Butyrophenones And Related Structures

Haloperidol was discovered by Janssen Laboratories (1958) as a byproduct while they were investigating analgesics structurally related to meperidine.73 The behavioral profile of haloperidol was found to be very similar to that of chlor-promazine, but the required dose was about 50-fold less to exert the same behavioral effect. It was rapidly studied and pursued as a new drug. Soon after, Janssen Laboratories discovered and developed droperidol, another butyrophe-none analog. Conformationally, the butyrophenones can assume a conformation resembling portions of the phenothiazine molecule. The three-carbon side chain of the phenothiazines may be analogous to the three-carbon bridge that separates the amino function from the carbonyl moiety of haloperidol. Moreover, the piperidine ring would correspond to the side chain amine or piperazine of the phenothiazines. After the introduction of haloperidol and droperidol, a great number of SAR studies were carried out.92 As for the pharmacophore of the butyrophenones (Fig. 13.6), it is known that a tertiary amino group at the fourth carbon as well as the para-substituted (F is preferred) phenyl ring at the 1-position are required for D2 affinity.93,94 Possible variations on the butyrophenone group are at the piperidine moiety, in particular at the 4-position of the ring. Modifications by lengthening, shortening, or branching of the three-carbon propyl chain decrease neuroleptic activity. Replacement of the keto group also decreases D2 affinity. The tertiary amino group is usually part of an N-containing heterocycles, preferably a piperidine ring. Replacement of the six-member basic ring by smaller or larger heterocyclic rings or by noncyclic amines decreases DA affinity.

Conformationally restricted butyrophenones also possess high D2 affinity. Haloperidol and droperidol are the only butyrophenones currently commercially available in the United States. Replacement of the keto group for a di-4-fluo-rophenylmethane moiety produced diphenylbutylpiperidines, another class of neuroleptics. Pimozide, the prototype of this group of drugs, is structurally related to droperidol and is the only member commercially available within the diphenyl-butylpiperidines class.

Figure 13.6 • Pharmacophore of the butyrophenones.

Figure 13.6 • Pharmacophore of the butyrophenones.

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