Cinazepam

Cinazepam (BD-798, sold under brand name Levana) is an atypical benzodiazepine derivative.^[1] It produces pronounced hypnotic, sedative, and anxiolytic effects with minimal myorelaxant side effects.^[2][3][4] In addition, unlike many other benzodiazepine and nonbenzodiazepine hypnotics such as diazepam, flunitrazepam, and zopiclone, cinazepam does not violate sleep architecture, and the continuity of slow-wave sleep and REM sleep are proportionally increased.^[2][3][4] As such, cinazepam produces a sleep state close to physiological, and for that reason, may be advantageous compared to other, related drugs in the treatment of insomnia and other sleep disorders.^[2]

Cinazepam

Clinical data
ATC code	None
Identifiers
IUPAC name 4-{[7-Bromo-5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]oxy}-4-oxobutanoic acid
CAS Number	172986-25-3
PubChem CID	629281
ChemSpider	546502
UNII	U4SS7UFXC7
CompTox Dashboard (EPA)	DTXSID201031961
Chemical and physical data
Formula	C19H14BrClN2O5
Molar mass	465.68 g·mol−1
3D model (JSmol)	Interactive image
SMILES c1ccc(c(c1)C2=NC(C(=O)Nc3c2cc(cc3)Br)OC(=O)CCC(=O)O)Cl
InChI InChI=1S/C19H14BrClN2O5/c20-10-5-6-14-12(9-10)17(11-3-1-2-4-13(11)21)23-19(18(27)22-14)28-16(26)8-7-15(24)25/h1-6,9,19H,7-8H2,(H,22,27)(H,24,25) Key:NQTRBZXDWMDXAQ-UHFFFAOYSA-N

Cinazepam has an order of magnitude lower affinity for the benzodiazepine receptor of the GABA_A complex relative to other well-known hypnotic benzodiazepines such as nitrazepam and phenazepam.^[2] Moreover, in mice, it is rapidly metabolized, with only 5% of the base compound remaining within 30 minutes of administration.^[2] As such, cinazepam is considered to be a benzodiazepine prodrug; specifically, to 3-hydroxyphenazepam, as the main active metabolite.^[2]

Synthesis

Patents:^[5][6] Compound #6:^[7]

The reaction between 2-amino-5-bromo-2'-chlorobenzophenone [60773-49-1] (1) and bromoacetyl bromide [598-21-0] gives 5-bromo-2'-chloro-2-bromoacetamido-benzophenone, PC33695403 (2). Finkelstein reaction with sodium iodide gives PC11375008 (3). Reaction with hydroxylamine preferentially causes alkylation by displacement of the leaving group than oxime formation. Hence, the product of this step is PC129780422 (4). Ring closure in acid led to Phenazepam 4-Oxide [1177751-52-8] (5). Treatment with acetic anhydride and Polonovski rearrangement gave PC630731 (6). Saponification of the ester yielded 3-Hydroxyphenazepam [70030-11-4] (7). Treatment with succinic anhydride completed the synthesis of Cinazepam (8).

See also

• Gidazepam
• Cloxazolam

References

1. Sleep Research. Vol. 26. Brain Information Service/Brain Research Institute, University of California. 1997. p. 115.
2. Schukin SI, Zinkovsky VG, Zhuk OV (2011). "Elimination kinetics of the novel prodrug cinazepam possessing psychotropic activity in mice". Pharmacological Reports. 63 (5): 1093–1100. doi:10.1016/s1734-1140(11)70628-4. PMID 22180351. S2CID 4744087.
3. Makan SY, Boiko IA, Smul'skii SP, Andronati SA (2007). "Effect of cinazepam administration on the ligand affinity of neuromediator system receptors in rat brain". Pharmaceutical Chemistry Journal. 41 (5): 249–252. doi:10.1007/s11094-007-0055-9. ISSN 0091-150X. S2CID 24532012.
4. Andronati SA, Makan SY, Neshchadin DP, Yakubovskaya LN, Sava VM, Andronati KS (1998). "Bioaccessibility of cinazepam introduced as inclusion complex with β-cyclodextrin". Pharmaceutical Chemistry Journal. 32 (10): 513–515. doi:10.1007/BF02465736. ISSN 0091-150X. S2CID 26513288.
5. С.А. Андронати, et al. RU1828645C (1996).
6. Кирил Сергійович Андронаті, et al. UA60361C2 (2003).
7. Сергей Андреевич Андронати, et al. SU1162800 (1985).