Butyrophenone derivative

The initial series of major tranquilizers consists of alkylated derivatives of 4-aryl-4-hydroxypiperidines. Construction of this ring system is accomplished by a set of rather unusual reactions. Condensation of methylstyrenes with formaldehyde and ammonium chloride afford the corresponding hexahydro-1,3-oxazines (119). Heating these oxazines in the presence of acid leads to rearrangement with loss of water to the tetrahydropyridines. Scheme 1 shows a possible reaction pathway for these transformations. Addition of hydrogen bromide affords the expected 4-bromo compound (121). This last is easily displaced by water to lead to the desired alcohol (122) The side chain (123) is obtained by Friedel-Crafts acylation of p-fluorobenzene with 4-chloro-butyryl chloride. Alkylation of the appropriate arylpiperidinol with 123 affords the desired butyrophenone derivative. Thus,... 

A number of different compounds of the piperidine and piperazine series with p-fluorobuty-rophenone group substitutions at the nitrogen atom display significant neuroleptic activity (haloperidol, trifluperidol, droperidol, methorin). There is a considerable interest in butyrophenone derivatives as antipsychotic agents as well as in anesthesiology. They exhibit pharmacological effects and a mechanism of action very similar to that of phenothiazines and thioxanthenes in that they block dopaminergic receptors. However, they are more selective with respect to D2 receptors. 

Brand Name(s) Haidoi, Haidoi Decanoate Chemical Class Butyrophenone derivative... 

Lengthening of the N-substituent in meperidine leads to active analgesics such as the propiophenone analog, which is 200 times more active than meperidine. However, the butyrophenone derivative suddenly becomes a highly active neuroleptic without any analgesic activity. 

Haloperidol (156) and similar butyrophenone derivatives, e.g. droperidol (123), are neuroleptics that were developed from the pethidine series of analgesics. Some (3-aminoketones (Mannich bases) also have neuroleptic activity, an example being molindone (157). 

Gyclobutanones reacted with arylboronic acids in the presence of a rhodium(i) complex to afford butyrophenone derivatives via addition-ring-opening process (Equation (224)).991 On the other hand, the addition-/ -hydride-elimination process provided a direct method for synthesizing ketones from aldehydes and arylboronic acids.992... 

In the flesinoxan series (100), replacement of the amide NH with a methylene to give the butyrophenone derivative (101) had no effect... 

Haloperidol was discovered in the Janssen Laboratories in 1958 (280,315,320,322). It is a butyrophenone derivative and was pursued because of its ability to block the behavioral activating effects of amphetamine in rat models. The amphetamine models were used as screening tools, because symptoms observed in paranoid schizophrenia were noted to be similar to those that developed in chronic amphetamine abusers. The behavioral profile of haloperidol was qualitatively similar to that of CPZ, but haloperidol required up to 50-fold lower doses to exert the same behavioral effects as CPZ. Around this time, the term "major tranquilizer" began to be replaced by the term "neuroleptic." The compound was pursued very vigorously, and the initial clinical results were published only 10 months after the initial synthesis of the compound. Haloperidol is still one of the most widely pre-... 

Haloperidol is a butyrophenone derivative with antipsychotic action similar to that of piperazine phenothiazines such as fluphenazine. Haloperidol (0.5 to 2 mg t.i.d.) is indicated in the management of psychotic disorders in Tourette s disorder for the control of tics and vocal utterances in severe behavioral problems of children with combative and explosive nature in hyperactive impulse disorder in children associated with aggression, low fmstration tolerance, and impulsive behavior, and in elderly subjects with senile dementia (see also Table 9). 

Phenothiazine derivatives (e.g., chlorpromazine) Thioxanthene derivatives (e.g., thiothixene) Butyrophenone derivatives (e.g., haloperidol) Dihydroindolone derivatives (e.g., molindone) Dibenzoxazepine derivatives (e.g., loxapine) Atypical neuroleptics (e.g., sulpiride, pimozide, and clozapine)... 

Aii butyrophenone derivatives dispiaying high neuroieptic potency have the foiiowing generai structure ... 

Butyrophenone Derivative (terfenadine (Seldane) PO 60 md bid Pregnancy category C Protein bound 97% Half-life 20 hours... 

Figure 6.7. Relative rate constants for photodegradation of a butyrophenone derivative in the presence of varying amounts of UV-transparent (halloysite, hectorite) and UV-absorbing (kaolinite) clay minerals. From Miller and Zepp (1979). Reprinted by permission of Pergamon Press Ltd.

The same tactic was employed to prepare new cyclic butyrophenone derivatives in the indole series as potential atypical anti-psychotics. The Knorr pyrrole synthesis provided a simple and practical access of 6-aminomethyltetrahydroindol-4-ones and their affinities for D2, and 5-HT2a receptors were evaluated for their potential as atypical anti-psychotics. As... 

Monosubstituted cyclobutanones reacted with arylboronic acids in the presence of a Rh(I)-P(f-Bu)3 catalyst to afford butyrophenone derivatives by the addition of an arylrhodium(I) species to the carbonyl group, followed by ring opening of the resulting rhodium(I) cyclobutanolate by P-carbon elimination... 

Oral and facial dyskinesia have been described during acute treatment with L-dopa and dopamine receptor agonists and after therapy with anti-psychotic drugs, especially phenothiazine and butyrophenone derivatives (see Chapter 5). 

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