From Wikipedia, the free encyclopedia
Chemical compound
Piperoxan , also known as benodaine , was the first
antihistamine to be discovered.
[1]
[2] This compound, derived from
benzodioxan , was prepared in the early 1930s by
Daniel Bovet and
Ernest Fourneau at the
Pasteur Institute in
France .
[1]
[2] Formerly investigated by Fourneau as an
α-adrenergic -
blocking agent, they demonstrated that it also
antagonized
histamine -induced
bronchospasm in
guinea pigs , and published their findings in 1933.
[1]
[2]
[3] Bovet went on to win the 1957
Nobel Prize in Physiology or Medicine for his contribution.
[4] One of Bovet and Fourneau's students,
Anne-Marie Staub , published the first
structure–activity relationship (SAR) study of antihistamines in 1939.
[1] Piperoxan and
analogues themselves were not clinically useful due to the production of
toxic effects in humans and were followed by
phenbenzamine (Antergan) in the early 1940s, which was the first antihistamine to be marketed for medical use.
[5]
Synthesis
Synthesis:
[6] Patent:
[7]
Condensation of
catechol [120-80-9] (1 ) with
epichlorohydrin in the presence of an aqueous base can be visualized as proceeding initially with the epoxide (2 ) Opening of the oxirane ring by the phenoxide anion then leads to 2-hydroxymethyl-1,4-benzodioxane [3663-82-9] (3 ). Halogenation with
thionyl chloride gives 2-chloromethyl-1,4-benzodioxane [2164-33-2] (4 ). Displacement of the leaving group by piperidine completed the synthesis of piperoxan (5 ).
References
^
a
b
c
d Scriabine A, Landau R, Achilladelis B (1999).
"Discovery and Development of Major Drugs" . Pharmaceutical innovation: revolutionizing human health . Philadelphia: Chemical Heritage Press.
ISBN
0-941901-21-1 .
^
a
b
c Nelson WL (2008).
"Antihistamines and Related Antiallergic and Antiulcer Agents" . In Williams DH, Lemke TL, Foye WO (eds.). Foye's Principles of Medicinal Chemistry . Hagerstwon, MD: Lippincott Williams & Wilkins.
ISBN
978-0-7817-6879-5 .
^ Fourneau E,
Bovet D (1933). "Recherches sur l'action sympathicolytique d'un nouveau dérivé du dioxane". Archives Internationales de Pharmacodynamie et de Thérapie . 46 : 178–91.
ISSN
0003-9780 .
^
"Daniel Bovet" . Biography . NobelPrize.org.
^ Landau R, Achilladelis B, Scriabine A (1999).
"Discovery and Development of Major Drugs" . Pharmaceutical Innovation: Revolutionizing Human Health . Chemical Heritage Foundation. pp. 230–.
ISBN
978-0-941901-21-5 .
^ Nelson WL, Wennerstrom JE, Dyer DC, Engel JE (July 1977). "Absolute configuration of glycerol derivatives. 4. Synthesis and pharmacological activity of chiral 2-alkylaminomethylbenzodioxans, competitive alpha-adrenergic antagonists". Journal of Medicinal Chemistry . 20 (7): 880–885.
doi :
10.1021/jm00217a002 .
eISSN
1520-4804 .
PMID
17749 .
^
US 2056046 , Fourneau E, "Manufacture of bases derived from benz-dioxane", issued 29 September 1936, assigned to Rhone Poulenc SA
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