Diphenidol

Diphenidol
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of; administration	Oral
ATC code	none;
Pharmacokinetic data
Elimination half-life	4 hours
Identifiers
	IUPAC name 1,1-di(phenyl)-4-piperidin-1-ylbutan-1-ol;
CAS Number	972-02-1 ;
PubChem CID	9175;
IUPHAR/BPS	7163;
DrugBank	DB01231 ;
ChemSpider	2947 ;
UNII	NQO8R319LY;
KEGG	D03858 ;
ChEBI	CHEBI:4638 ;
ChEMBL	ChEMBL936 ;
CompTox Dashboard (EPA)	DTXSID3022950 ;
ECHA InfoCard	100.012.310
Chemical and physical data
Formula	C21H27NO
Molar mass	309.453 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES OC(c1ccccc1)(c2ccccc2)CCCN3CCCCC3;
	InChI InChI=1S/C21H27NO/c23-21(19-11-4-1-5-12-19,20-13-6-2-7-14-20)15-10-18-22-16-8-3-9-17-22/h1-2,4-7,11-14,23H,3,8-10,15-18H2 ; Key:OGAKLTJNUQRZJU-UHFFFAOYSA-N ;
	(verify)

Diphenidol is a muscarinic antagonist employed as an antiemetic and as an antivertigo agent. It is not marketed in the United States or Canada.

Although the mechanism of action of diphenidol on the vestibular system has not yet been elucidated, it exerts an anticholinergic effect due to interactions with mACh receptors, particularly M₁, M₂, M₃ and M₄. Hence, its actions may take place at the vestibular nuclei, where a significant excitatory input is mediated by ACh receptors, and also at the vestibular periphery where mACh receptors are expressed at efferent synapses. A series of selective mACh-receptor antagonists based on the diphenidol molecule has been synthesized, but they have not yet been the subject of clinical trials.^[1]

Synthesis

Synthesis:^[2]^[3]^[4]^[5] 10%:^[6] Patents:^[7]^[8]^[9]

Alkylation of 1-Bromo-3-chloropropane [109-70-6] (1) with piperidine (2) gives 3-Piperidinopropyl chloride [1458-63-5] (3). The Grignard reaction of this intermediate with benzophenone [119-61-9] gives the benzhydrol and hence, Diphenidol (4).

References

^ Soto E, Vega R (March 2010). "Neuropharmacology of vestibular system disorders". Current Neuropharmacology. 8 (1): 26–40. doi:10.2174/157015910790909511. PMC 2866460. PMID 20808544.
^ Katz, Leon; Karger, Lawrence S. (1952). "The Mannich Reaction on α,α-Diphenylacetone". Journal of the American Chemical Society. 74 (16): 4085–4086. doi:10.1021/ja01136a034.
^ Gautier, J.A. et al, Bull. Soc. Chim. Fr., 1964, 2145.
^ Marxer, A. (1941). "Grignard-Reaktionen mit Halogen-alkyl-aminen". Helvetica Chimica Acta. 24 (2): 209E–225E. doi:10.1002/hlca.19410240225.
^ Vitale, Arturo A.; Doctorovich, F.; Sbarbati Nudelman, N. (1987). "One-pot synthesis of diarylalkylcarbinols and substituted derivatives through carbon monoxide insertion reactions into aryllithiums". Journal of Organometallic Chemistry. 332 (1-2): 9–18. doi:10.1016/0022-328X(87)85117-3.
^ Schmidt, Andreas; Marchetti, Mauro; Eilbracht, Peter (2004). "Regioselective hydroaminomethylation of 1,1-diaryl-allyl-alcohols: a new access to 4,4-diarylbutylamines". Tetrahedron. 60 (50): 11487–11492. doi:10.1016/j.tet.2004.09.058.
^ Marxer Adrian, Miescher Karl, U.S. patent 2,411,664 (1946 to Ciba Pharmaccutical Products I).
^ Barrett Paul Anthony & Wilkinson Samuel, GB683950 (1952 to Wellcome Found).
^ , BE620404 (1961 to SKF Labs).

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[1] Soto E, Vega R (March 2010). "Neuropharmacology of vestibular system disorders". Current Neuropharmacology. 8 (1): 26–40. doi:10.2174/157015910790909511. PMC 2866460. PMID 20808544.

[2] Katz, Leon; Karger, Lawrence S. (1952). "The Mannich Reaction on α,α-Diphenylacetone". Journal of the American Chemical Society. 74 (16): 4085–4086. doi:10.1021/ja01136a034.

[3] Gautier, J.A. et al, Bull. Soc. Chim. Fr., 1964, 2145.

[4] Marxer, A. (1941). "Grignard-Reaktionen mit Halogen-alkyl-aminen". Helvetica Chimica Acta. 24 (2): 209E–225E. doi:10.1002/hlca.19410240225.

[5] Vitale, Arturo A.; Doctorovich, F.; Sbarbati Nudelman, N. (1987). "One-pot synthesis of diarylalkylcarbinols and substituted derivatives through carbon monoxide insertion reactions into aryllithiums". Journal of Organometallic Chemistry. 332 (1-2): 9–18. doi:10.1016/0022-328X(87)85117-3.

[6] Schmidt, Andreas; Marchetti, Mauro; Eilbracht, Peter (2004). "Regioselective hydroaminomethylation of 1,1-diaryl-allyl-alcohols: a new access to 4,4-diarylbutylamines". Tetrahedron. 60 (50): 11487–11492. doi:10.1016/j.tet.2004.09.058.

[7] Marxer Adrian, Miescher Karl, U.S. patent 2,411,664 (1946 to Ciba Pharmaccutical Products I).

[8] Barrett Paul Anthony & Wilkinson Samuel, GB683950 (1952 to Wellcome Found).

[9] , BE620404 (1961 to SKF Labs).

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