Piperoxan, also known as benodaine, was the first

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides ...

to be discovered. This compound, derived from benzodioxan, was prepared in the early 1930s by

Daniel Bovet Daniel Bovet (23 March 1907 – 8 April 1992) was a Swiss-born Italian pharmacologist who won the 1957 Nobel Prize in Physiology or Medicine for his discovery of drugs that block the actions of specific neurotransmitters. He is best known for hi ...

and

Ernest Fourneau Ernest Fourneau (4 October 1872 – 5 August 1949) was a French pharmacist who graduated in 1898 for the Paris university specialist in medicinal chemistry and pharmacology. He played a major role in the discovery of synthetic local anesthetics s ...

at the

Pasteur Institute The Pasteur Institute (, ) is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who invented pasteurization and vaccines for anthrax and rabies. Th ...

France France, officially the French Republic, is a country located primarily in Western Europe. Overseas France, Its overseas regions and territories include French Guiana in South America, Saint Pierre and Miquelon in the Atlantic Ocean#North Atlan ...

. Formerly investigated by Fourneau as an

α-adrenergic The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...

- blocking agent, they demonstrated that it also antagonized

histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...

-induced

bronchospasm Bronchospasm or a bronchial spasm is a sudden bronchoconstriction, constriction of the muscles in the walls of the bronchioles. It is caused by the release (degranulation) of substances from mast cells or basophils under the influence of anaphylat ...

guinea pig The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy ( ), is a species of rodent belonging to the genus ''Cavia'', family Caviidae. Animal fancy, Breeders tend to use the name "cavy" for the ani ...

s, and published their findings in 1933. Bovet went on to win the 1957

Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine () is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, acco ...

for his contribution. One of Bovet and Fourneau's students, Anne-Marie Staub, published the first

structure–activity relationship The structure–activity relationship (SAR) is the relationship between the chemical structure of a molecule and its biological activity. This idea was first presented by Alexander Crum Brown and Thomas Richard Fraser at least as early as 1868. Th ...

(SAR) study of antihistamines in 1939. Piperoxan and

analogues ''Analogues'' (Spanish: ''Análogos'') is a 2023 Chilean science fiction drama film written, scored and directed by Jorge Olguín. Starring Mónica Carrasco and Jorge Gajardo accompanied by Cindy Díaz. It is about an elderly couple who feel alone ...

themselves were not clinically useful due to the production of

toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

effects in humans and were followed by phenbenzamine (Antergan) in the early 1940s, which was the first antihistamine to be marketed for medical use.

Synthesis

Condensation of

catechol Catechol ( or ), also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amounts. It ...

20-80-9(1) with

epichlorohydrin Epichlorohydrin (abbreviated ECH) is an organochlorine compound and an epoxide. Despite its name, it is not a halohydrin. It is a colorless liquid with a pungent, garlic-like odor, moderately soluble in water, but miscibility, miscible with most p ...

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 663-82-9(3). Halogenation with

thionyl chloride Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately Volatility (chemistry), volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a Halogenation, chlorinating reagen ...

gives 2-chloromethyl-1,4-benzodioxane 164-33-2(4). Displacement of the leaving group by piperidine completed the synthesis of piperoxan (5).

References

{{Histamine receptor modulators Abandoned drugs Alpha blockers Antihistamines Benzodioxans French inventions 1-Piperidinyl compounds