Benzydamine

Benzydamine

File:Benzydamine-2D-skeletal.png
Clinical data
Trade names	Maxtra Gargle, Difflam, Tantum verde
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: B2
Routes of administration	Oral, topical
ATC code	A01AD02 (WHO) G02CC03 (WHO) M01AX07 (WHO) M02AA05 (WHO) R02AX03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) / Schedule 2 BR: Class C1 (Other controlled substances) UK: P and POM EU: OTC
Pharmacokinetic data
Protein binding	<20%
Elimination half-life	13 hours
Excretion	Kidney
Identifiers
IUPAC name 3-(1-benzyl-1H-indazol-3-yloxy)-N,N-dimethylpropan-1-amine
CAS Number	642-72-8 checkY
PubChem CID	12555
ChemSpider	12036 checkY
UNII	4O21U048EF
KEGG	D07516 checkY
ChEBI	CHEBI:94563 checkY
ChEMBL	ChEMBL12610 checkY
E number	{{#property:P628}}
CompTox Dashboard (EPA)	{{#property:P3117}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C19H23N3O
Molar mass	309.413 g·mol−1
3D model (JSmol)	Interactive image
SMILES n2c(OCCCN(C)C)c1ccccc1n2Cc3ccccc3
InChI InChI=1S/C19H23N3O/c1-21(2)13-8-14-23-19-17-11-6-7-12-18(17)22(20-19)15-16-9-4-3-5-10-16/h3-7,9-12H,8,13-15H2,1-2H3 checkY Key:CNBGNNVCVSKAQZ-UHFFFAOYSA-N checkY
(verify)

Benzydamine (also known as Tantum Verde and branded in some countries as Maxtra Gargle, Difflam and Septabene), available as the hydrochloride salt, is a locally acting nonsteroidal anti-inflammatory drug (NSAID) with local anaesthetic and analgesic properties for pain relief and anti-inflammatory treatment of inflammatory conditions of the mouth and throat. It falls under class of chemicals known as indazole.

History

It was synthesized in Italy in 1964 and marketed in 1966.

Uses

Medical

• Odontostomatology: gingivitis, stomatitis, glossitis, aphthous ulcers, dental surgery and oral ulceration due to radiation therapy.
• Otorhinolaryngology: glandular fever, pharyngitis, tonsillitis, post-tonsillectomy, radiation or intubation mucositis.

It may be used alone or as an adjunct to other therapy giving the possibility of increased therapeutic effect with little risk of interaction.

In some markets, the drug is supplied as an over-the-counter cream (Lonol in Mexico from Boehringer Ingelheim) used for topical treatment of musculoskeletal system disorders: sprains, strains, bursitis, tendinitis, synovitis, myalgia, periarthritis.

Recreational

Benzydamine has been used recreationally. If taken in excess amounts, it acts as a deliriant and CNS stimulant. Such use, particularly among teenagers, has been reported in Brazil, Poland, Romania, and Turkey.

Contraindications

There are no contraindications to the use of benzydamine except for known hypersensitivity.

Side effects

Benzydamine is well tolerated. Occasionally oral tissue numbness or stinging sensations may occur, as well as itching, a skin rash, skin swelling or redness, difficulty breathing and wheezing.

Pharmacology

It selectively binds to inflamed tissues (Prostaglandin synthetase inhibitor) and is normally free of adverse systemic effects. Unlike other NSAIDs, it does not inhibit cyclooxygenase or lipooxygenase, and is not ulcerogenic.

It is described as having powerful reinforcing effects in animals and showing cross-sensitization with drugs of misuse such as heroin and cocaine. It is hypothesized that it has cannabinoid agonistic activity and this may account for its recreational and hallucinogenic effects. However, it has also been theorized that, based on structural similarity to lysergic acid diethylamide (LSD) and descriptions of its visual hallucinatory effects, benzydamine might be acting as a serotonin 5-HT_2A receptor agonist and hence as a serotonergic psychedelic. More research is needed to determine the mechanism of action of the effects of benzydamine as a drug of misuse.

Pharmacokinetic

Benzydamine is poorly absorbed through skin and vagina.

Synthesis

File:Benzydamine synthesis.svg

Benzydamine synthesis:

Synthesis starts with the reaction of the N-benzyl derivative from methyl anthranilate with nitrous acid to give the N-nitroso derivative. Reduction by means of sodium thiosulfate leads to the transient hydrazine (3), which undergoes spontaneous internal hydrazide formation. Treatment of the enolate of this amide with 3-chloro-1-dimethylamino propane gives benzydamine (5). Please note there is an error in this section: US3318905 states that the nitroso derivative is reduced with sodium hydrosulfite (sodium dithionite) and not with sodium hyposulfite (sodium thiosulfate), as shown in the above scheme and stated in text.

File:Benzydamine synthesis 2.svg

An interesting alternative synthesis of this substance starts by sequential reaction of N-benzylaniline with phosgene, and then with sodium azide to produce the corresponding carbonyl azide. On heating, nitrogen is evolved and a separatable mixture of nitrene insertion product and the desired ketoindazole # results. The latter reaction appears to be a Curtius rearrangement type product to produce an N-isocyanate #, which then cyclizes. Alkylation of the enol with sodium methoxide and 3-dimethylaminopropyl chloride gives benzydamine.

Alternatively, use of chloroacetamide in the alkylation step followed by acid hydrolysis produces bendazac instead.

Research

Studies indicate that benzydamine has notable in vitro antibacterial activity and also shows synergism in combination with other antibiotics, especially tetracyclines, against antibiotic-resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa.

It also has some cannabinoid activity in rats but has not been tested in humans. It is also hypothesized to act on 5-HT2A receptors due to its structural similarity with serotonin.