Piperidine antihistaminic

Second-Generation Piperidines (Prototype Terfena-dine). Terfenadine and astemizole were withdrawn from the market. Current drugs in this class include loratadine, deslor-atadine, and fexofenadine. These agents are highly selective for Hi receptors, lack significant anticholinergic actions, and penetrate poorly into the CNS. Taken together, these properties appear to account for the low incidence of side effects of piperidine antihistamines. 

The low structural specificity of the antihistamines has already been noted. It is perhaps not too surprising, therefore, to find Lhat attachment of the basic side chain directly onto one of the. iromatic rings affords active compounds. In an unusual reaction reminiscent of the Claisen rearrangement, benzyl chloride affords the substituted phenol, 46, on heating with phenol itself. Alkyl-.ition of 46 with 2-dimethylaminoethyl chloride gives phenyltolox-.imine (47).Alkylation of that same intermediate (46) with 1-bromo-2-chloropropane, leads to 48. Use of that halide to alkyl-,ite piperidine gives the antihistamine, pirexyl (49). ... 

Iatrogenic Reactions broadly refer to any adverse reactions that are unintentionally produced by physicians in their patients. For example, one of the side effects of many antihistaminic preparations (Hj antagonists) such as ethanolamine derivatives (prototype diphenhydramine) is heavy sedation. Although sedation may be desirable for some patients, it may interfere with daytime activities, and this needs to be considered when prescribing such medications. Other antihistaminic preparations (also 11 antagonists) such as piperidine derivatives (prototypes terfenadine or astemizole) have no sedative properties (Figure 3.2). 

In many of the first-generation, or classical, antihistamines. the terminal nitrogen atom is a simple dinicthylainiiw moiety. The amine may also be part of a heterocyclic stnic-ture. however, as illustrated by (he piperazines, some pin-pylamincs (pyrrolidines and piperidines), some phenMhia-zines. the dibenzocycloheptenes. and (he sccond-generatwn... 

DIphenylpyrallne Hydrochloride. USP. Dipheaylp)T-aline hydrochloride. 4-(diphenylmethoxy)-l-methylpipen-dine hydrochloride (Hispril. Diafen) occurs as a while m slightly off-white cry.stalline powder that is soluble in water or alcohol. Diphenylpyraline is structurally related to ifi-phenhydramine with the aminoalkyl side chain incotporated in a piperidine ring. It is a potent antihistaminic. oad ihc usual dose is 2 mg 3 or 4 times daily. The hydrochloride b available as S-mg sustained-release capsules. 

Tropinone enamines (28) have been prepared, with morpholine and piperidine respectively, and cyanoethylation of (28) gives the 2-j8-cyanoethyl derivative (29). On the other hand, quaternization with methyl iodide of (28) gave the quaternary salt showing adrenolytic and antihistaminic activity. 

First-generation piperidines (cyproheptadine, phenin-damine) Cyproheptadine uniquely has both antihistamine and antiserotonin activity. Cyproheptadine and phenin-damine cause drowsiness and also have significant anticholinergic effects. 

The piperidine ring is probably the most common heterocycle occurring in pharmaceuticals. Piperidine is often used as a secondary amine in the synthesis of drugs. The local anaesthetic bupivacaine 20 (used as the racemate or the ( S)-enantiomer levobupivacaine) is a pipecolinic acid derivative. The antihistamine bamipine 21 and the analgesic fentanyl 22 are derived from 4-aminopiperidines. The ... 

Nitrogen-linked ethylenediamines Oxygen-linked ethanolamines Carbon-linked alkylamines Phenothiazine antihistamines Cyclizines (piperazines) Piperidines Miscellaneous... 

Piperidine derivatives Ri-nJ R2 Neuroleptic, antidepressive, antihistaminic, psychotropic... 

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