Antihistamines oxatomide

Alkylation of the monobenzhydryl derivative of piperazine ( ) with the same alkylating agent gives oxatomide (59), after removal of the protecting group.This agent shows antihistaminic activity as well as some mediator release inhibiting activity, a... 

Inhibitors of histamine release One of the effects of the so-called mast cell stabilizers cromoglycate (cromolyn) and nedocromil is to decrease the release of histamine from mast cells (p. 72, 326). Both agents are applied topically. Release of mast cell mediators can also be inhibited by some Hi antihistamines, e.g., oxatomide and ketotifen, which are used systemically. 

Oxatomide is a second-generation antihistamine (SED-12, 371) (SEDA-18, 185) (SEDA-21, 176). 

Acute cjTolytic hepatitis has been attributed to oxatomide (5). An eruption and liver damage has been described in an elderly woman taking several different antihistamines oral rechallenge with both terfenadine and oxatomide caused erythema, and there was mild liver dysfunction after oxatomide (6). 

The final chapter in this section deals with oxatomide, an antiallergic antihistamine. This agent may act by a different mechanism than the cromolyn-related antiallergics or the classical antihistamines. Such compounds are clinically effective and seem to offer yet a new direction for exploration. 

Mediator release inhibitors with antihistamine activity Several agents which are both antihistamines and inhibitors of mediator release have also been reported (Figure 12). An early compound of this type was Schering 15,280 (C, azanator) (76). Three other compounds (Cl, Cll and ClII) have subsequently been reported (TJ-SI). The most advanced of these is ketotifen (Cl) which is structurally related to azanator. It is orally active in man at 1 mg (b.i.d.) (Z7) and has been marketed by Sandoz in Switzerland. Two other potent, orally active compounds in the rat PCA procedure are Janssen s oxatomide (7 ,79) and Boehringer Mannheim s BM 15,100 (S0>S1)- These compounds combine the properties of mediator release inhibition with antihistamine activity. 

A detailed study revealed that introduction of 1-alkyl-1, 3-dihydro-2H-benzimidazol-2-ones on known pharmacophores is compatible with neuroleptic (milenperone), antiemetic (domperidone, 7) and also with antihistaminic-antiallergic activity (oxatomide). 

In no case total protection from anaphylactic shock was found at 0. 16 mg/)s.g and the ED50 values for oxatomide (compound 8) and some of the most active compounds, namely R 35 918,R 37 280 and R 37 281 (compounds 23, 61, 25) are presented in Table IV. These compounds were not superior to oxatomide in affording protection from anaphylactic shock, whereas their antihistamine activity tended to be somewhat more pronounced. 

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