Imipramine hydrochloride Chemical Properties

Melting point:

168-1700C

Flash point:

9℃

storage temp. 

2-8°C

solubility 

H₂O: 50 mg/mL

form 

crystalline

color 

white

PH

4.2～5.2(100g/l,25℃)

Water Solubility 

Soluble in water

λmax

260nm(lit.)

Merck 

14,4920

CAS DataBase Reference

113-52-0(CAS DataBase Reference)

EPA Substance Registry System

5H-Dibenz[b,f]azepine-5-propanamine, 10,11-dihydro-N,N-dimethyl-, monohydrochloride (113-52-0)

Safety Information

Hazard Codes 

Xn,T,F

Risk Statements 

23/25-36/38-36/37/38-22-39/23/24/25-23/24/25-11

Safety Statements 

7-16-24-33-45-36-26-36/37

RIDADR 

UN 1230 3/PG 2

WGK Germany 

3

RTECS 

HO1925000

TSCA 

Yes

HS Code 

2933995800

Toxicity

LD50 in mice, rats (mg/kg): 400, 490 orally; 110, 90 i.p. (Tobe)

MSDS

• Language:English Provider:SigmaAldrich

Imipramine hydrochloride Usage And Synthesis

Chemical Properties

White Solid

Originator

Tofranil,Ciba Geigy,France,1959

Uses

Imipramine hydrochloride is used as a serotonin uptake inhibitor. It mainly used in the treatment of major depression and enuresis (inability to control urination). It has also been evaluated for use in panic disorder.

Uses

Tricyclic antidepressant; inhibits the serotonin and norepinephrine transporters. Has little effect on the dopamine transporter

Uses

Antidepressant;5-HT transport inhibitor

Manufacturing Process

20 parts of imino dibenzyl are dissolved in 100 parts by volume of absolutely dry benzene. A suspension of 4 parts NaNH2 in 50 parts by volume of absolute benzene are then added dropwise at 50° to 60°C after which the mixture is boiled for an hour under reflux. 13 parts of 3-dimethylamino n_x0002_propyl chloride are then added dropwise at 40° to 50°C and the mixture is boiled for 10 hours under reflux. After cooling, the benzene solution is thoroughly washed with water, whereupon the basic constituents are extracted with dilute hydrochloric acid.
The hydrochloric extract is then made alkaline and the separated base is extracted with ether. After drying, the solvent is evaporated and the residue is distilled in the high vacuum, whereby the N-(3-dimethylaminopropyl)-imino dibenzyl passes over at a temperature of 160°C under 0.1 mm pressure. The chlorohydrate with a melting point of 174° to 175°C is obtained therefrom with alcoholic hydrochloric acid.

brand name

Janimine (Abbott); Pramine (Alra); Presamine (Sanofi Aventis); Tofranil (Novartis); Tofranil (Tyco).

Therapeutic Function

Antidepressant

General Description

Imipramine hydrochloride, 5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride(Tofranil), is the lead compound of the TCAs. It is also a closerelative of the antipsychotic phenothiazines (replace the10–11 bridge with sulfur, and the compound is the antipsychoticagent promazine). It has weaker D₂ postsynaptic blockingactivity than promazine and mainly affects amines (5-HT,NE, and DA) via the transporters. As is typical of dimethylaminocompounds, anticholinergic and sedative (central H₁block) effects tend to be marked. The compound per se has a tendency toward a high 5-HT-to-NE uptake block ratio andprobably can be called a serotonin transport inhibitor(SERTI). Metabolic inactivation proceeds mainly by oxidativehydroxylation in the 2-position, followed by conjugationwith glucuronic acid of the conjugate. Urinary excretion predominates(about 75%), but some biliary excretion (up to25%) can occur, probably because of the large nonpolargrouping. Oxidative hydroxylation is not as rapid or completeas that of the more nucleophilic ring phenothiazine antipsychotics;consequently, appreciable N-demethylation occurs,with a buildup of norimipramine (or desimipramine).

Biological Activity

imipramine (hydrochloride) is a tricyclic antidepressant and is mainly used in the treatment of major depression and enuresis [1].antidepressants are antagonists of many neurotransmitter receptors in human brain [3].imipramine is the first tricyclic antidepressant that acts mainly as an inhibitor of serotonin and norepinephrine transporters [2]. in radioligand binding assays, imipramine inhibited serotonin and norepinephrine transporters with kd values of 1.4 and 37 nm, respectively [2]. imipramine is also inhibited histamine h1 receptor, muscarinic acetylcholine receptor and α1-adrenergic receptor with kd values of 37, 46, and 32 nm, respectively [4].in rodents, imipramine abolished the depressive syndrome produced by the acute administration of reserpine. imipramine also possessed central anticholinergic activity and attenuate the activity of the centrally acting muscarinic agents tremorine and oxotremorine. imipramine inhibited the presynaptic uptake of na and 5-ht, and relatively weak against da [1].

Biochem/physiol Actions

Tricyclic antidepressant; inhibits the serotonin and norepinephrine transporters with Kis of 7.7 nM and 67 nM, respectively. Has little effect on the dopamine transporter (Ki = 25 μM).

Clinical Use

The demethylated metabolite is less anticholinergic, lesssedative, and more stimulatory and is a SNERI.Consequently, a patient treated with imipramine has twocompounds that contribute to activity. Overall, the effect isnonselective 5-HT versus NE reuptake.

Safety Profile

Human poison by ingestion. An experimental poison by ingestion, intravenous, subcutaneous, and intraperitoneal routes. An experimental teratogen. Human systemic effects by ingestion: sleep, somnolence, convulsions, muscle contraction or spasticity, coma, blood pressure decrease, dyspnea (difficulty in breathing), paresthesia (abnormal sensations), and kidney changes. Experimental reproductive effects. Mutation data reported. Used in the treatment of depression. When heated to decomposition it emits very toxic fumes of NO, and HCl. See also DIAZEPAM.

Veterinary Drugs and Treatments

In dogs and cats, imipramine has been used to treat cataplexy and urinary incontinence. In horses, imipramine has been used to treat narcolepsy and ejaculatory dysfunction (no parenteral dosage forms available).

Drug interactions

Potentially hazardous interactions with other drugs
Alcohol: increased sedative effect.
Analgesics: increased risk of CNS toxicity with tramadol; possibly increased risk of side effects with nefopam; possibly increased sedative effects with opioids.
Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone - avoid; increased risk of ventricular arrhythmias with disopyramide, flecainide or propafenone; avoid with dronedarone.
Antibacterials: increased risk of ventricular arrhythmias with delamanid, moxifloxacin and possibly telithromycin - avoid with delamanid and moxifloxacin.
Anticoagulants: may alter anticoagulant effect of coumarins.
Antidepressants: enhanced CNS excitation and hypertension with MAOIs and moclobemide - avoid; concentration possibly increased with SSRIs; risk of ventricular arrhythmias with citalopram and escitalopram - avoid; possible increased risk of convulsions with vortioxetine.
Antiepileptics: convulsive threshold lowered; concentration reduced by carbamazepine, phenobarbital and possibly fosphenytoin, phenytoin and primidone.
Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: increased risk of ventricular arrhythmias especially with droperidol, fluphenazine, haloperidol, pimozide, sulpiride and zuclopenthixol - avoid; increased antimuscarinic effects with clozapine and phenothiazines; concentration increased by antipsychotics.
Antivirals: increased risk of ventricular arrhythmias with saquinavir - avoid; concentration possibly increased with ritonavir.
Atomoxetine: increased risk of ventricular arrhythmias and possibly convulsions.
Beta-blockers: increased risk of ventricular arrhythmias with sotalol; concentration increased by labetalol and propranolol
. Clonidine: tricyclics antagonise hypotensive effect; increased risk of hypertension on clonidine withdrawal.
Dapoxetine: possibly increased risk of serotonergic effects - avoid. Dopaminergics: avoid use with entacapone; CNS toxicity reported with selegiline and rasagiline.
Pentamidine: increased risk of ventricular arrhythmias.
Sympathomimetics: increased risk of hypertension and arrhythmias with adrenaline and noradrenaline; metabolism possibly inhibited by methylphenidate.

Metabolism

Imipramine is extensively demethylated by first-pass metabolism in the liver, to its primary active metabolite, desipramine (desmethylimipramine). Paths of metabolism of both imipramine and desipramine include hydroxylation and N-oxidation.
About 80% is excreted in the urine and about 20% in the faeces, mainly in the form of inactive metabolites. Urinary excretion of unchanged imipramine and of the active metabolite desipramine is about 5% and 6% respectively. Only small quantities of these are excreted in the faeces.

storage

Store at -20°C

References

[1]. spencer ps. review of the pharmacology of existing antidepressants. br j clin pharmacol. 1977;4suppl 2:57s-68s.
[2]. tatsumi m, groshan k, blakely rd, et al. pharmacological profile of antidepressants and related compounds at human monoamine transporters. eur j pharmacol. 1997 dec 11;340(2-3):249-58.
[3]. cusack b, nelson a, richelson e. binding of antidepressants to human brain receptors: focus on newer generation compounds. psychopharmacology (berl). 1994 may;114(4):559-65.

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