DOBUTAMINE

Description

Dobutamine, (±) 4-[2(4′-hydroxyphenyl)-1-methylpropyl]-3,4-dihydroxyphenylethylamine (11.1.31), differs significantly from all of the presented drugs in terms of structure, the main difference being the absence of a hydroxyl group at the β-carbon atom of the phenylethylamine moiety of classic sympathomimetics. The second considerable difference from the examined drugs is the presence of p-hydroxyphenyl-iso-butylamine group as a terminal amine substituent.

Originator

Dobutrex,Lilly,UK,1977

Uses

Cardiotonic.

Uses

Dobutamine is used in situations where, during severe cardiac decompensation, it is necessary to temporarily strengthen contractions of the myocardium, and in particular during decompensation of cardiac activity associated with surgical intervention on the heart or in organic diseases.

Manufacturing Process

In a stainless steel hydrogenation bottle were placed 17.6 g (0.1 mol) of 4-(pmethoxyphenyl)-3-buten-2-one, 80 ml of ethyl acetate, and 1 g of Raney nickel catalyst. The hydrogenation bottle was attached to a Paar low-pressure hydrogenation apparatus and the solution was hydrogenated under an initial hydrogen pressure of 50 psi. The hydrogenation was carried out at room temperature and after about 12 hours one equivalent of hydrogen had been absorbed. The catalyst was filtered from the reduction mixture and 18.1 g (0.1 mol) of homoveratrylamine were added to the reduction mixture.
To the reduction mixture was then added 3.5 g of 5% palladium on carbon catalyst and the mixture was hydrogenated under a hydrogen pressure of 50 psi at room temperature for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated to a small volume. The concentrated filtrate was dissolved in diethyl ether and the ethereal solution was saturated with anhydrous hydrogen chloride. The reduction product, 3,4-dimethoxy-N-[3-(4- methoxyphenyl)-1-methyl-n-propyl]phenethylamine was precipitated as the hydrochloride salt. The salt was filtered and recrystallized from ethanolmelting at about 147°C to 149°C.
To a solution of 101.2 g of the trimethoxy secondary amine, obtained as described above, in 3,060 ml of glacial acetic acid was added 1,225 ml of 48% hydrobromic acid and the reaction mixture heated at the reflux temperature for 4 hours. The reaction mixture was then cooled and evaporated to a small volume. The crystalline residue which formed was filtered and dried in vacuo. The dried crystalline residue was then triturated with ethyl acetate and redried to yield 97.3 g of crude crystalline material. The crude product was dissolved in 970 ml of warm water to obtain a yellow solution. To the solution was added successively by dropwise addition 75 ml of 1 N and 75 ml of 2 N hydrochloric acid. Following the dropwise addition, the solution was allowed to stir with ice cooling. The impurities which precipitated were removed by filtration through a gauze filter. Concentrated hydrochloric acid was then added dropwise. When approximately 50 to 75 ml of the concentrated acid had been added with ice bath cooling a pale yellow oil precipitated along with a while solid precipitate. With continued stirring of the cold solution, the pale yellow oil crystallized.
The cold solution was then allowed to stand overnight and all crystalline material filtered through a sintered glass filter. The filtrate was treated with an additional 300 ml of concentrated hydrochloric acid to yield a heavy white precipitate. The precipitate was filtered, dried and combined with the initial precipitate obtained as described above. The combined precipitated product, 3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methyl-n-propyl-β-phenethylamine hydrochloride, had a melting point of about 184°C to 186°C after recrystallization from boiling 4 N hydrochloric acid.

Therapeutic Function

Cardiotonic

General Description

Dobutamine (Dobutrex) is a positive inotropic agentadministered intravenously for congestive heart failure. Itresembles DA structurally but possesses a bulky 1-(methyl)-3-(4-hydroxyphenyl)propyl group on the amino group. Itpossesses a center of asymmetry, and both enantiomericforms are present in the racemic mixture used clinically. The(-) isomer of dobutamine is a potent 1-agonist, which iscapable of causing marked pressor responses. In contrast,(+)-dobutamine is a potent 1-antagonist, which canblock the effects of (-)-dobutamine. Importantly, the effectsof these two isomers are mediated via 1-receptors.Both isomers appear to be full agonists, but the (+) isomeris a more potent β1-agonist than the (-) isomer (approximatelytenfold).
Dobutamine contains a catechol group and is orally inactiveand thus is given by intravenous infusion. Solutionsof the drug can exhibit a slight pink color because of oxidationof the catechol function. It has a plasma half-life ofabout 2 minutes because it is metabolized by COMT and byconjugation, although not by MAO.

General Description

Dobutamine (Dobutex) is a sympathomimeticdrug that is a β1-adrenergic agonist with α1-activity.It is primarily used in cases of cardiogenic shock, which resultfrom its β1-inotropic effects, which increase heart contractilityand cardiac output. The drug is dispensed and administeredas a racemic mixture consisting of both (+) and(-) isomers. The (+) isomer is a potent 1-agonist, whereasthe (-) isomer is an α1-agonist.

Clinical Use

Among the most promising β1 adrenergic agonists are those derived from dopamine, the endogenous precursor to norepinephrine. Dopamine itself is a potent stimulator of the β1-receptors, but it results in many of the undesirable side effects described in Chapter 13. The new analogs of dopamine that have been developed retain the potent inotropic effect but possess fewer effects on heart rate, vascular tone, and arrhythmias. Dobutamine is a prime representative of this group of agents.
Dobutamine is a potent β1-adrenergic agonist on the myocardium with beneficial effects, the composite of a variety of actions on the heart and the peripheral vasculature. Dobutamine is active only by the intravenous route because of its rapid first-pass metabolism via COMT (catechal-O-methyl transferase). Therefore, its use is limited to critical care situations. Nonetheless, its parenteral success has led to the search and development of orally active drugs. One of the major limitations associated with β1-agonists is the phenomenon of myocardial β-receptor desensitization. This lowered responsiveness (desensitization) of the receptors appears to be due to a decrease in the number of β1-receptors and partial uncoupling of the receptors from adenylate cyclase.

Synthesis

Dobutamine is synthesized by the reaction of 3,4-dimethoxyphenyl-2-amine and 1-(4- methoxyphenyl)-3-butanone with a simultaneous reduction of formed imine, giving the product (11.1.30), the methoxyl-protecting groups of which are cleaved by hydrogen bromide, giving dobutamine (11.1.31) [32,33].

Raw materials

Preparation Products