Bambuterol

Bambuterol (INN) is a long-acting β adrenoceptor agonist (LABA) used in the treatment of asthma; it also is a prodrug of terbutaline. Commercially, the AstraZeneca pharmaceutical company produces and markets bambuterol as Bambec and Oxeol.^[1]

Bambuterol

Bambuterol (top), and (R)-bambuterol (bottom)
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	Unknown
Routes of administration	Oral (tablets)
ATC code	R03CC12 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	20%
Metabolism	Extensive hepatic. Further metabolized to terbutaline by plasma cholinesterase
Elimination half-life	13 hours (bambuterol) 21 hours (terbutaline)
Excretion	Renal
Identifiers
IUPAC name (RS)-5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diyl bis(dimethylcarbamate)
CAS Number	81732-65-2 Y HCl: 81732-46-9 Y
PubChem CID	54766
IUPHAR/BPS	6601
DrugBank	DB01408 N
ChemSpider	49466 Y
UNII	Y1850G1OVC HCl: 786Q84QZ3F Y
KEGG	D07377 Y
ChEBI	CHEBI:553827 N
ChEMBL	ChEMBL521589 Y
CompTox Dashboard (EPA)	DTXSID5048550
Chemical and physical data
Formula	C18H29N3O5
Molar mass	367.446 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES O=C(Oc1cc(cc(OC(=O)N(C)C)c1)C(O)CNC(C)(C)C)N(C)C
InChI InChI=1S/C18H29N3O5/c1-18(2,3)19-11-15(22)12-8-13(25-16(23)20(4)5)10-14(9-12)26-17(24)21(6)7/h8-10,15,19,22H,11H2,1-7H3 Y Key:ANZXOIAKUNOVQU-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

It is not available in the U.S.

Indications

As other LABAs, bambuterol is used in the long-term management of persistent asthma.^[1] It should not be used as a rescue medication for short-term relief of asthma symptoms.

Contraindications

Bambuterol is contraindicated in pregnancy and in people with seriously impaired liver function. It can be used by people with renal impairment, but dose adjustments are necessary.^[1]

Adverse effects

The adverse effect profile of bambuterol is similar to that of salbutamol, and may include fatigue, nausea, palpitations, headache, dizziness and tremor.^[1]

Interactions

Concomitant administration of bambuterol with corticosteroids, diuretics, and xanthine derivatives (such as theophylline) increases the risk of hypokalemia (decreased levels of potassium in the blood).^[2]

Bambuterol acts as a cholinesterase inhibitor, and can prolong the duration of action of suxamethonium (succinylcholine) and other drugs whose breakdown in the body depends on cholinesterase function.^[1] Butyrylcholinesterase activity returns to normal approximately two weeks after bambuterol is stopped.^[3] It can also enhance the effects of non-depolarizing neuromuscular blockers, such as vecuronium bromide.^[2]

Synthesis

Thieme ChemDrug Synthesis:^[4] Patent:^[5] Korean:^[6] Sino:^[7] Asymmetric:^[8][9]

The reaction between 3',5'-Dihydroxyacetophenone [51863-60-6] (1) and Dimethylcarbamoyl chloride [79-44-7] (2) gives 5-Acetyl-1,3-phenylene bis(dimethylcarbamate) [81732-48-1] (3). Halogenation with bromine led to 5-(Bromoacetyl)-1,3-phenylene bis(dimethylcarbamate) [81732-49-2] (4). Treatment with N-(tert-Butyl)benzylamine [3378-72-1] (5) afforded [81732-47-0] (6). Catalytic hydrogenation completed the synthesis of bambuterol (7).

References

1. Sweetman SC, ed. (2009). "Bronchodilators and Anti-asthma Drugs". Martindale: The complete drug reference (36th ed.). London: Pharmaceutical Press. pp. 1115–16. ISBN 978-0-85369-840-1.
2. Sweetman (2009), pp. 1132–33.
3. Sitar DS (October 1996). "Clinical pharmacokinetics of bambuterol". Clinical Pharmacokinetics. 31 (4): 246–56. doi:10.2165/00003088-199631040-00002. PMID 8896942. S2CID 25696134.
4. Castaer, J.; Prous, J.; Bambuterol. Drugs Fut 1986, 11, 7, 553.
5. EP0043807 idem Otto Agne Olsson, et al. U.S. patent 4,419,364 (1983 to DRACO AB); CA, 96, 199263.
6. 김신종, et al. KR100803291 (2008).
7. 唐冬军 & 寇景平, CN104262202 (2016 to Guangdong HEC Pharmaceutical).
8. Asami, K., Machida, T., Jung, S., Hanaya, K., Shoji, M., Sugai, T. (December 2013). "Synthesis of (R)-bambuterol based on asymmetric reduction of 1-[3,5-bis(dimethylcarbamoyloxy)phenyl]-2-chloroethanone with incubated whole cells of Williopsis californica JCM 3600". Journal of Molecular Catalysis B: Enzymatic. 97: 106–109. doi:10.1016/j.molcatb.2013.08.003.
9. Cao, G., Hu, A., Zou, K., Xu, L., Chen, J., Tan, W. (July 2008). "Highly enantioselective synthesis, crystal structure, and circular dichroism spectroscopy of ( R )-bambuterol hydrochloride". Chirality. 20 (7): 856–862. doi:10.1002/chir.20558.