Dicycloverine

Dicycloverine
Clinical data
Trade names Byclomine, Bentyl, Dibent, Di-Spaz, Dilomine
AHFS/Drugs.com International Drug Names
MedlinePlus a684007
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
ATC code A03AA07 (WHO)
Legal status
Legal status
Pharmacokinetic data
Protein binding >99%
Biological half-life 5 h
Identifiers
CAS Number 77-19-0 YesY
PubChem (CID) 3042
IUPHAR/BPS 355
DrugBank DB00804 YesY
ChemSpider 2934 YesY
UNII 4KV4X8IF6V YesY
KEGG D07820 YesY
ChEBI CHEBI:4514 YesY
ChEMBL CHEMBL1123 YesY
ECHA InfoCard 100.000.919
Chemical and physical data
Formula C19H35NO2
Molar mass 309.487 g/mol
3D model (Jmol) Interactive image
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Dicycloverine, also known as dicyclomine, is a prescription medication that relieves muscle spasms in the gastrointestinal tract through an apparent mechanism of nonselective smooth muscle relaxation, and that presents a range of anticholinergic side effects. It was first synthesized in the United States circa 1947.

Medical uses

A 10-mg oral capsule of dicyclomine hydrochloride, manufactured by Mylan

Dicyclomine is used to treat intestinal hypermotility, and the symptoms of irritable bowel syndrome[1] (also known as spastic colon). It relieves muscle spasms in the gastrointestinal tract; while the mechanism or mechanisms of dicycloverine action were, as of 2004, unestablished, the drug "appears to act as nonselective smooth muscle relaxant."[1] The drug presents adverse events that are "manifestations of pharmacologic effects at muscarinic-cholinergic receptors," events which are "usually... reversible when therapy is discontinued."[1]

In the UK, it is an ingredient of a multiple-ingredient preparation, with an antiflatulent (simethicone) and two antacids, under the trade name Kolanticon. In India, it is of a compound with paracetamol under the trade name Cyclopam. It is also marketed as Meftal-SPAS containing mefenamic acid along with dicyclomine hydrochloride as an analgesic and antispasmodic. Also it is a part of Normaxin containing two other salts clidinium bromide and chlordiazepoxide.

Side effects

Dicycloverine can cause a range of anticholinergic side effects such as dry mouth, nausea,[1] and, at higher doses, deliriant effects. Recreational use of this drug for its anticholinergic effects (both low dose for euphoria and high dose for delirium) has been rarely reported.

Precautions

Because dicycloverine is known to "impair mental alertness or physical coordination," those taking the drug should "avoid driving or operating machinery until effect on [the] individual are known."[1] It is also important that women inform their clinicians "if they are or plan to become pregnant or plan to breast-feed."[1]

Discovery

Chemical synthesis in discovery

Original cyclomine discovery synthesis.[2]

Dicycloverine was first synthesized chemically in the United States circa 1945 (with patent from Wm S Merrell Company filed in January 1946, presentation at the September 1946 meeting of the Medicinal Chemistry Section of the A.C.S., and publication of the preparation in that Society's journal in November 1947).[2][3]

The discovery synthesis came in the preparation of a family of aminoesters of 1-substituted cycloalkane-carboxylic acids, and proceeded for this specific compound (see scheme) via "condensation" (double alkylation) of phenylacetonitrile with 1,5-dibromopentane in the presence of sodamide (NaNH2) dissolved in diethyl ether-liquid ammonia at low-temperature, which gave the 1,1-disubstituted cyclohexanenitrile. Alcoholysis of that nitrile in ethanol (EtOH) and sulfuric acid (H2SO4) gave the corresponding carboxylic acid ethyl ester, which was transesterified as its crude mixture in toluene or xylene with 2-(diethylamino)ethanol [a sodium (Na)-catalysed reaction]. Catalytic hydrogenation using hydrogen gas (H2) over Adam's catalyst (PtO2, abbreviated here PtO) in acetic acid reduced the aromatic ring of the original phenylacetonitrile the corresponding second cyclohexane ring,[4] to give the final drug.[2]

References

  1. 1 2 3 4 5 6 AHFS Staff (2006). "Dicyclomine hydrochloride". AHFS DI Essentials. Bethesda, MD: American Society of Health-System Pharmacists / drugs.com. Retrieved November 12, 2016.
  2. 1 2 3 Tilford, C. H.; Van Campen, Jr., M. G.; Shelton, R. S. (1947). "Aminoesters of Substituted Alicylic Carboxylic Acids". Journal of the American Chemical Society. 69 (11): 2902–2906. doi:10.1021/ja01203a077.
  3. ↑ US patent 2474796A, Van Campen, Jr., Marces George & Tilford, Charles Harmon, "Alkylaminoalkyl esters of alicyclyl-alicyclic carboxylic acids", published June 28, 1949, assigned to Wm S Merrell Co.
  4. ↑ The generation of Adam's catalyst in this situation is inferred; see Norman, Richard O.C. & Coxon, James M. (1993). Principles of Organic Synthesis (3rd ed.). Boca Raton, FL: CRC Press. p. 631 and passim. ISBN 0748761624. The involvement of transfer hydrogenation is not ruled out by the primary source description.

Further reading

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