Cromakalim

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(Redirected from
Levcromakalim
)
Cromakalim
Structural formula of cromakalim
Ball-and-stick model of the cromakalim molecule
Clinical data
ATC code
  • none
Identifiers
  • (3R,4S)-3-hydroxy-2,2-dimethyl-4-(2-oxopyrrolidin-1-yl)chroman-6-carbonitrile
JSmol)
  • O=C3N([C@H]1c2c(OC([C@@H]1O)(C)C)ccc(C#N)c2)CCC3

Cromakalim (

vasodilator. The active isomer is levcromakalim. It acts on ATP-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

Levcromakalim synthesis:[1][2] racemate:[3] of isomers:[4]

Reaction of

bromohydrin (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 3S,4R-enantiomer used in the next stage. That isomer is next acylated with 4-Chlorobutyryl chloride[6] 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

  1. ^ Anon., Drugs Future 11, 175 (1986).
  2. PMID 3783581
    .
  3. ^ EP 76075, Evans, John Morris; Buckingham, Robert Edwin & Willcocks, Kenneth, "Pharmaceutically active benzopyran compounds", published 1983-04-06, assigned to Beecham Group plc ; J. M. Evans et al., U.S. patent 4,446,113 (1984 to Beecham).
  4. ^ EP 120428, Faruk, Erol, "Benzopyran isomers", published 1984-10-03, assigned to Beecham Group plc 
  5. ^ U.S. patent 3,444,236
  6. ^ "Synthesis of 4-Chlorobutyryl Chloride". cnki.com.cn. Archived from the original on 2022-10-14. Retrieved 2015-11-20.