The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated to involve several mechanisms. More recently, it has been speculated that the metabolic transformation to MPP+-like species may contribute to the Parkinsonism-like side effects. Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking the structural features necessary to form neurotoxic quaternary species but retaining their dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify analogues with DA binding profiles similar to that of clozapine at the dopamine receptor subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of clozapine was mimicked by 7 [K(i)(D2) = 33, K(i)(D3) = 200, K(i)(D4) = 11 nM; K(i)(D2)/K(i)(D4) = 3] and 9 [K(i)(D2) = 44, K(i)(D3) = 170, K(i)(D4) = 24 nM; K(i)(D2)/K(i)(D4) = 2]. A preliminary in-vivo testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This profile suggests that there is a need for further evaluation of these two synthetic agents and their enantiomers for efficacy and lack of catalepsy in animal models.
Dithianes are unparalleled as lynchpin carbanions 1 that directly assemble protected ketones. The unrivaled versatility of dithianes 2 is tempered only by the ultimate unmasking of the dithiane to the corresponding ketone, 3 a seemingly trivial conversion for which numerous reagents have been developed. 4 Dithiane deprotection is particularly challenging for dithiane-containing alkaloids since alkylative, oxidative, and Lewis acidic reagents exhibit similar affinities toward the alkaloid as for the dithiane. 5 The dithiane-containing quinolizidine 2a is potentially an excellent alkaloid precursor, being rapidly synthesized by a unique intramolecular conjugate addition reaction. 6 The potential deployment of 2a in alkaloid syntheses hinges on deprotecting the dithiane in the presence of the tertiary amine. Of the few reagents developed for deprotecting dithiane-containing alkaloids, the combination of SbCl 5 -Me 2 S 2 7 is regarded as being particularly mild 8 and well suited for dithiane-containing amines. Quinolizidine 2a reacts readily with the SbCl 5 -Me 2 S 2 reagent resulting in a smooth conversion, not to the anticipated ketone, but rather to the vinyl sulfide 3 (Scheme 1)!The mechanistically challenging formation of vinyl sulfide 3 is surprisingly well precedented. 9 SbCl 5 reacts with MeSSMe to generate SbCl 3 and the powerful thiomethylating 10 reagent 4 7 (Scheme 2) that thiomethylates the more accessible equatorial sulfur atom. Dissociation of the resulting sulfonium salt 5 and addition of excess dimethyl disulfide generates 7 that undergoes sequential thiomethyl transfers to afford 8. Disulfide elimination from 8 cleanly affords 3 (33% yield) accompanied by a polymeric material that presumably arises from selfcondensation of intermediate carbocations. Although the dithiane was not hydrolyzed, 11 valuable insight into the precise conditions for hydrolysis was obtained. Specifically, attempts to protect the amine by precomplexing 2a with SbCl 3 , 12 or other transition metals, led to poor mass recovery suggesting that 2a functions as an excellent ligand with a pronounced affinity toward transition metals! 13 The inability to hydrolyze 14 or couple the vinyl sulfide 3 15 further indicated the necessity for deprotecting under aqueous conditions to preferentially intercept the sulfonium intermediate 6.Armed with mechanistic insight the dithiane hydrolysis of 2a was pursued in aqueous media. Alkaloid 2a is readily protonated with aqueous acids (TFA, 16 H 2 SO 4 , 17 HClO 4 ) forming an ammonium salt without perceptible hydrolysis of 2a. Isolation of the perchlorate salt and exposure to trimethyloxonium tetrafluoroborate resulted in the recovery of only a small amount of unreacted 2a, despite this procedure successfully cleaving a closely related dithiane-containing alkaloid. 5c Direct alkylative (1) Smith, Amos B., III; Pitram, Suresh M. Difficulties in unmasking dithianes have often emerged during syntheses with complex intermediates necessitating reagent screening and, in some cases, indirect transaceta...
Potassium tert-butoxide triggers the chemoselective cyclization between nitrile anions and remote, enolizable carbonyl groups, despite the acidity difference favoring enolate formation and addition to the nitrile group. Domino deprotonation, cyclization, and dehydration efficiently transform a diverse array of omega-oxonitriles into carbocyclic and heterocyclic five- and six-membered alkenenitriles in a single synthetic operation.
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