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Diclofensine

Chemical compound

Diclofensine

Chemical compound

Diclofensine (Ro 8-4650) was developed by Hoffmann-La Roche in the 1970s in the search for a new antidepressant. It was found that the (S)-isomer was responsible for activity. Diclofensine is a stimulant drug which acts as a triple monoamine reuptake inhibitor, primarily inhibiting the reuptake of dopamine and norepinephrine, with affinities (Ki) of 16.8 nM, 15.7 nM, and 51 nM for DAT, NET, and SERT (dopamine, norepinephrine and serotonin transporters), respectively. It was found to be an effective antidepressant in human trials, with relatively few side effects, but was ultimately dropped from clinical development, possibly due to concerns about its abuse potential.

Diclofensine is chemically a tetrahydroisoquinoline (THIQ) derivative, as is nomifensine.

Synthesis

2010132442}} (2010 to Albany Molecular Research, Inc.). Page column 32.</ref>

The condensation of m-anisaldehyde [591-31-1] (1) with methylamine gives N-methyl-3-methoxybenzenemethanimine [16928-30-6]. Reduction of this Schiff-base intermediate with sodium borohydride gives (3-methoxybenzyl)methylamine [41789-95-1] (2). Alkylation of this with 3,4-dichlorophenacylbromide [2632-10-2] (3) would give CID:59580342 (4). Reduction of the benzoyl ketone with sodium borohydride gives the alcohol [802051-24-7] (5). Acid catalyzed intramolecular cyclization then completes the synthesis of the 4-aryl-THIQ derivative, diclofensine (6).

References

References

  1. "Substituted 4-Phenyl Isoquinolines".
  2. (1995). "Chirality and the Biological Activity of Drugs". CRC Press, Inc..
  3. (1982). "Diclofensine (Ro 8-4650)--a potent inhibitor of monoamine uptake: biochemical and behavioural effects in comparison with nomifensine". Advances in Biochemical Psychopharmacology.
  4. (July 1982). "Pilot trials with diclofensine, a new psychoactive drug in depressed patients". International Journal of Clinical Pharmacology, Therapy, and Toxicology.
  5. (1988). "Pure uptake blockers of dopamine can reduce prolactin secretion: studies with diclofensine". Life Sciences.
  6. (May 1986). "Effect of diclofensine, a novel antidepressant, on peripheral adrenergic function". Clinical Pharmacology and Therapeutics.
  7. (August 1989). "The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action". European Journal of Pharmacology.
  8. (1981). "A controlled trial with diclofensine, a new psychoactive drug, in the treatment of depression". The Journal of International Medical Research.
  9. (March 1984). "Therapeutic efficacy and tolerance of diclofensine in psychoreactive depression--a double-blind comparison with placebo". Methods and Findings in Experimental and Clinical Pharmacology.
  10. (May 1986). "Double-blind comparison of diclofensine with nomifensine in outpatients with dysphoric mood". Pharmacopsychiatry.
  11. (May 1983). "A clinical pharmacological comparison of diclofensine (Ro 8-4650) with nomifensine and amitriptyline in normal human volunteers". British Journal of Clinical Pharmacology.
  12. (1990). "Self-administration in baboons and the discriminative stimulus effects in rats of bupropion, nomifensine, diclofensine and imipramine". Psychopharmacology.
  13. (August 1995). "Effects of various dopamine uptake inhibitors on striatal extracellular dopamine levels and behaviours in rats". European Journal of Pharmacology.
  14. Rheiner Alfred Jr Dr, {{Cite patent. CH. 538477 (1973 to Hoffmann La Roche).
  15. Alfred Rheiner, {{US patent. 3947456 (1976 to Hoffman-La Roche Inc.).
  16. Shuang Liu, Bruce F. Molino, Kassoum Nacro, {{Cite patent. WO. 2010132442 (2010 to Albany Molecular Research, Inc.). Page column 32.
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chlorobenzene-derivatives phenol-ethers tetrahydroisoquinolines serotonin–norepinephrine–dopamine-reuptake-inhibitors stimulants
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