6-chloro-10-(4-methylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.03,8]pentadeca-1(11),3,5,7,9,12,14-heptaene

• ChemBase ID: 247
• Molecular Formular: C18H19ClN4
• Molecular Mass: 326.82326
• Monoisotopic Mass: 326.12982431
• SMILES: C1(=Nc2c(Nc3c1cccc3)ccc(c2)Cl)N1CCN(CC1)C
• Canonical SMILES: CN1CCN(CC1)C1=Nc2cc(Cl)ccc2Nc2c1cccc2
• InChI: InChI=1S/C18H19ClN4/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20H,8-11H2,1H3
• InChIKey: QZUDBNBUXVUHMW-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 6-chloro-10-(4-methylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.0^3,^8]pentadeca-1(11),3,5,7,9,12,14-heptaene; 6-chloro-10-(4-methylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,9,12,14-heptaene; 6-chloro-10-(4-methylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.0^3,^8]pentadeca-1(11),3(8),4,6,9,12,14-heptaene
• IUPAC Traditional name: clozapine; 6-chloro-10-(4-methylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,9,12,14-heptaene; 6-chloro-10-(4-methylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.0^3,^8]pentadeca-1(11),3(8),4,6,9,12,14-heptaene
• Brand Name: Asaleptin; Clozaril; Fazaclo ODT; Iprox; Leponex; Lepotex
• Synonyms: Clozaril; Azaleptin; Leponex; Fazaclo; Clozapin; Clozapine; Clozapine; HF1854; Clorazil; Lepotex; 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo (b,e)(1,4)diazepine; Iprox; W-801; 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine, HF-1854, Liponex; 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine; 8-氯-11-(4-甲基-1-哌嗪基)-5H-二苯并[b,e][1,4]-二氮杂草; 氯氮平

Database IDs

• CAS Number: 5786-21-0
• EC Number: 227-313-7
• MDL Number: MFCD00153785
• PubChem SID: 24277892; 160963710; 46506474
• PubChem CID: 2818
• CHEBI ID: 3766
• ATC CODE: N05AH02
• CHEMBL: 42
• Chemspider ID: 10442628
• DrugBank ID: DB00363
• IUPHAR ligand ID: 38
• KEGG ID: D00283
• Unique Ingredient Identifier: J60AR2IKIC
• Wikipedia Title: Clozapine
• Medline Plus: a691001

CALCULATED PROPERTIES

JChem

• Acid pKa: 15.900125
• H Acceptors: 4
• H Donor: 1
• LogD (pH = 5.5): 1.541766
• LogD (pH = 7.4): 3.1230726
• Log P: 3.4002411
• Molar Refractivity: 97.3565 cm^3
• Polarizability: 35.86072 Å^3
• Polar Surface Area: 30.87 Å^2
• Rotatable Bonds: 0
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 3.67
• LOG S: -3.25
• Solubility (Water): 1.86e-01 g/l

PROPERTIES

Physical Property

• Solubility: 0.1 M HCl: soluble30 mg/mL; 0.1889 mg/mL (20°C) in water; 11.8 mg/L; Acetone; Chloroform; DMSO: soluble4.8 mg/mL; ethanol: soluble1 mg/mL; ethanol: soluble11 mg/mL; Ether; Methanol
• Apperance: pale yellow solid; Pale Yellow Solid
• Melting Point: 183°C (361.4°F); 183-184°C; 184 - 186°C
• Hydrophobicity(logP): 2.518; 2.7

Safety Information

• Storage Condition: -20°C; -20°C Freezer; Room Temperature (15-30°C), Protect from light
• RTECS: HP1750000
• European Hazard Symbols: Harmful (Xn)
• UN Number: 2811
• German water hazard class: 3
• Hazard Class: 6.1
• Packing Group: 3
• Risk Statements: 22-36/37/38; 63-22-68; R:22-36/37/38
• Safety Statements: 26; 36/37; S:25-26-36/37/39
• GHS Pictograms: GHS06; GHS08
• GHS Signal Word: Danger
• GHS Hazard statements: H301-H341-H361
• GHS Precautionary statements: P281-P301 + P310
• RID/ADR: UN 2811 6.1/PG 3

Pharmacology Properties

• Admin Routes: Oral
• Bioavailability: 60 to 70%
• Excretion: 80% in metabolized state: 30% biliary and 50% renal
• Half Life: 6 to 26 hours (mean value 14.2 hours in steady state conditions)
• Metabolism: Hepatic, by several CYP isozymes
• Legal Status: Prescription only, special restrictions imposed in many countries
• Pregnancy Category: B
• Gene Information: human ... ADRA1A(148), ADRA2A(150), ADRA2C(152), CHRM1(1128), DRD2(1813), DRD3(1814), DRD4(1815), HRH1(3269), HRH4(59340), HTR2A(3356), HTR2C(3358), HTR3A(3359), HTR3B(9177), HTR3C(170572), HTR3D(200909), HTR3E(285242), HTR6(3362), HTR7(3363), KCNH1(3756), KCNH2(3757), UGT1A4(54657)rat ... Adra1a(29412), Adra2a(25083), Adrb1(24925), Chrm1(25229), Drd1a(24316), Drd2(24318), Drd3(29238), Drd4(25432), Hrh1(24448), Htr1a(24473), Htr1b(25075), Htr2a(29595), Htr2b(29581), Htr2c(25187), Htr3a(79246), Htr7(65032), Slc6a4(25553)

Product Information

• Purity: 95%
• Salt Data: Free Base
• Quality Level: PREMIUM

DETAILS

MP Biomedicals - 02159760

Potent, selective muscarinic antagonist. Also exhibits the highest reported affinity for 5-HT_1a and 5-HT_1C sites.

DrugBank - DB00363

• Drug Groups: approved
• Description: A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. [PubChem]
• Indication: For use in patients with treatment-resistant schizophrenia.
• Pharmacology: Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. Clozapine is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT₂), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors. Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT₂ with similar receptor affinities may explain some of the other therapeutic and side effects of Clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug.
• Toxicity: Clozapine carries a black-box warning for agranulocytosis.
• Affected Organisms: Humans and other mammals
• Biotransformation: Hepatic
• Absorption: Rapid and almost complete
• Half Life: 8 hours (range 4-12 hours)
• Protein Binding: 97% (bound to serum proteins)
• Elimination: Approximately 50% of the administered dose is excreted in the urine and 30% in the feces.
• References: Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA: Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993 Jul 15;329(3):162-7. [Pubmed] ; Vaddadi KS, Soosai E, Vaddadi G: Low blood selenium concentrations in schizophrenic patients on clozapine. Br J Clin Pharmacol. 2003 Mar;55(3):307-9. [Pubmed] ; Naheed M, Green B: Focus on clozapine. Curr Med Res Opin. 2001;17(3):223-9. [Pubmed] ; Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW: Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry. 1999 Jan;60(1):36-40. [Pubmed]
• External Links: Wikipedia; RxList; PDRhealth; Drugs.com

Selleck Chemicals - S2459

Research Area: Neurological Disease
Biological Activity:
Clozapine (Clozaril) is a potent 5-HT1C receptor antagonist with an IC50 of 110 nM for 5-HT-stimulated phosphoinositide hydrolysis. It is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Clozapine is classified as an atypical antipsychotic drug because its profile of binding to serotonergic as well as dopamine receptors; its effects on various dopamine mediated behaviors also differ from those exhibited by more typical antipsychotics. [1][2]

Sigma Aldrich - C6305

Biochem/physiol Actions
Atypical antipsychotic compound. Selective antagonist for D4-dopamine receptor. Antagonist at 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 serotonin receptors.

Sigma Aldrich - C171

Biochem/physiol Actions
非典型抗精神病药，对 D4 多巴胺受体比对 D2 或 D3 多巴胺受体表现出更大的亲和性；在用典型抗精神病药无效的患者中，对精神分裂症的阳性和阴性症状均表现出抗精神病疗效。

Toronto Research Chemicals - C587500

An antipsychotic.

REFERENCES

• Mason and Reynolds, Eur. J. Pharmacol. , 221 : 397 (1992).
• Naheed M, Green B: Focus on clozapine. Curr Med Res Opin. 2001;17(3):223-9. Pubmed
• Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA: Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993 Jul 15;329(3):162-7. Pubmed
• Vaddadi KS, Soosai E, Vaddadi G: Low blood selenium concentrations in schizophrenic patients on clozapine. Br J Clin Pharmacol. 2003 Mar;55(3):307-9. Pubmed
• Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW: Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry. 1999 Jan;60(1):36-40. Pubmed
• Kuoppam?ki M et al. Eur J Pharmacol. 1993 Apr 15
• Stille, et al: Farnaco, Ed. Prat., 26, 603 (1971)
• Hane, J.M., et al.: Psychopharmacol. Bull., 24, 62 (1971)
• Meltzer, H.Y.: J. Clin. Psychiatry, 55, Suppl. B, 47 (1994)