2423. Clozapine

Nomenclature

CAS number: 5786-21-0
8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine; HF-1854; Clozaril (Novartis); Leponex (Novartis).
C18H19ClN4; mol wt 326.82.
C 66.15%, H 5.86%, Cl 10.85%, N 17.14%.

Description and references

Combined serotonin (5HT2) and dopamine (D2) receptor antagonist. Prepn: FR 1334944 (1963 to Wander); Schmutz, Hunziker, US 3539573 (1970); NL 293201 (1965 to Wander), C.A. 64, 8221a (1966); Hunziker et al., Helv. Chim. Acta 50, 1588 (1967). Structure-activity studies: Schmutz et al., Chim. Ther. 2, 424 (1967). Pharmacology: Stille et al., Farmaco Ed. Prat. 26, 603 (1971). Metabolism: Gauch, Michaelis, ibid. 667. Toxicology: Lindt et al., ibid. 585. Review: A. C. Sayers, H. A. Amsler, in Pharmacological and Biochemical Properties of Drug Substances vol. 1, M. E. Goldberg, Ed. (Am. Pharm. Assoc., Washington, DC, 1977) pp 1-31. Review of pharmacology and clinical use: R. J. Baldessarini, F. R. Frankenburg, N. Engl. J. Med. 324, 746-754 (1991). Comprehensive description: M. J. McLeish et al., Anal. Profiles Drug Subs. Excip. 22, 145-184 (1993). Overview of mechanism of action: H. Y. Meltzer, J. Clin. Psychiatry 55, Suppl. B, 47-52 (1994). Clinical trial in suicide prevention in schizophrenia: H. Y. Meltzer et al., Arch. Gen. Psychiatry 60, 82 (2003). Review of safety and tolerability: J. Fitzsimons et al., Expert Opin. Drug Saf. 4, 731-744 (2005).

Chemical structure

Properties

Yellow crystals from acetone-petr ether, mp 183-184°. Soly w/w at 25° (%): acetone >5; acetonitrile 1.9; chloroform >20; ethyl acetate >5; abs ethanol 4.0; water <0.01. pKa1 3.70; pKa2 7.60. Partition coefficient (octanol/water): 0.4 (pH 2); 600 (pH 7); 1000 (pH 7.4); 1500 (pH 8). uv max (ethanol): 215, 230, 261, 297 nm (ε 27400, 25800, 16800, 10500). LD50 in mice, rats (mg/kg): 61, 58 i.v.; 199, 260 orally (Lindt).

Therapeutic Category

Antipsychotic.

Keywords

Antipsychotic; Other Tricyclics; Serotonin-Dopamine Antagonist