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 re ...

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 his ...

and

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

at the

Pasteur Institute The Pasteur Institute (french: Institut Pasteur) 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 f ...

France France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...

. 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 beta ...

- blocking agent, they demonstrated that it also antagonized

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

-induced

bronchospasm Bronchospasm or a bronchial spasm is a sudden 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 anaphylatoxins. It causes di ...

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'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe 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, accord ...

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 Crum-Brown and Fraser in 1865. The analysis of SAR enables the determination o ...

(SAR) study of antihistamines in 1939. Piperoxan and analogues 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 Phenbenzamine, sold under the brand name Antergan and known by the former developmental code name RP-2339, is an antihistamine of the ethylenediamine class which also has anticholinergic properties. It was introduced in 1941 or 1942 and was the f ...

(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 a toxic organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amoun ...

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 miscible with most polar organi ...

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 volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a chlorinating reagent, with approximately per year bein ...

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