Methotripremazine

• 60-99-1 
  7104-38-3 (maleate),
  1236-99-3 HCl)

• CL 36467
• CL 39743
• N05AA02
• RP 7044
• RP-7044
• SK&F 5116
• XP-03
• XP03

Product Ingredients

INGREDIENT	UNII	CAS	INCHI KEY
Methotrimeprazine hydrochloride	42BB1Y2586	1236-99-3	ODLGFPIWRAEFAN-PFEQFJNWSA-N
Methotrimeprazine maleate	5KN5Y9V01K	7104-38-3	IFLZPECPTYCEBR-VIEYUMQNSA-N

Methotrimeprazine 
CAS Registry Number: 60-99-1 
CAS Name: (bR)-2-Methoxy-N,N,b-trimethyl-10H-phenothiazine-10-propanamine 
Additional Names: (-)-10-(3-dimethylamino-2-methylpropyl)-2-methoxyphenothiazine; levomepromazine; 2-methoxytrimeprazine; levomeprazine 
Manufacturers’ Codes: RP-7044 
Trademarks: Sinogan-Debil; Tisercin (EGYT); Neozine (Rh>e-Poulenc); Nirvan; Nozinan (Rh>e-Poulenc); Levoprome (Lederle) 
Molecular Formula: C19H24N2OS 
Molecular Weight: 328.47 
Percent Composition: C 69.47%, H 7.36%, N 8.53%, O 4.87%, S 9.76% 
Literature References: Prepn: Courvoisier et al.,C.R. Seances Soc. Biol. Ses Fil.151, 1378 (1957); Jacob, Robert, US2837518 (1958 to Rhône-Poulenc).Optical Rotatory Power, -17, Conc: 5 g/100mL; Solv: chloroform; Wavlen: 589.3 nm; Temp: 20 °C 
Derivative Type: Maleate 
CAS Registry Number: 7104-38-3 
Trademarks: Minozinan; Milezin (Spofa); Neuractil; Neurocil (Bayer); Sofmin (Dainippon); Veractil 
Molecular Formula: C19H24N2OS.C4H4O4 
Molecular Weight: 444.54 
Percent Composition: C 62.14%, H 6.35%, N 6.30%, O 18.00%, S 7.21% 
Properties: Crystals, darkened by light. Dec about 190°. Sparingly sol in water (0.3% at 20°) and in ethanol (0.4%). pH of a 0.3% aq soln is 4.3. The free base is levorotatory: [a]D20 -17° (c = 5 in chloroform). 
Optical Rotation: [a]D20 -17° (c = 5 in chloroform) 
Therap-Cat: Analgesic. 
Keywords: Analgesic (Non-Narcotic).

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Methotrimeprazine is a phenothiazine used in the management of psychosis, particular those of schizophrenia, and manic phases of bipolar disorder.

A phenothiazine with pharmacological activity similar to that of both chlorpromazine and promethazine. It has the histamine-antagonist properties of the antihistamines together with central nervous system effects resembling those of chlorpromazine. (From Martindale, The Extra Pharmacopoeia, 30th ed, p604)

Levomepromazine, also known as methotrimeprazine, is a phenothiazine neuroleptic drug. Brand names include Nozinan, Levoprome, Detenler, Hirnamin, Levotomin and Neurocil. It is a low-potency antipsychotic (approximately half as potent as chlorpromazine) with strong analgesic, hypnotic and antiemetic properties that are primarily used in palliative care.^[1][2]

Serious side effects include tardive dyskinesia, akathisia, abnormalities in the electrical cycle of the heart, low blood pressure and the potentially fatal neuroleptic malignant syndrome.^[1][2]

As is typical of phenothiazine antipsychotics, levomepromazine is a “dirty drug“, that is, it exerts its effects by blocking a variety of receptors, including adrenergic receptors, dopamine receptors, histamine receptors, muscarinic acetylcholine receptors and serotonin receptors.^[1][2]

Medical uses

It can be used as an analgesic for moderate to severe pain in non-ambulant patients (the latter being because of its strong sedative effects).^[3]

Levomepromazine is also used at lower doses for the treatment of nausea and insomnia.^[1]

Levomepromazine is frequently prescribed and valued worldwide in palliative care medicine for its multimodal action, to treat intractable nausea or vomiting, and for severe delirium/agitation in the last days of life. Palliative care physicians will commonly prescribe it orally or via subcutaneous syringe drivers in combination with opioid analgesics such as hydromorphone.^[1][2]

Levomepromazine is used for the treatment of psychosis, particularly those of schizophrenia, and manic phases of bipolar disorder. It should only be used with caution in the treatment of agitated depressions, as it can cause akathisia as a side effect, which could worsen the agitation.^[1][2] A 2010 systematic review compared the efficacy of levomepromazine with atypical antipsychotic drugs:

Adverse effects

The most common side effect is akathisia.^[2] Levomepromazine has prominent sedative and anticholinergic/sympatholytic effects (dry mouth, hypotension, sinus tachycardia, night sweats) and may cause weight gain.^[2] These side effects normally preclude prescribing the drug in doses needed for full remission of schizophrenia, so it has to be combined with a more potent antipsychotic.^[2] In any case, blood pressure and EKG should be monitored regularly.^[2]

A rare but life-threatening side effect is neuroleptic malignant syndrome (NMS).^[2] The symptoms of NMS include muscle stiffness, convulsions and fever.^[2]

PAPER

Bulletin de la Societe de Pharmacie de Bordeaux (1964), 103(4), 224-30.

The authors define an extn. equil. const., pK_e.  When a basic mol., A, in an org. solvent (immiscible with water) is shaken with an aq. acid, part of A passes into the aq. phase in the equil. A + H⁺ .rdblhar. AH⁺, and K_e and pK_e are defined by the equations K_e = [A]_org[H⁺]_H2O/[AH⁺]_H2O and pK_e = pK_a -log ([A]_org/[A]_H2O), resp.  Values of pK_e are reported for levomepromazine, properidiazine, thioridazine, chlorpromazine, alimenazine, propiomazine, promethazine, and aminopromazine.  Where 2 C atoms sep. the 2 N chain atoms, pK_e is of the order of 5, and if 3, the value is near 4.3.

PATENT

JP 40009030

A soln. of 10.5 g.  l-3-dimethylamino-2-methylpropanol in xylene is added a suspension of 2.5 g. Na in xylene and a soln. of 18 g. p-tosyl chloride in xylene is dropped in to give l-3-dimethylamino-2-methylpropanol tosylate (I), hydrochloride m. 98-100%.  I is treated with 18 g. 2-methoxyphenothiazine and NaNH₂ (prepd. from 1.85 g. Na) to give 80% l-3-(2-methoxy-10-phenothiazinyl)-2-methyl-1-dimethylaminopropane, m. 125-6° (hexane).  Similarly are prepd. l-3-(3-ethyl-10-phenothiazinyl)-2-methyl-1-dimethylaminopropane (maleate m. 136°) and l-3-(10-phenothiazinyl)-2-methyl-1-dimethylaminopropane (maleate m. 174-5°).  The products are tranquilizers.

PATENT

HU 152208

HU 157158

PL 66636

PAPER

Bulletin de la Societe Chimique de France (1968), (8), 3220-2.

Folia medica (1970), 12(1), 88-9

Journal of pharmaceutical sciences (1987), 76(7), 541-4.

SYN

IN201203390

Deprotonation of 2-methoxyphenothiazine by means of KOH in refluxing touene/DMSO, followed by condensation of resulting pottasium salt with N-(3-chloro-2-methylpropyl)-N,N-dimethylamine  in refluxing toluene leads to racemic levomepromazine , which upon finally resolution using (-)-dibenzoyl-L-tartaric acid in acetone or using di-p-toluoyl-L-tartaric acid and, optionally, HCOOH in EtOH at 60 °C affords the target levomepromazine

SYN

References

1. ^ Jump up to:^{a b c d e f} Brayfield A, ed. (13 December 2013). “Levomepromazine”. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 12 May 2014.
2. ^ Jump up to:^{a b c d e f g h i j k} Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
3. ^ “Levomepromazine”. Farmacotherapeutisch Kompas (in Dutch). Retrieved 5 October 2016.
4. ^ Jump up to:^a b Sivaraman P, Rattehalli RD, Jayaram MB (October 2010). “Levomepromazine for schizophrenia”. The Cochrane Database of Systematic Reviews. 10 (10): CD007779. doi:10.1002/14651858.CD007779.pub2. PMC 3283151. PMID 20927765.

External links

• “Levomepromazine”. PubChem. National Center for Biotechnology Information.
• NOZINAN – Lévomépromazine Doctissimo Guides des Medicaments
• “Levomepromazine” (PDF). Grampians Palliative Care Team Publication. Victoria, Australia. May 2010. Archived from the original (PDF) on 2011-02-26.
• “Levomepromazine in Palliative Care” (PDF). Scotland, UK. August 2013. Archived from the original (PDF) on 2013-05-22.

Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy category	Only if clearly needed
Routes of administration	Oral, seldom IM
Drug class	Typical antipsychotic
ATC code	N05AA02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability	~50–60%
Metabolism	Hepatic
Elimination half-life	~20 hours
Excretion	In feces and urine (metabolites), unchanged drug only 1%
Identifiers
showIUPAC name
CAS Number	60-99-1  7104-38-3 (maleate), 1236-99-3 HCl)
PubChem CID	72287
IUPHAR/BPS	7603
DrugBank	DB01403
ChemSpider	65239
UNII	9G0LAW7ATQ
KEGG	D00403
ChEBI	CHEBI:6838
ChEMBL	ChEMBL1764
CompTox Dashboard (EPA)	DTXSID1023289
ECHA InfoCard	100.000.450
Chemical and physical data
Formula	C19H24N2OS
Molar mass	328.47 g·mol−1
3D model (JSmol)	Interactive image
showSMILES
showInChI
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///////////methotripremazine, L 36467, CL 39743, N05AA02, RP 7044, RP-7044, SK&F 5116, XP-03, XP03

O(c2cc1N(c3c(Sc1cc2)cccc3)C[C@H](C)CN(C)C)C