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{{drugbox |
{{Drugbox
| IUPAC_name = ''9-chloro-2-methyl-6-phenyl-<BR>2,5-diazabicyclo[5.4.0]undeca-<BR>5,8,10,12-tetraene''
| Verifiedfields = changed
| image = Medazepam.svg
| Watchedfields = changed
| image2 = Medazepam3d.png
| verifiedrevid = 462101416
| width = 150
| IUPAC_name = 9-Chloro-2-methyl-6-phenyl-2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraene
| image =Medazepam skeletal.png
| width = 120
| image2 =Medazepam3d.png
 
<!--Clinical data-->
| tradename = 
| Drugs.com = {{drugs.com|international|medazepam}}
| pregnancy_category = ?
| legal_status = [[Schedule IV controlled substance|Schedule IV]](US)
| routes_of_administration = Oral
 
<!--Pharmacokinetic data-->
| bioavailability = ?
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 36-150 hours
| excretion = [[Kidney|Renal]]
 
<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 2898-12-6
| CAS_number = 2898-12-6
| ATC_prefix = N05
| ATC_prefix = N05
| ATC_suffix = BA03
| ATC_suffix = BA03
| PubChem = 4041
| PubChem = 4041
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = none
| DrugBank = none
| C=16 | H=15 | Cl=1 | N=2
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3901
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = P0J3387W3S
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01292
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 28333
 
<!--Chemical data-->
| C=16 | H=15 | Cl=1 | N=2  
| molecular_weight = 270.8
| molecular_weight = 270.8
| bioavailability = ?
| smiles = ClC1=CC(C(C2=CC=CC=C2)=NCCN3C)=C3C=C1
| metabolism = [[Liver|Hepatic]]
| InChI = 1/C16H15ClN2/c1-19-10-9-18-16(12-5-3-2-4-6-12)14-11-13(17)7-8-15(14)19/h2-8,11H,9-10H2,1H3
| elimination_half-life = 36-150 hours
| InChIKey = YLCXGBZIZBEVPZ-UHFFFAOYAU
| excretion = [[Kidney|Renal]]
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| pregnancy_category = ?
| StdInChI = 1S/C16H15ClN2/c1-19-10-9-18-16(12-5-3-2-4-6-12)14-11-13(17)7-8-15(14)19/h2-8,11H,9-10H2,1H3
| legal_status = [[Schedule IV controlled substance|Schedule IV]](US)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| routes_of_administration = Oral
| StdInChIKey = YLCXGBZIZBEVPZ-UHFFFAOYSA-N
}}
}}
__Notoc__
{{SI}}
{{CMG}}
==Overview==
'''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'''.<ref>[http://www.drug-encyclopedia.eu/DW_EN/benzodiazepines.shtml Encyclopedia of Drugs: Benzodiazepines<!-- Bot generated title -->]</ref> Medazepam is a long-acting benzodiazepine drug. The half-life of medazepam is 36 – 200 hours.<ref>{{cite web | url = http://www.bcnc.org.uk/equivalence.html | title = BENZODIAZEPINE EQUIVALENCY TABLE | accessdate = September 23, 2007 | author = Professor heather Ashton |date=April 2007 }}</ref>
==Pharmacology==
Benzodiazepine drugs including medazepam increase the inhibitory processes in the cerebral cortex by allosteric modulation of the GABA receptor.<ref>{{cite journal | author = Zakusov VV |author2=Ostrovskaya RU |author3=Kozhechkin SN |author4=Markovich VV |author5=Molodavkin GM |author6=Voronina TA.  |date=October 1977 | title = Further evidence for GABA-ergic mechanisms in the action of benzodiazepines. | volume = 229 | issue = 2 | pages = 313–26 | pmid = 23084 | journal = Archives internationales de pharmacodynamie et de thérapie. }}</ref> Benzodiazepines may also act via [[micromolar]] benzodiazepine-binding sites as [[Calcium in biology|Ca<sup>2+</sup>]] 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.<ref>{{cite journal | journal = Proc Natl Acad Sci USA |date=May 1984 | volume = 81 | issue = 10 | pages = 3118–22 | url = http://www.pnas.org/cgi/reprint/81/10/3118.pdf |format=PDF| type = PDF | title = Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations | author = Taft WC |author2=DeLorenzo RJ | pmid = 6328498 | doi = 10.1073/pnas.81.10.3118 | pmc = 345232}}</ref> It has major active benzodiazepine metabolites, which gives it a more prolonged therapeutic effects after administration.<ref>{{cite journal |author=Jochemsen R, Breimer DD |title=Pharmacokinetics of benzodiazepines: metabolic pathways and plasma level profiles |journal=Curr Med Res Opin |volume=8 Suppl 4 |issue= |pages=60–79 |year=1984 |pmid=6144464 |doi= 10.1185/03007998409109545|url=}}</ref>
==Chemistry==
{{Technical|section|date=November 2014}}
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]]. [[Nota bene|N.B.]] If diazepam is reduced with [[Lithium aluminum hydride|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.
[[File:Medazepam synthesis 1.png|600px|center|thumb|Medazepam synthesis 1:<ref>{{Cite doi|10.1021/jo01044a514}}</ref> E. Reeder, Nutley, L.H. Sternbach, {{US Patent|3109843}} (1963).]]


'''Medazepam''' is a drug which is a [[benzodiazepine]] derivative. It possesses [[anxiolytic]], [[anticonvulsant]], [[sedative]] and [[skeletal muscle relaxant]] properties.
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.


It is known by the following brand names: Nobrium®, Rudotel®, Raporan®,Ansilan® .<ref>http://www.drug-encyclopedia.eu/DW_EN/benzodiazepines.shtml</ref> Medazepam is a long acting benzodiazepine drug. The half life of medazepam is 36 - 200 hours.<ref>{{cite web | url = http://www.bcnc.org.uk/equivalence.html | title = BENZODIAZEPINE EQUIVALENCY TABLE | accessmonthday = Sept 23 | accessyear = 2007 | author = Professor heather Ashton | year = 2007 | month = April }}</ref>
[[File:Medazepam synthesis 2.png|500px|center|thumb|Medazepam synthesis 2: S. Inaba, H. Nagata, {{Cite patent|DE|1934385}} (1971). G.A. Archer, E. Fells, L.H. Sternbach, {{US Patent|3131178}} (1964).]]


==Pharmacology==
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
Medazepam and other [[benzodiazepines]] may influence [[neurosteroid]] metabolism and altering levels of [[progesterone]] which in turn may adversely influence the functions of the [[brain]] and [[reproductive system]]. The [[pharmacological]] actions of benzodiazepines at the GABAa receptor are similar to those of [[neurosteroids]]. [[Neuroactive]] steroids are positive [[allosteric]] modulators of the GABAa receptor, enhancing [[GABA]] function. Many benzodiazepines ([[diazepam]], medazepam, [[estazolam]], [[flunitrazepam]] and [[nitrazepam]]) potently inhibit the [[enzymes]] involved in the [[metabolism]] of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of [[endogenous]] neurosteroids, and thereby would modulate the emotional state. Factors which effects benzodiazepines ability to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine molecule. Presence of a substituent at N1 position of the diazepine ring and/or the chloro or nitro group at position 7 of the [[benzene]] ring contribute to potent inhibition of the isoenzymes, and in turn a [[bromo]] group at position 7 (for bromazepam) and additional substituents (3-hydroxy group for [[oxazepam]] and tetrahydroxazole ring for [[cloxazolam]] and [[oxazolam]]) decrease the [[inhibitory]] potency of benzodiazepines on neurosteroids.<ref>{{cite journal | author = Usami N | coauthors = Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A. | year = 2002 | month = Apr | title = Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines. | journal = Biol Pharm Bull. | volume = 25 | issue = 4 | pages = 441-5 | pmid = 11995921 | url = http://www.jstage.jst.go.jp/article/bpb/25/4/441/_pdf | format = pdf }}</ref>
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
Benzodiazepine drugs including medazepam increase the inhibitory processes in the cerebral cortex.<ref>{{cite journal | author = Zakusov VV | coauthors = Ostrovskaya RU, Kozhechkin SN, Markovich VV, Molodavkin GM, Voronina TA. | year = 1977 | month = Oct | title = Further evidence for GABA-ergic mechanisms in the action of benzodiazepines. | volume = 229 | issue = 2 | pages = 313-26 | pmid = 23084 | Archives internationales de pharmacodynamie et de thérapie. }}</ref>
with [[phenylmagnesium bromide]].
 
[[File:Medazepam synthesis 3.png|800px|center|thumb|Medazepam synthesis 3: S. Inaba, H.Nagata, {{Cite patent|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.<ref>{{Cite patent|GB|1153103}}</ref>  [[Acylation]] of the resulting product with [[BzCl]] gives the respective [[amide]], which cyclizes into the desired medazepam using [[phosphorus oxychloride]].
 
[[File:Medazepam synthesis 4.png|800px|thumb|center|Medazepam synthesis 4: K.H. Heinrich, {{Cite patent|DE|1695188}} (1967) {{Cite patent|DE|1795811}} (1967).]]


==Overdose==
A fifth method also exists:
Medazepam is a drug which is very frequently involved in drug intoxication, including overdose.<ref>{{cite journal | author = Zevzikovas A | coauthors = Kiliuviene G, Ivanauskas L, Dirse V. | year = 2002 | month = | date  = | title = [Analysis of benzodiazepine derivative mixture by gas-liquid chromatography] | journal = Medicina (Kaunas). | volume = 38 | issue = 3 | pages = 316-20 | pmid = 12474705 }}</ref>
[[File:Medazepam synth1.png|700px|center|thumb|Medazepam synthesis 5<ref>{{Cite doi|10.1002/cber.19691021133}}</ref>]]


==The Committee on the Review of Medicines==
<!-- Finally, a couple of last methods:<ref>{{Cite doi|10.1002/jhet.5570140545}}</ref><ref>{{Cite doi|10.1248/cpb.20.1628}}</ref> -->


The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, [[drug dependence]] and [[benzodiazepine withdrawal]] problems and other adverse effects. The committee found that benzodiazepines do not have any [[antidepressant]] or [[analgesic]] properties and are therefore unsuitable treatments for conditions such as depression, [[tension headaches]] and [[dysmenorrhoea]]. Benzodiazepines are also not beneficial in the treatment of [[psychosis]] due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of [[anxiety]] or [[insomnia]] in children. The committee was in agreement with the [[Institute of Medicine]] (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the [[National Institute on Drug Abuse]] (USA) that there was little evidence that long term use of benzodiazepine hypnotics were benefitial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3 - 14 days of continuous use and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the [[benzodiazepine withdrawal syndrome]] including symptoms such as [[anxiety]], [[apprehension (fear)|apprehension]], [[tremor]], [[insomnia]], [[nausea]], and [[vomiting]] upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours on the cessation of a short acting benzodiazepine and within 3 - 10 days after the cessation of a more short acting benzodiazepine. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels however withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was noted in the review that alcohol can potentiate the [[central nervous system]] depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous and the elderly are more prone to these adverse effects. In the [[neonate]] high single doses or repeated low doses have been reported to produce [[hypotonia]], poor sucking, and [[hypothermia]] in the [[neonate]] and irregularities in the [[fetal]] heart. Benzodiazepines should be avoided in [[lactation]]. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause [[confusion]], [[toxic psychosis]], [[convulsions]], or a condition resembling [[delirium tremens]]. Abrupt withdrawal from lower doses may cause depression, [[nervousness]], [[rebound insomnia]], [[irritability]], [[sweating]], and [[diarrhoea]].<ref>{{cite journal | author = Committee on the Review of Medicines | year = 1980 | month = Mar | date  = 29 | title = Systematic review of the benzodiazepines. Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Committee on the Review of Medicines. | journal = Br Med J. | volume = 280 | issue = 6218 | pages = 910-2 | pmid = 7388368 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1601049&blobtype=pdf | format = pdf }}</ref>
==See also==
*[[Benzodiazepine]]
*[[Benzodiazepine dependence]]
*[[Benzodiazepine withdrawal syndrome]]
*[[Long-term effects of benzodiazepines]]


==References==
==References==
<references/>
{{Reference|2}}


==External links==
==External links==
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{{Benzodiazepines}}
{{Benzodiazepines}}
{{Anxiolytics}}
{{Anxiolytics}}
[[Category:Anticonvulsants]]
{{GABAAR PAMs}}
[[Category:Anxiolytics]]
 
[[Category:Drug]]
[[Category:Benzodiazepines]]
[[Category:Benzodiazepines]]
[[Category:Hypnotics]]
[[Category:Organochlorides]]
[[Category:Muscle relaxants]]
[[Category:GABAA receptor positive allosteric modulators]]
[[Category:Sedatives]]
 
 
{{pharma-stub}}
 
[[ja:メダゼパム]]
[[pl:Medazepam]]
[[ru:Мезапам]]
[[sv:Medazepam]]
{{WikiDoc Sources}}

Revision as of 18:28, 9 April 2015

Medazepam
Clinical data
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • ?
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability?
MetabolismHepatic
Elimination half-life36-150 hours
ExcretionRenal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC16H15ClN2
Molar mass270.8
3D model (JSmol)
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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

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

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, Template:US Patent (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, Template:US Patent (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

References

Template:Reference

External links

Template:Benzodiazepines Template:Anxiolytics Template:GABAAR PAMs

  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. ↑ Template:Cite doi
  7. ↑ GB 1153103 
  8. ↑ Template:Cite doi
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