Medazepam

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Medazepam
Medazepam skeletal.svg
Medazepam3d.png
Systematic (IUPAC) name
9-Chloro-2-methyl-6-phenyl-2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraene
Clinical data
AHFS/Drugs.com International Drug Names
Pregnancy cat.
  •  ?
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability ?
Metabolism Hepatic
Half-life 36-150 hours
Excretion Renal
Identifiers
CAS number 2898-12-6 N
ATC code N05BA03
PubChem CID 4041
DrugBank none
ChemSpider 3901 YesY
UNII P0J3387W3S YesY
KEGG D01292 YesY
ChEMBL CHEMBL28333 YesY
Chemical data
Formula C16H15ClN2 
Mol. mass 270.8
 N (what is this?)  (verify)

Medazepam is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties. It is known by the following brand names: Azepamid, Nobrium, Tranquirax (mixed with Bevonium), Rudotel, Raporan, Ansilan and Mezapam.[1] Medazepam is a long-acting benzodiazepine drug. The half-life of medazepam is 36 – 200 hours.[2]

Pharmacology[edit]

Benzodiazepine drugs including medazepam increase the inhibitory processes in the cerebral cortex by allosteric modulation of the GABA receptor.[3] Benzodiazepines may also act via micromolar benzodiazepine-binding sites as Ca2+ channel blockers and significantly inhibited depolarization-sensitive calcium uptake in experiments with cell components from rat brains. This has been conjectured as a mechanism for high dose effects against seizures in a study.[4] It has major active benzodiazepine metabolites, which gives it a more prolonged therapeutic effects after administration.[5]

Chemistry[edit]

Medazepam can be synthesized in various ways. One is via the reduction of the carbonyl group in diazepam (lacking methyl in Ex 1) by lithium aluminium hydride. N.B. If diazepam is reduced with LAH as in Ex 9, actually the product produced is 7-chloro-1-methyl-5-phenyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine, not medazepam.

Medazepam synthesis 1:[6] E. Reeder, Nutley, L.H. Sternbach, U.S. Patent 3,109,843 (1963).

A second way of making medazepam consists of the initial reduction of the carbonyl group by lithium aluminum hydride into 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one—the first intermediate product in the synthesis of diazepam—which is synthesized by the cyclocondensation of 2-amino-5-chlorobenzophenone with glycine ethyl ester into 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine, and the subsequent methylation of the secondary amine nitrogen atom of the resulting product by methyl iodide, using sodium hydride as a base.

Medazepam synthesis 2: S. Inaba, H. Nagata, DE 1934385  (1971). G.A. Archer, E. Fells, L.H. Sternbach, U.S. Patent 3,131,178 (1964).

A third method of making medazepam consists of a new way of making 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine, which consists in heterocyclization of 1-(2,5-dichlorophenyl)-1-phenylimine with ethylenediamine. The starting 1-(2,5-dichlorophenyl)-1-phenylimine is synthesized by the reaction of 2,5-dichlorobenzonitrile with phenylmagnesium bromide.

Medazepam synthesis 3: S. Inaba, H.Nagata, DE 1934385  (1969).

A fourth method of making medazepam from 4-chloro-N-methylaniline is suggested. The last is reacted with aziridine (or ethylene imine) in the presence of aluminum chloride, giving N-(4-chlorophenyl)-N-methylethylenediamine.[7] Acylation of the resulting product with BzCl gives the respective amide, which cyclizes into the desired medazepam using phosphorus oxychloride.

Medazepam synthesis 4: K.H. Heinrich, DE 1695188  (1967) DE 1795811  (1967).

A fifth method also exists:

Medazepam synthesis 5[8]


See also[edit]

References[edit]

  1. ^ Encyclopedia of Drugs: Benzodiazepines
  2. ^ Professor heather Ashton (April 2007). "BENZODIAZEPINE EQUIVALENCY TABLE". Retrieved September 23, 2007. 
  3. ^ Zakusov VV; Ostrovskaya RU; Kozhechkin SN; Markovich VV; Molodavkin GM; Voronina TA. (October 1977). "Further evidence for GABA-ergic mechanisms in the action of benzodiazepines.". Archives internationales de pharmacodynamie et de thérapie. 229 (2): 313–26. PMID 23084. 
  4. ^ Taft WC; DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations" (PDF). Proc Natl Acad Sci USA (PDF) 81 (10): 3118–22. doi:10.1073/pnas.81.10.3118. PMC 345232. PMID 6328498. 
  5. ^ Jochemsen R, Breimer DD (1984). "Pharmacokinetics of benzodiazepines: metabolic pathways and plasma level profiles". Curr Med Res Opin. 8 Suppl 4: 60–79. doi:10.1185/03007998409109545. PMID 6144464. 
  6. ^ Sternbach, L. H.; Reeder, E.; Archer, G. A. (1963). The Journal of Organic Chemistry 28 (9): 2456. doi:10.1021/jo01044a514.  edit
  7. ^ GB 1153103 
  8. ^ Wünsch, K. H.; Dettmann, H.; Schönberg, S. (1969). "Benzokondensierte 7-Ring-Heterocyclen, III. Synthese und Cyclisierung vonN-Aryl-N′-aroyl-äthylendiaminen". Chemische Berichte 102 (11): 3891. doi:10.1002/cber.19691021133.  edit

External links[edit]