Clemizole, sold under the brand names Allercur and Histacur, is a histamine H₁ receptor antagonist of the

benzimidazole Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals. Preparation Benzimi ...

group described as an

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 ...

antipruritic Antipruritics, abirritants, or anti-itch drugs, are medications that inhibit itching (Latin: ''pruritus''). Itching is often associated with sunburns, allergic reactions, eczema, psoriasis, chickenpox, Fungal infection in animals, fungal infections ...

, and

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

which is no longer marketed. It is also a

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

and is being studied for the potential treatment of

Dravet syndrome Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures o ...

, Lennox-Gastaut syndrome, and

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

under the development code name EPX-100. The drug was first described in the

scientific literature Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

by 1952. Its serotonin receptor agonist and

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

properties were discovered in 2017.

Synthesis

Benzimidazoles substituted with an alkylamine at position 2 have a venerable history as H₁ antihistaminic agents. The standard starting material for many benzimidazoles consists of

phenylenediamine Phenylenediamine may refer to: * ''o''-Phenylenediamine or OPD, a chemical compound C6H4(NH2)2 * ''m''-Phenylenediamine or MPD, a chemical compound C6H4(NH2)2 * ''p''-Phenylenediamine or PPD, a chemical compound C6H4(NH2)2 Related compounds * ''N ...

, or its derivatives. Clemizole synthesis

Reaction of that compound with

chloroacetic acid Chloroacetic acid, industrially known as monochloroacetic acid (MCA), is the organochlorine compound with the formula . This carboxylic acid is a useful building block in organic synthesis. It is a colorless solid. Related compounds are dichlo ...

can be rationalized by invoking initial formation of the chloromethyl amide.

Imide In organic chemistry, an imide is a functional group consisting of two acyl groups bound to nitrogen. The compounds are structurally related to acid anhydrides, although imides are more resistant to hydrolysis. In terms of commercial applications ...

formation with the remaining free amino group closes the ring to afford 2-chloromethyl benzimidazole (3). Displacement of halogen with

pyrrolidine Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula (CH2)4NH. It is a cyclic secondary amine, also classified as a saturated heterocycle. It is a colourless liquid that is miscible with water and most ...

affords the alkylation product. The proton on the fused imidazole nitrogen is then removed by reaction with

sodium hydride Sodium hydride is the chemical compound with the empirical formula Na H. This alkali metal hydride is primarily used as a strong yet combustible base in organic synthesis. NaH is a saline (salt-like) hydride, composed of Na+ and H− ions, in co ...

. Treatment of the resulting anion with α,4-dichlorotoluene gives the H₁ antihistaminic agent clemizole (5).

References

{{Serotonin receptor modulators Abandoned drugs Benzimidazoles 4-Chlorophenyl compounds Experimental drugs H1 receptor antagonists 1-Pyrrolidinyl compounds

Synthesis

See also

References