Flazalone

Flazalone is an anti-inflammatory drug that has not been approved as a medicine.^[1]^[2]^[3]

Other namesFlumefenine, R-760.

CAS Number

21221-18-1

PubChem CID

36663

ChemSpider

33682

Quick facts Clinical data, Other names ...

Flazalone
Clinical data

Other names	Flumefenine, R-760.
Identifiers
IUPAC name (4-fluorophenyl)-[4-(4-fluorophenyl)-4-hydroxy-1-methylpiperidin-3-yl]methanone
CAS Number	21221-18-1
PubChem CID	36663
ChemSpider	33682
UNII	5A1Y43ML91
KEGG	D04189
ChEMBL	ChEMBL120951
CompTox Dashboard (EPA)	DTXSID9046283
Chemical and physical data
Formula	C₁₉H₁₉F₂NO₂
Molar mass	331.363 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CN1CCC(C(C1)C(=O)C2=CC=C(C=C2)F)(C3=CC=C(C=C3)F)O
InChI InChI=1S/C19H19F2NO2/c1-22-11-10-19(24,14-4-8-16(21)9-5-14)17(12-22)18(23)13-2-6-15(20)7-3-13/h2-9,17,24H,10-12H2,1H3 Key:PPQZABOURJVKNI-UHFFFAOYSA-N

Further Analogues

According to Shaomeng Wang and co-workers, replacement of the para-fluoro halogen with a meta,para-dichloro substitution arrangement resulted in dopamine reuptake inhibitors useful in treating cocaine addiction.^[4]^[5] Whereas Diclazalone achieved a Ki of 10.9nM for the mazindol binding site (DAT), flazalone only achieved 5700nM for the same receptor (even weaker than for the phenindamine precursor which was 4420nM). However, the para-methyl compound was the one titled in the article publications. This had a Ki of 492nM for the mazindol binding site (DAT), which is more promising than flazalone if we are only talking about this receptor. For comparison consider WIN 35,428 versus RTI-32.

Synthesis

The synthesis has been covered:^[6]^[7] Patents:^[8]^[9] Alternate synthesis:^[10] 62%:^[11]

N.B. The p-fluoroacetophenone [403-42-9] has dual use in the synthesis of Enecadin [259525-01-4].

References

[1]
Levy L, McClure D (August 1976). "The pharmacology of flazalone: a new class of anti-inflammatory agent". The Journal of Pharmacology and Experimental Therapeutics. 198 (2): 473–480. doi:10.1016/S0022-3565(25)30615-4. PMID 7668.
[2]
"Flazalone". Inxight Drugs. The National Center for Advancing Translational Sciences (NCATS).
[3]
Castañer, J., Arrigoni-Martelli, E. (1977). "Flazalone". Drugs of the Future. 2 (3): 169. doi:10.1358/dof.1977.002.03.998237. ISSN 0377-8282.
[4]
Wang S, Sakamuri S, Enyedy IJ, Kozikowski AP, Deschaux O, Bandyopadhyay BC, et al. (February 2000). "Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies". Journal of Medicinal Chemistry. 43 (3): 351–60. doi:10.1021/jm990516x. PMID 10669562.
[5]
Wang S, Sakamuri S, Enyedy IJ, Kozikowski AP, Zaman WA, Johnson KM (July 2001). "Molecular modeling, structure--activity relationships and functional antagonism studies of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors". Bioorganic & Medicinal Chemistry. 9 (7): 1753–64. doi:10.1016/s0968-0896(01)00090-6. PMID 11425577.
[6]
Lednicer, D., Mitscher, L. A. (1980). The organic chemistry of drug synthesis. 2. Wiley. ISBN 9780471043928.
[7]
Draper, M. D., Petracek, F. J., Klohs, M. W., McClure, D. A., Levy, L., Ré, O. N. (October 1972). "Fluorophenyl-4-(p-fluorophenyl)-4-hydroxy-1-methyl-3-piperidyl ketone (flazalone): a novel non-steroidal anti-inflammatory agent". Arzneimittel-Forschung. 22 (10): 1803. PMID 4677080.
[8]
Daniel Draper Marshall, CH496700 & NL6811811 (1970 to Rexall Drug Chemical).
[9]
M Draper & L Levy, U.S. patent 3,849,578 (1974 to Riker Laboratories Inc).
[10]
Charles M Leir, U.S. patent 3,887,568 (1975 to Riker Laboratories Inc).
[11]
Stenlake, J. (December 1989). "Synthèse et étude préliminaire de quelques arylpropanonamines substitués sur le cycle et leurs sels quaternaires". European Journal of Medicinal Chemistry. 24 (6): 591–597. doi:10.1016/0223-5234(89)90026-3. ISSN 0223-5234.

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Further Analogues

Synthesis

See also

References

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