Cromakalim ( INN) is a potassium channel-opening

vasodilator Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...

. The active

isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...

is levcromakalim. It acts on

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-sensitive potassium channels and so causes membrane hyperpolarization. It can be used to treat hypertension as it will relax vascular smooth muscle to lower blood pressure. Hyperpolarisation of smooth muscle cell membranes pulls their membrane potential away from the threshold, so making it more difficult to excite them and thereby cause relaxation.

Synthesis

Reaction of 4-cyanophenol (4-Hydroxybenzonitrile) with 2-hydroxy-2-methyl-3-butyne under PTC probably proceeds to initial formation of a propargyl carbocation. The course of the reaction can be envisaged by assuming that this then attacks the aromatic ring; the resulting allylic cation can then capture the adjacent phenol oxygen and thus form the observed product (3). Treatment of that product with aqueous NBS leads to the addition of the elements of hypobromous acid and formation of the

bromohydrin In organic chemistry a halohydrin (also a haloalcohol or β-halo alcohol) is a functional group in which a halogen and a hydroxyl are bonded to adjacent carbon atoms, which otherwise bear only hydrogen or hydrocarbyl groups (e.g. 2-chloroethanol, ...

(4) as a mixture of the ''trans'' enantiomers. This cyclizes to the epoxide 5 in the presence of sodium hydroxide (5). Ring opening of the oxirane with ammonia gives a mixture of the ''trans'' amino alcohols (6). These are probably resolved at this stage and the 3''S'',4''R''-enantiomer used in the next stage. That isomer is next acylated with 4-Chlorobutyryl chloride to give the chloroamide (7). The anion from reaction of the amide with sodium hydride then displaces the chlorine on the end of the chain to form the pyrrolidine ring. There is thus obtained levcromakalim (8).

References

Vasodilators Nitriles Pyrrolidones Chromanes Potassium channel openers {{cardiovascular-drug-stub