Flazalone

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

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

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.

Diclazalone (Flazalone analog)

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].

See also

• Phenindamine

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.