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PubMed2003

A three-component reaction for diversity-oriented synthesis of polysubstituted piperidines: solution and solid-phase optimization of the first tandem aza[4+2]/allylboration.

This article describes the design and optimization of a simple three-component aza[4+2]/allylboration reaction to access polysubstituted alpha-hydroxyalkyl piperidines in a highly diastereocontrolled fashion from maleimides, 4-boronohydrazonodienes, and aldehydes. The aldehyde component does not interfere with the first aza[4+2] step, and it was found that this tandem reaction provides better yields of piperidine products 5 when carried out in one-pot. The required 4-borono-hydrazonodienes 1 are synthesized efficiently from the condensation of 3-boronoacrolein pinacol ester (4) with hydrazines. Overall, the three-component process using N-substituted maleimides as dienophiles produces four stereogenic centers and is quite general. It tolerates the use of a wide variety of aldehydes and hydrazine precursors with different electronic and steric characteristics. By allowing such a wide substrate scope and up to four elements of diversity, this reaction process is particularly well adapted towards applications in diversity-oriented synthesis of polysubstituted piperidine derivatives. The suitability of the aza[4+2]/allylboration reaction for use in solid-phase chemistry was also demonstrated using a N-arylmaleidobenzoic acid functionalized resin. This novel multicomponent reaction thus offers a high level of stereocontrol and versatility in the preparation of densely functionalized nitrogen heterocycles.

Journal Article↗
PubMed1983

2,3-dihydro-3-(1-pyrryl)spiro[benzofuran-2,4'-piperidine]s and 2,3-dihydro-3-(1-pyrryl)spiro[benzofuran-2,3'-pyrrolidine]s: novel antihypertensive agents.

A series of 2,3-dihydro-3-(1-pyrryl)spiro[benzofuran-2,4'-piperidine]s (IV) and 2,3-dihydro-3-(1-pyrryl)spiro[benzofuran-2,3'-pyrrolidine]s (V) was synthesized and evaluated for cardiovascular activity. The majority of the compounds displayed good antihypertensive activity in the spontaneous hypertensive rat model at 50 mg/kg po. Compounds 5 (2,3-dihydro-1'-methyl-3-(1-pyrryl)spiro[benzofuran-2,4'-piperidine] ) and 12a (2,3-dihydro-1'-ethyl-3-(1-pyrryl)-spiro[benzofuran-2,4'-piperidine] ) were selected for a more detailed cardiovascular evaluation in the renal hypertensive rat and for standard cardiovascular challenges in anesthetized dogs and the sinoaortic-deafferented dog.

Animals↗
PubMed1987

Analogues of 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione as selective inhibitors of aromatase: derivatives with variable 1-alkyl and 3-alkyl substituents.

3-Ethyl-3-(4-pyridyl)piperidine-2,6-dione (1) is a strong competitive inhibitor of human placental aromatase (Ki = 1.1 microM; testosterone as substrate) that, unlike the structurally related aromatase inhibitor aminoglutethimide (2), is not also an inhibitor of the cholesterol side-chain cleavage enzyme desmolase. An improved synthesis of 1 is described, which was readily adapted to the preparation of homologues in a series of 3-alkyl-3-(4-pyridyl)-piperidine-2,6-diones (6-13). Alkylation of 1 afforded a second series, comprising 1-alkyl-3-ethyl-3-(4-pyridyl)-piperidine-2,6-diones (14-23). Inhibitory activity toward aromatase was maximal in both series for the octyl derivatives. Respective Ki values for the competitive inhibition exerted by the 3-octyl (12) and the 1-octyl (21) analogues with testosterone as substrate were 0.09 and 0.12 microM. The compounds 1, 2, 12, and 21 differed in their relative potencies as inhibitors of the aromatization of testosterone and androstenedione. Respective Ki values were as follows: for 1, 1.1 and 14 microM (ratio 12.7); for 2, 0.6 and 1.8 microM (3); for 12, 0.09 and 0.20 microM (2.2); and for 21, 0.12 and 0.48 microM (4).

Alkylation↗
PubMed1996

Preparation of 2,3,4-Trisubstituted Piperidines by a Formal Hetero-Ene Reaction of Amino Acid Derivatives.

N-Benzyl- or N-tosyl-N-(4-methyl-3-pentenyl)amino aldehyde benzylimines, which are obtained from alanine, leucine, or phenylalanine methyl esters in five steps, can be cyclized diastereoselectively in the presence of Lewis acids to give 3-amino-2,4-dialkyl-substituted piperidines. The product distribution and diastereoselectivity depends on the type of Lewis acid and nitrogen-protecting group. Benzyl-protected imines give 2-alkyl-3-(benzylamino)-4-isopropenyl piperidines with FeCl(3) and 2-alkyl-3-(benzylideneamino)-4-isopropylpiperidines with TiCl(4). Tosyl-protected imines show a decreased level of selectivity. The relative configurations of the piperidines were established by NMR and X-ray crystal structure analyses. Iminium ion cyclization followed by two competitive ionic pathways, i.e. either proton elimination or hydride transfer are discussed for these reactions.

Journal Article↗
PubMed2002

Synthesis of trans-(3S)-amino-(4R)-alkyl- and -(4S)-aryl-piperidines via ring-closing metathesis reaction.

[reaction: see text] trans-(3S)-Amino piperidines bearing various alkyl and aryl substituents at the C-4 position were synthesized via a ring-closing metathesis reaction. The absolute stereochemistry was controlled using a protected D-serine as a starting material. Stereoselective hydrogenation of allylamines provided trans-(3S)-amino-(4R)-alkyl- and -(4S)-aryl-piperidines. This procedure presents the first method for the asymmetric synthesis of 4-substituted 3-amino piperidines.

Journal Article↗
PubMed2005

A Diels-Alder approach to the stereoselective synthesis of 2,3,5,6-tetra- and 2,3,4,5,6-pentasubstituted piperidines.

[structures: see text] A stereoselective synthesis of 2,3,5,6-tetra- and 2,3,4,5,6-pentasubstituted piperidines was achieved from oxidative cleavage of 2-aza-bicyclo[2.2.2]octene Diels-Alder adducts derived from N-protected 2-methyl-1,2-dihydropyridine. A chiral auxiliary mediated asymmetric synthesis of the pentasubstituted piperidine is also demonstrated. This methodology incorporates orthogonal protecting groups, thus providing a piperidine scaffold with easily modified points of diversity.

Journal Article↗
PubMed1986

Inhibition of gonadotropin-stimulated adenylate cyclase by dansyl-arginyl-(4'-ethyl)piperidine amide (DAPA).

Protease inhibitors are known to suppress basal, fluoride-, and hormone-stimulated adenylate cyclase activities. The thrombin inhibitor, dansyl-arginyl-(4'-ethyl)piperidine amide (DAPA), also specifically inhibits the binding of gonadotropins to their receptors. Our studies were undertaken to find a concentration of DAPA that would specifically inhibit gonadotropin-stimulated adenylate cyclase without significantly altering basal, fluoride-, isoproterenol-, or prostaglandin E1-stimulated cyclase. Basal adenylate cyclase activity was not inhibited by DAPA in either human chorionic gonadotropin (hCG)- or follicle-stimulating hormone (FSH)-responsive rat ovarian plasma membranes. Human chorionic gonadotropin-stimulated cyclase was completely inhibited by DAPA at a concentration of 2.96 mM; the ID50 was 1.32 mM. Follicle-stimulating hormone-stimulated cyclase was completely inhibited by a DAPA concentration of 4.44 mM, and the ID50 was 1.75 mM. Dansyl-arginyl-(4'-ethyl)piperidine amide (2.96 mM) inhibited isoproterenol-, prostaglandin E1-, and fluoride-stimulated cyclase in hCG-responsive membranes by 11%, 28%, and 35%, respectively. Dansyl-arginyl-(4'-ethyl)piperidine amide (4.44 mM) inhibited fluoride- and prostaglandin-stimulated cyclase in FSH-responsive membranes by 10% and 11%, respectively. The data show that appropriate concentrations of DAPA can antagonize gonadotropin-stimulated adenylate cyclase while only minimally affecting fluoride- and other receptor-activated cyclase activities.

Adenylyl Cyclase Inhibitors↗
PubMed2002

Spirotetrahydronaphthalene analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3'-piperidines].

The 5,6- (5a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3'-piperidine] (6a) and their N-isopropyl derivatives (5b and 6b), DDSNPs, were synthesized. These compounds can be viewed as the result of the combination of the structure of the 3-(3,4-dihydroxyphenyl)-piperidine 2a or 2b, with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy-(3a or 3b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (4a or 4b), 1-AMDTNs. The new compounds (5a, b and 6a, b) were assayed for their alpha and beta adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described 3-(3,4-dihydroxyphenyl)piperidine (3-DPP; 2) and 1-AMDTNs (3, 4). Comparison of the affinity and activity data of novel derivatives with those of reference compounds 2, 3 and 4 shows a general low ability of DDSNPs 5 and 6 to interact with both alpha and beta- adrenoceptors.

Animals↗
PubMed2002

Crowded piperidines with intramolecularly hydrogen-bonded nitrogen: synthesis and conformation study.

2,2,6,6-Tetramethyl substituted piperidines with a beta-branched N-alkyl substituent were synthesized by the photoreaction of N-Me precursors with ketones. The main conformation features of these sterically-hindered amines (established by NMR and IR spectroscopy) are a ring in the chair form, an eclipsed conformation for the N-substituent and an intramolecular OH...N bond. High barriers for the geminal substituent topomerization were measured for these piperidines at different temperatures by means of line-shape analysis of the temperature-dependent 13C and 1H NMR spectra. An MM3-derived conformation scheme indicated that, for one of the studied analogues, the rotation of the N-substituent determines a slow topomerization rate. A new mechanism of nitrogen inversion--a concerted hydrogen-bond dissociation/nitrogen inversion process--is considered for hydrogen-bonded amines.

Hydrogen Bonding↗
PubMedDate not supplied

Synthesis and dopaminergic properties of 3- and 4-substituted 1-[2-[5-(1H-benzimidazole-2-thione)]ethyl]piperidines and related compounds.

With an aim of creating new, high affinity dopaminergic ligands, six different 3- and 4-substituted 1-[2-[5-(1H-benzimidazole-2-thione)] ethyl]piperidines and nine related heterocyclic congeners were synthesized and evaluated for in vitro binding affinity at D1 and D2 dopamine receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei were used as a source of the dopamine receptors. Only 4-[bis-(4-fluorophenyl)methylene]-piperidines, compounds 9e, 10d, and 11d, expressed moderate affinity for the D1 receptors, while all other compounds were inactive competitors of [3H]SCH 23390. Compounds 9c, 9d, 10c, 11a, and 11c were inactive in the D2 receptor binding assay, as well. Derivatives of 4-phenylpiperidine (9-11b) and 3-phenylpiperidine (10a) expressed a moderate to low affinity for the D2 receptors. However, racemic (+/-)-1-[2-[5-(1H-benzimidazole-2-thione)] ethyl]-3-phenylpiperidine 9a and its enantiomer (+)-9a behaved as selective, high affinity D2 receptor ligands, the latter being some four times more active than the racemate.

Animals↗
PubMed1985

4-(Indolyl-3)-1-(benzimidazolonylalkyl)-piperidines, a novel group of potential antiallergy compounds.

A group of indolyl-benzimidazolone-piperidines is described and the structure-activity with reference to the passive cutaneous anaphylaxis (PCA) in rats is discussed. Compound 7b, 4-(indolyl-3)-1-(benzimidazolonyl-propyl)-piperidine, which has the highest potency in this test, was studied in more detail with regard to antihistaminic and secretory cell stabilization properties.

Animals↗
PubMed2003

Asymmetric carbon-carbon bond-forming reaction at the 2-position of a piperidine skeleton.

An asymmetric carbon-carbon bond-forming reaction at the 2-position of a piperidine skeleton was exploited. This method consisted of a reaction between 1-(4-methoxybenzoyl)-3,4-didehydro-2-methoxypiperidines and dimethyl malonate catalyzed by Cu(II)-chiral 2,2'-isopropylidenebis(4-phenyl-2-oxazoline) to afford a 2-substituted piperidine skeleton with moderate enantioselectivity.

Indicators and Reagents↗
PubMed1982

Conformational aspects of the actions of some piperidine dicarboxylic acids at excitatory amino acid receptors in the mammalian and amphibian spinal cord.

A series of piperidine dicarboxylates (PDA) has been tested for excitatory amino acid agonist and antagonist activity and for synaptic depressant properties of the spinal cords of frogs and immature rats in vitro and of cats in vivo. The substances tested comprised (+/-)-cis-2,3-PDA, (+/-)-cis-2,4-PDA, (+/-)-cis-2,5-PDA, (+/-)-cis-2,6-PDA, (+/-)-trans-2,3-PDA, (+/-)-trans-2,4-PDA and both (+) and (-) forms of cis-2,3-PDA. Peak excitatory amino acid agonist activity was observed with (+/-)-trans-2,3- and (+/-)-trans-2,4-PDA. Excitatory amino acid antagonism and synaptic depressant activity was observed only with cis-dicarboxylates, this activity being greatest in the 2,3-analogue. The agonist actions of piperidine dicarboxylates were effectively depressed by the specific NMDA receptor antagonist, (-)-2-amino-5-phosphonovalerate and, where tested, also by D-alpha-aminoadipate and low concentrations of Mg2+. It was concluded that the major part of these agonist actions were mediated by NMDA receptors. The main structural feature of the NMDA agonist actions of these substances was considered to be their close relationship to N-alkyl-aspartic and glutamic acid molecules, with the trans arrangement of the respective 2,3- and 2,4-situated carboxyl groups promoting most effective interaction with the active sites of the NMDA receptor. (+/-)-Cis-2,3-PDA depressed excitatory responses induced by NMDA, kainate, quisqualate, (+/-)-trans-2,3-PDA and (+/-)-trans-2,4-PDA, or evoked by dorsal root stimulation. Both monosynaptic and polysynaptic excitation were susceptible to the depressant action of this substance. The (-) isomer of cis-2,3-PDA carried both excitatory amino acid agonist and antagonist activity and also the synaptic depressant properties observed with the racemic form of this substance. The (+) isomer showed little pharmacological activity. It is proposed that the structure-activity features of these heterocyclic amino acids indicate some of the conformational requirements for interaction with physiological excitatory amino acid receptors.

Animals↗
PubMed1992

DNA strand cleavage at 8-hydroxyguanine residues by hot piperidine treatment.

The two findings indicate that 8-hydroxyguanine(8-OH-Gua) is a hot piperidine-sensitive lesion in DNA. These are cleavages of DNA containing 8-OH-Gua at the site of this residue and decomposition of 8-hydroxydeoxyguanosine when the DNA and nucleoside were treated in 1 M piperidine for 30 min at 90 degrees C. However, no cleavage was observed in DNA containing 8-hydroxyadenine or O6-methylguanine. 8-OH-Gua was found to be different from apurinic sites that are also alkali-labile lesions since the former was more resistant to alkali treatment. This property of 8-OH-Gua can be used as a check for the incorporation of this base into DNA after the synthesis of DNA containing 8-OH-Gua at a specific position or possibly can be one of the markers for the identification of 8-OH-Gua formed in DNA exposed to reactive oxygen species.

Base Sequence↗
PubMed1993

Synthesis and evaluation of 1-(1-[5-(2'-[18F]fluoroethyl)-2-thienyl]-cyclohexyl)piperidine as a potential in vivo radioligand for the NMDA receptor-channel complex.

1-(1-[5-(2'-[18F]Fluoroethyl)-2-thienyl]cyclohexyl)piperidine (18FE-TCP) was prepared as a fluorine-substituted analogue of the potent NMDA receptor channel blocker, 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), by the mesylate displacement with [18F]fluoride ion with isolated radiochemical yields of 6-12%, and the synthesis time including a two step HPLC purification was 120 min. The regional distribution in rat brain after i.v. injection of 18FE-TCP was heterogeneous and similar to the known distribution of phencyclidine recognition sites, with hippocampus-cerebellum, striatum-cerebellum and cerebral cortex-cerebellum concentration ratios of 2.08, 1.7 and 1.54, respectively, 15 min post-injection. Furthermore, this localized regional cerebral distribution was blocked by co-injection with the unlabelled FE-TCP or pretreatment with cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl)cyclohexane, with the greatest reductions seen in the hippocampus followed by the striatum and cerebral cortex. However, relatively low receptor binding affinity and high non-specific binding due to its high lipophilicity suggest that 18FE-TCP may not be a suitable radioligand for in vivo PET investigations of the NMDA receptor-channel complex.

Animals↗
PubMed2005

The discovery and preparation of disubstituted novel amino-aryl-piperidine-based renin inhibitors.

Recently, trans-disubstituted oxo-aryl-piperidines have been identified as small molecule nonpeptide renin inhibitors for the modulation of hypertension. Herein, we report on the discovery and preparation of a new class of novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent in vitro renin inhibitors and also, possess in vivo antihypertensive activity in a double transgenic mouse model.

Animals↗
PubMed2003

trans-3,4-dimethyl-4-(3-carboxamidophenyl)piperidines: a novel class of micro-selective opioid antagonists.

trans-3,4-Dimethyl-4-(3-carboxamidophenyl)piperidines constitute a novel class of micro opioid receptor antagonists. The CONH(2) group was found to be an effective isostere of the phenolic OH moiety. Structure-activity relationships at the piperidine nitrogen position led to the identification of several ligands displaying high affinity toward the cloned human micro opioid receptors, good selectivity micro/delta, micro/kappa, and potent in vitro antagonist activity.

Binding, Competitive↗
PubMed2004

Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains.

Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.

Animals↗