ZIMELIDINE DIHYDROCHLORIDE

Chemical properties

Tan Oil

Originator

Normud ,Astra ,W. Germany ,1981

The Uses of ZIMELIDINE DIHYDROCHLORIDE

Zimelidine Dihydrochloride, is a selective 5-HT uptake inhibitor. It modulates nociception and induces hyperglycemia in vivo, and is an orally active antidepressant.

The Uses of ZIMELIDINE DIHYDROCHLORIDE

Zimeldine is a serotonin uptake inhibitor. Antidepressant.

Background

Zimelidine has been banned worldwide due to serious, sometimes fatal, cases of central and/or peripheral neuropathy known as Guillain-Barré syndrome and due to a peculiar hypersensitivity reaction involving many organs including skin exanthema, flu-like symptoms, arthralgias, and sometimes eosinophilia. Additionally, zimelidine was charged to cause an increase in suicidal ideation and/or attempts among depressive patients.

Indications

For the treatment of depression.

Definition

ChEBI: Zimeldine is a member of styrenes.

Manufacturing Process

To 9 g of n-butyl lithium in 200 ml of dry ether 20 g of 3-bromopyridine is added as quickly as possible at -40°C without raising the temperature. When the addition is finished the mixture is stirred for another 30 minutes. Thereafter 32.5 g of ω-dimethylamino-4'-bromopropiophenone is added in such a way that the temperature does not exceed -40°C. The cooling is discontinued and the mixture is stirred during the night whereupon the reaction mixture is poured onto ice and diluted HCl, which is washed with ether and is extracted with 20 ml of methylene dichloride. The methylene dichloride is dried and evaporated. The crystals are dissolved in water, which then is made alkaline with a solution of Na 2 CO 3 , is extracted with ether, dried, and evaporated and recrystallized from isopropyl ether, petroleum ether 1:1. Yield 4 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(3''-pyridyl)- propanol. Melting point 67°C.
3.6 g of 1-(4'-bromophenyl)-3-(N,N-dimethylamino)-1-(3''-pyridyl)-propanol are dissolved in 15 ml of 85% H 2 SO 4 and heated at 170°C for 10 minutes. The reaction mixture is poured into 60 ml of water, which is then made alkaline with 10 N NaOH, and is extracted with 2 x 25 ml of ether. The ether is dried with Na 2 SO 4 , treated with active carbon and evaporated. The residue is dissolved in 25 ml of acetone and an equivalent amount of oxalic acid dissolved in 25 ml of acetone is added. The precipitate obtained is filtered off, is dissolved in 50 ml of water, which is made alkaline with 10 N NaOH and is extracted with 2 x 25 ml of ether. The ether solution is dried with Na 2 SO 4 and is filtered, whereupon dry HCl is introduced. The precipitate obtained is filtered off. Yield 1.2 g of 3-(4'-bromophenyl)-3-(3''-pyridyl)- dimethylallylamine dihydrochloride (H 102/09). Melting point 193°C.

brand name

Normid;Normud;Zelmidine.

Therapeutic Function

Antidepressant

World Health Organization (WHO)

Zimeldine, an inhibitor of serotonin uptake, was introduced in 1982 for the treatment of depressive illness. By 1983 its use had been associated with incidences of hypersensitivity of varying severity and serious neurological side effects including the Guillain-Barr, syndrome. Following discussions with the National Board of Health and Welfare of Sweden, the major manufacturer decided to withdraw the drug on a worldwide basis.

Biological Activity

5-HT re-uptake inhibitor; selective over noradrenalin and dopamine uptake (IC 50 values are 0.33, 8.2 and 12 μ M respectively). Modulates nociception and induces hyperglycemia in vivo , and is an orally active antidepressant.

Pharmacokinetics

Zimelidine was the first marketed selective serotonin reuptake inhibitor (SSRI) antidepressant. It is a pyridylallylamine, structurally different from other antidepressants.

Metabolism

Not Available