other secondary TCAs, with a mechanism of action similar to that of desipramine.
Pharmacokinetics
Amoxapine is a tricyclic antidepressant of the dibenzoxazepine class, chemically distinct from the dibenzodiazepines, dibenzocycloheptenes, and dibenzoxepines. It has a mild sedative component to its action. The mechanism of its clinical action in man is not well understood. In animals, amoxapine reduced the uptake of nor-epinephirine and serotonin and blocked the response of dopamine receptors to dopamine. Amoxapine is not a monoamine oxidase inhibitor. Clinical studies have demonstrated that amoxapine has a more rapid onset of action than either amitriptyline or imipramine
Pharmacology
The antidepressant action of amoxapine is comparable to that of imipramine and amitriptyline. It exhibits antagonistic activity on dopamine (D2) receptors.
Pharmacokinetics
Amoxapine shares the toxic potentials of the TCAs, and the usual precautions of TCA administration should be observed. Amoxapine resembles the atypical antipsychotic drugs in its intermediate affinity as an antagonist of dopamine-2 and of 5-HT2 receptors. Amoxapine is rapidly and almost completely absorbed from the gastrointestinal (GI) tract. Amoxapine and its 8-hydroxyamoxapine metabolite have been detected in human milk at concentrations below steady-state therapeutic concentrations.
Clinical Use
Amoxapine is a dibenzoxazepine TCA with antidepressant and antipsychotic effects that has shown therapeutic effectiveness in patients with delusional depression.
Safety Profile
Poison by ingestion andintraperitoneal routes. Human systemic effects byingestion: acute renal failure, acute tubular necrosis, BPlowering, coma, convulsions, decreased body temperature,EKG changes, excitement, fasciculations, heart ratechanges, hype
Synthesis
Amoxapine, 2-chloro-11-(1-piperazinyl)-dibenz[b,f]oxazepine (7.3.2), is a direct analog of the neuroleptic loxapine (6.5.3), differing only in the absence of a methyl group in the piperazine region of the molecule. On the other hand, it could be included in the class of tricyclic antidepressants, the main difference being the presence of a side chain on the central 7-membered ring of the tricyclic system. Amoxapine, like loxapine, is synthesized from 2-(4-chlorobenzoxy)aniline, which as in loxapine synthesis is acidified with chlorocarbonic acid into (6.5.1) and further transformed into ureide (7.3.1) upon reaction with 1-carboethoxypiperazine. Cyclization by a mixture of phosphorous pentoxide and phosphorous oxychloride into the dibenzoxazepine and subsequent alkaline hydrolysis gives amoxapine (7.3.2) [50¨C53].
Metabolism
Amoxapine is almost completely metabolized in the liver to its major metabolite, 8-hydroxyamoxapine, and a minor metabolite, 7-hydroxyamoxapine. Both metabolites are phamacologically inactive and have half-lives of approximately 30 and 6.5 hours, respectively.
Metabolism
Amoxapine has the shortest elimination time (~8 hours) of the secondary TCAs. It is metabolized in the liver principally to 8-hydroxyamoxapine and to 7-hydroxyamoxapine. Both of these metabolites are pharmacologically active and have half-lives of 30 and 6.5 hours, respectively. The hydroxylation of amoxapine is inhibited by ketoconazole, suggesting the involvement of CYP3A4."
Properties of Amoxapine
Melting point: | 175-1760C |
Boiling point: | 469.9±55.0 °C(Predicted) |
Density | 1.2613 (rough estimate) |
refractive index | 1.5800 (estimate) |
Flash point: | 9℃ |
storage temp. | Keep in dark place,Inert atmosphere,Room temperature |
solubility | methanol: soluble |
form | Solid |
pka | pKa 7.6 (Uncertain) |
color | Crystals from benzene/pet ether |
Merck | 14,576 |
Stability: | Stable under recommended storage conditions., Stable Under Recommended Storage C |
CAS DataBase Reference | 14028-44-5(CAS DataBase Reference) |
NIST Chemistry Reference | Amoxapine(14028-44-5) |
Safety information for Amoxapine
Signal word | Warning |
Pictogram(s) |
Exclamation Mark Irritant GHS07 |
GHS Hazard Statements |
H302:Acute toxicity,oral |
Precautionary Statement Codes |
P264:Wash hands thoroughly after handling. P264:Wash skin thouroughly after handling. P270:Do not eat, drink or smoke when using this product. P301+P312:IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. P501:Dispose of contents/container to..… |
Computed Descriptors for Amoxapine
Abamectin manufacturer
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