Lofexidine hydrochloride Chemical Properties

Melting point:

230-232°C

storage temp. 

-20°C Freezer

solubility 

H2O: soluble20mg/mL, clear

form 

powder

color 

white to beige

InChI

InChI=1S/C11H12Cl2N2O.ClH/c1-7(11-14-5-6-15-11)16-10-8(12)3-2-4-9(10)13;/h2-4,7H,5-6H2,1H3,(H,14,15);1H

InChIKey

DWWHMKBNNNZGHF-UHFFFAOYSA-N

SMILES

C1(=C(Cl)C=CC=C1Cl)OC(C)C1=NCCN1.Cl

CAS DataBase Reference

21498-08-8(CAS DataBase Reference)

Safety Information

Hazard Codes 

T

Risk Statements 

25

Safety Statements 

45

RIDADR 

UN 2811 6.1 / PGIII

WGK Germany 

3

HazardClass 

6.1

Toxicity

LD50 in mice, rats, dogs (mg/kg): between 74-147 orally (all species); between 8-18 i.v. (all species) (Tsai)

Lofexidine hydrochloride Usage And Synthesis

Chemical Properties

Crystalline Solid

Originator

Lofetensin,Nattermann,W. Germany,1981

Uses

a2-Adrenoceptor agonist related structurally to Clonidine. Used in treatment of opioid withdrawal symptoms; antihypertensive.

Uses

Lofexidine hydrochloride is an α2-adrenergic receptor agonist (Kd = 7.6 nM for rat cerebral cortex membranes) that has transient antihypertensive effects. It is used in managing opioid withdrawal symptoms during detoxification from heroin and methadone.

Uses

α2-Adrenoceptor agonist related structurally to Clonidine. Used in treatment of opioid withdrawal symptoms; antihypertensive.

Manufacturing Process

10.4 ml of absolute ethanol are added to 57.5g of α-2,6- dichlorophenoxypropionitrile, followed by the introduction of 100 ml of chloroform dried over phosphorus pentoxide; 10.4 g of carefully dried hydrogen chloride being slowly introduced with stirring and cooling with ice/common salt. Most of the chloroform and excess hydrogen chloride is then removed by filtration in vacuo at room temperature, and dry ether added to the residue until the imido acid ester hydrochloride is quantitatively precipitated. The α-dichlorophenoxypropionimido acid ethyl ester hydrochloride can be obtained analytically pure in the form of white, strongly hygroscopic crystals by repeated dissolution in a little absolute ethanol in the absence of heat, and precipitation with ether.
The crude α-(2,6-dichlorophenoxy)propionamido acid ethyl ester hydrochloride is added in portions to a stirred, ice-cooled solution of 29.5 g of anhydrous ethylenediamine in 200 ml of absolute ethanol in such a way that the temperature does not exceed 0°C to 5°C. The cooling bath is then removed and the reaction mixture heated for 1 hour on a water bath to approximately 70°C.
After cooling, unreacted ethylenediamine is neutralized in a cooling mixture with the absolute ethanolic hydrochloric acid, filtered off from any components that are insoluble in ethanol and approximately two-thirds of the solvent filtered off under suction in a water jet pump vacuum. Residual quantities ofethylenediamine dihydrochloride are precipitated in fractions by the careful addition of ethyl methyl ketone, after which the imidazoline hydrochloride is separated off by the addition of dry ether. Following repeated recrystallization from ethanol ether, 2-[α-(2,6-dichlorophenoxy)ethyl]-δ2-imidazoline hydrochloride is obtained in the form of small white crystals melting at 221°C to 223°C.

brand name

Lofexidine (Rhone-Poulenc Rorer).

Therapeutic Function

Antihypertensive

Biological Activity

lofexidine is a α2-receptor agonist for opioid detoxification. lofexidine shows a strong affinity for the α2a-receptor subtype [1].the α2 adrenergic receptor is a g protein-coupled receptor (gpcr) consisting three highly homologous subtypes, α2a-, α2b-, and α2c-adrenergic. the α-receptors in brain are important presynaptic modulators of central noradrenergic function (autoreceptors) and postsynaptic mediators of many effects of catecholamines and related drugs. the α2-adrenergic agonists can be used as antihypertensives and preanesthetic agents [2].lofexidine is extensively absorbed, reaching peak concentrations at approximately 3 hours after oral administration. the mean maximum serum concentrations following a single 1.2 or 2.0 mg dose in healthy male adults were 1755 ± 306 and 2795 ± 593 ng/ml, respectively [1].

References

[1] gish e c, miller j l, honey b l, et al. lofexidine, an α2-receptor agonist for opioid detoxification[j]. annals of pharmacotherapy, 2010, 44(2): 343-351.
[2] scheinin m, lomasney j w, hayden-hixson d m, et al. distribution of α2-adrenergic receptor subtype gene expression in rat brain[j]. molecular brain research, 1994, 21(1): 133-149.

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