3-Ethyl-2-methyl-5-(morpholin-4-ylmethyl)-1,5,6,7-tetrahydroindol-4-one

Absorption

Rapidly absorbed from the gastrointestinal tract following oral administration.

Originator

Moban,Endo,US,1974

The Uses of 3-Ethyl-2-methyl-5-(morpholin-4-ylmethyl)-1,5,6,7-tetrahydroindol-4-one

Antipsychotic.

The Uses of 3-Ethyl-2-methyl-5-(morpholin-4-ylmethyl)-1,5,6,7-tetrahydroindol-4-one

Molindone is a more active antipsychotic than chloropromzine. Its sedative effect is less expressed. Side effects are also expressed less than with powerful neuroleptics. It facilitates the reduction of spontaneous movements and aggressiveness, and is used for treatment of psychotic disturbances, particularly in cases of chronic and severe schizophrenia.

Background

An indole derivative effective in schizophrenia and other psychoses and possibly useful in the treatment of the aggressive type of undersocialized conduct disorder. Molindone has much lower affinity for D2 receptors than most antipsychotic agents and has a relatively low affinity for D1 receptors. It has only low to moderate affinity for cholinergic and alpha-adrenergic receptors. Some electrophysiologic data from animals indicate that molindone has certain characteristics that resemble those of clozapine. (From AMA Drug Evaluations Annual, 1994, p283)

Indications

Molindone is used for the management of the manifestations of psychotic disorders.

Definition

ChEBI: Molindone is a member of indoles.

Manufacturing Process

Diethyl ketone may be reacted with methyl nitrite and that product in turn reacted with cyclohexan-1,3-dione to give 3-ethyl-4,5,6,7-tetrahydro-2- methyl-4-oxoindole.
3-ethyl-4,5,6,7-tetrahydro-2-methyl-4-oxoindole 14.1 g (0.08 mol), 14.8 g morpholine hydrochloride (0.12 mol), and 3.6 g paraformaldehyde (0.12 mol) were refluxed in 200 ml ethanol for 40 hours. The solution was evaporated to dryness in vacuo on a steam bath and the residue digested with a mixture of 150 ml water and 10 ml 2N HCl. An insoluble residue of unreacted starting material was filtered off. To the acid solution, ammonia water was added dropwise with stirring and the amine crystallized out. It was purified by dissolving in 1N HCl and addition of ammonia, then by 2 crystallizations from benzene followed by 2 crystallizations from isopropanol, to yield 3-ethyl- 4,5,6,7-tetrahydro-2-methyl-4-oxoindole, melting point 180°C to 181°C.

brand name

Moban (Endo).

Therapeutic Function

Antipsychotic

Pharmacokinetics

Molindone is a dihydroindolone compound which is not structurally related to the phenothiazines, the butyrophenones, or the thioxanthenes. Molindone has a pharmacological profile in laboratory animals which predominantly resembles that of major tranquilizers causing reduction of spontaneous locomotion and aggressiveness, suppression of a conditioned response and antagonism of the bizarre stereotyped behavior and hyperactivity induced by amphetamines. In addition, molindone antagonizes the depression caused by the tranquilizing agent tetrabenazine.

Side Effects

Molindone hydrochloride, a tetrahydro-indolone derivative, is a neuroleptic agent that is structurally unrelated to any of the other marketed neuroleptics. Molindone is less potent than haloperidol at blocking D2 receptors; however, it nonetheless can produce extrapyramidal side effects.

Synthesis

Molindone, 3-ethyl-6,7-dihydro-2-methyl-5-(morpholinomethyl)indol-4(5H)- one (6.4.3), is synthesized by the nitrozation of diethylketone using nitric acid or methylnitrite into nitrozodiethylketone (6.4.1). Reduction of this product with zinc in acetic acid into 2-aminodiethylketone in the presence of cyclohexandion-1,3 gives 3-ethyl-2-methyl- 4,5,6,7-tetrahydroindol-4-one (6.4.2). Aminomethylation of this product using morpholine and formaldehyde gives molindone (6.4.3) [51¨C52].

Metabolism

Most likely hepatic. 36 metabolites have been recognized, some of which may be active.

Metabolism

Metabolism studies in humans show molindone to be rapidly absorbed and metabolized when given orally. There are 36 recognized metabolites, with less than 2 to 3% unmetabolized molindone being excreted in urine and feces. Clinical studies show that the antipsychotic effects of molindone last more than 24 hours, suggesting that one or more metabolites may contribute to its activity in vivo (62).