Spiropiperidines

Signal-to-noise ratio, 71, 154 Simpson s paradox, 231 Slope covariance, 2491 Spare receptors, 21 Specific binding, 60 Spiropiperidines, 155f Spongo thymidine, 148 Spongouridine, 148 SSq, 239 SSqc, 241... 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

Table 7.2 BINDING AFFINITIES OF SPIROPIPERIDINE OXYTOCIN ANTAGONISTS...

A retro-l,3-dipolar cycloaddition followed by an 1,3-dipolar cycloaddition was used for a highly efficient total synthesis of (-)-histrionicotoxin (4-354) (HTX) by Holmes and coworkers [123]. HTX is a spiropiperidine-containing alkaloid which was isolated by Doly, Witkop and coworkers [124] from the brightly colored poison-arrow frog Dendrobates histrionicus. It is of great pharmacological interest as a noncompetitive inhibitor of acetylcholine receptors. 

Compound 24 represents a series of potent spiropiperidine GlyT-1 inhibitors that showed significant binding to the p opioid and nociceptin/ orphanin FQ peptide (NOP) receptors [67]. The hydroxy analog 25 demonstrated improved selectivity and N-propyl analog 26 exhibited increased microsomal stability but reduced GlyT-1 potency (EC50 = 450 nM) [68]. 

Hydroamination of olefins has received considerable attention this year as a route to functionalized piperidines and spiropiperidines, particularly in regard to the investigation of new catalysts. In the synthesis of spiro-piperidines, two new mild and more general intramolecular hydroamination protocols were developed this year. One protocol uses a cationic gold-phosphine complex (Au[P(fBu)2(o-biphenyl)]Cl) as the catalyst... 

Figure 18.1 Schematic depiction of the putative filter form the inner cavity and the ligand-binding interactions between a spiropiperidine site. For clarity, S6 and pore helix domainsofonly...

Intramolecular oxidative coupling of silylated phenols 251 with IBTA leads to the formation of spiropiperidine derivatives 253, called aza-anthraquinone-spirodienones (89TL1119) (Scheme 64). The first step of this conversion is the electrophilic attack of reagent on the phenolic group to give intermediate 252. Intramolecular C—C bond formation leads... 

Further examples of the endocychc nitrone route to spirocychc adducts are the total syntheses of (—)-histrionicotoxin (230) by Holmes and of cyhndricines by Weinreb. Histrionicotoxin is one of many spiropiperidine alkaloids isolated from the poison-arrow frog Dendrobates histrionicus and has been the subject of many attempted total syntheses by a nitrone cycloaddition strategy that failed to provide the desired regioisomer, possibly through unfavorable steric interactions (265-268). Unlike these reports, Holmes and co-workers (101) found that the intermolecular reaction of nitrone (231), prepared by the 1,3-APT of the corresponding alkynyl-hydroxylamine carrying Oppolzer s chiral sultam auxiliary, afforded the styrene... 

However, in many other series results have been obtained that are compatible with those from other methods and that gave the dipole-moment method an appearance of general reliability now known to be unjustified. Such compatible results include spiropiperidines (Section III,A,4), tropanes (Section III,B,4), 2-alkyltetrahydro-l,2-oxazines (Section III,C,2), perhydro-pyrido[l,2-c][l,3]oxazines (Section III,D,IX perhydropyrido[l,2-c][l,3]thi-azines (Section III,D,2), dialkylhexahydropyrimidines and perhydropyrido-[l,2-c]pyrimidines (Section III,D,3), 5-alkyldihydro-l,3,5-dithiazines (Section III,G,3), 3,5-dialkyltetrahydro-l,3,5-thiadiazines (Section III,G,4) and, in part, l,2,4,5-tetraalkylhexahydro-l,2,4,5-tetrazines (Section III,H,4) as well as piperidines, tetrahydro-l,3-oxazines, and tetrahydro-l,3-thiazines containing an N-H group. 

Spiropiperidine Alkaloids.—Full details of a preliminarily reported synthesis of ( )-perhydrohistrionicotoxin (25) have been provided.24... 

Palladium-mediated intramolecular aminations onto an allylic alcohol <1998TL5971> or allene <1998TL5421> are reported for the synthesis of piperidines. An intermolecular version of the allene-based reactions has been reported in the synthesis of spiropiperidines (Equation 167) <1998JOC2154>. 

Spiropiperidines can also be prepared by tandem RCM <02CC1542> (Scheme 23). 

Spiropiperidine Alkaloids.—The spirocyclic keto-base (18), which possesses a histrionicotoxin skeleton, undergoes an acid-catalysed retro-Mannich reaction, followed by re-condensation, to afford the unsaturated imine (19), with a pumiliotoxin skeleton. A mechanism for the transformation has been proposed.29... 

Figure 5.5 Examples of empirically identified privileged structures of GPCR ligands. The privileged structures are highlighted. A ligand pair is shown for each privileged motif. A privileged structure does not always correspond to an exact substructure, as shown for the capped amino acid and spiropiperidine types [8, 44, 104-106].

Spiropiperidine amidine analogues of the current invention, such as ethyl 4-(9-(4-(aminoiminomethyl)benzoyl)-3-oxo-l-oxa-4,9-diaza-spiro[5.5]undec-4-yl)butanoate hydrochloride, (IV), have also been prepared and are described (3). 

The synthesis of 2 and related analogs proceeded as shown in Scheme 1. The spiropiperidine iminohydantoin core was obtained in a one-step, four-component Ugi coupling of piperidones, isocyanides, amines and KOCN, and proceeded in moderate yields. Deprotection of the piperidine nitrogen and further elaboration provided the final products. 

Barrow JC, Stauffer SR, Rittle KE et al (2008) Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of 8-secretase. J Med Chem 51 6259-6262... 

Perhydro-oxazolo[3,4- ]pyridines have long been prepared by condensation between the appropriate piperidyl-2-carbinol and an aldehyde or ketone. For example, the antidepressant spiropiperidine derivative (135) is obtained by the reaction between a-phenyl-2-piperidine methanol and N-benzyl-4-piperidone (81USP4260623). Perhydro-oxazolo[3,4-a]pyridin-3-one (136) is obtained by phosgenation of 2-(hydroxymethyl)piperidinium p-toluene sulfonate followed by cyclization of the resultant chloroformate salt by treatment with triethylamine in dichloromethane. This ring system... 

Histrionicotoxin, one of the spiropiperidine alkaloids from the skin of the Colombian frog Dendrobates histrionicus, containing two c/s-but-3-en-l-yne groups, is the first acetylenic alkaloid and also the first acetylene of animal origin. (The acid 12, present in the secretion of the soldier beetle, ChauHognatus lecontei. ... 

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