Showing papers on "Piperidine published in 1992"
127 citations
TL;DR: In this paper, an active conformation for 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride (1a), a potent AChE inhibitor, is defined with respect to the flexible geometry of the benzyl piperidine moiety.
Abstract: Conformational analyses and molecular-shape comparisons were carried out on an analogue series of indanone-benzylpiperidine inhibitors of acetylcholinesterase (AChE). It was possible to define an active conformation with respect to the flexible geometry of the benzylpiperidine moiety, as well as an active conformation of the indanone ring-piperidine ring substructure for analogues having a single spacer group between these rings. No active conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine rings. Still, a receptor binding model can be constructed for all indanone and piperidine ring substructures. The postulated active conformation for 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride (1a), a potent AChE inhibitor, is close to the crystal structures of 1a with respect to the indanone-piperidine substructure, but differs from the crystal structures for the benzylpiperidine moiety. However, the crystal conformations and the postulated active conformation of the benzylpiperidine portion of the AChE inhibitor are estimated to be about equally stable. A trans-decalin analogue of 1a can adopt the postulated active conformation as shown by calculation and as seen in its crystal structure. The inactivity of this analogue is explained by the added steric size of the decalin unit and/or the time-average valence geometry behavior at the spiro junction to the indanone ring.
71 citations
TL;DR: One of the compounds prepared in this series, 1-benzyl-4-[2-[4-(benzoylamino)phthalimido]ethyl]piperidine hydrochloride (19) (IC50 = 1.2 nM) is one of the most potent inhibitors of AChE.
Abstract: Following the discovery of a new series of 1-benzyl-4-[2-(N-benzoyl-N-methylamino)ethyl]piperidine (2) derivatives with a potent anti-acetylcholinesterase (anti-AChE) activity, we extended the structure-activity relationships (SAR) to rigid analogues (4) and 1-benzyl-4-[2-(N-benzoyl-N-phenylamino)ethyl]piperidine derivatives (3). Introduction of a phenyl group on the nitrogen atom of the amide moieties resulted in enhanced activity. The rigid analogue containing isoindolone (9) was found to exhibit potent anti-AChE activity comparable to that of 2. Furthermore, replacement of the isoindolone with other heterobicyclic ring systems was examined. Among the compounds prepared in these series, 1-benzyl-4-[2-[4-(benzoylamino)phthalimido]ethyl]piperidine hydrochloride (19) (IC50 = 1.2 nM) is one of the most potent inhibitors of AChE. Compound 19 showed a definite selectivity to AChE over the BuChE (about 34700-fold) and, at dosages of 10-50 mg/kg, exerted a dose-dependent inhibitory effect on AChE in rat brain.
69 citations
62 citations
TL;DR: In this article, the effect of surface acidity on denitrogenation selectivity was studied by means of the reactions of piperidine in a continuous-flow fixed-bed reactor operated at atmospheric pressure and 320-340°C.
57 citations
TL;DR: Comparison of both the sigma receptor affinities and nitrogen atom geometry of the compounds revealed that a gauche relation of the nitrogen atoms of cis-1,2-cyclohexanediamines is not imperative for high affinity as it had previously thought.
Abstract: The synthesis and sigma receptor affinity of a series of conformationally restricted derivatives of 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenedi amine (1) is described. The pyrrolidinyl (or N,N-dialkyl),ethylenediamine,N-alkyl, and phenylethyl portions of this sigma receptor pharmacophore were restricted by its incorporation into 1,2-cyclohexanediamine-, pyrrolidine-, piperidine-, homopiperidine-, and tetrahydroisoquinoline-containing ligands. The sigma receptor binding affinities of these compounds were determined using [3H](+)-pentazocine in guinea pig brain homogenates. The synthesis of all but one class was achieved by acylation and alane reduction of the appropriate diamine precursors whose synthesis is also reported. sigma receptor affinities ranged from 1.34 nM for 6,7-dichloro-2-[2-(1-pyrrolidinyl)ethyl]tetrahydroisoquinoline (12) to 455 nM for (1R,2R)-trans-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2- (1-pyrrolidinyl)cyclohexylamine [(-)-4]. In this displacement assay, (+)-pentazocine exhibited a Ki of 3.1 nM while DTG and haloperidol showed Ki values of 27.7 and 3.7 nM, respectively. The conformationally free parent compound 1 exhibited a Ki value of 2.1 nM. Comparison of both the sigma receptor affinities and nitrogen atom geometry of the compounds revealed that a gauche relation of the nitrogen atoms of cis-1,2-cyclohexanediamines is not imperative for high affinity as we had previously thought. It is highly likely that nitrogen lone pair orientations and steric factors on the aliphatic portions of these ligands play a major role in the sigma receptor binding of this pharmacophore.
46 citations
TL;DR: In this article, a 1.5-dideoxy-1,5-imino-d-glycero-D-allo-heptitol was synthesized in ca. 9% overall yield by utilizing 2,3-O-isopropylidene-D,glyceraldehyde-N-benzylimine as a chiral source and 2-(trimethylsiloxy)furan (2) as a homologative reactant.
42 citations
TL;DR: Stereodefined 2-alkylidene-pyrrolidines and -piperidine were synthesized by treatment of an acetylenic amines with n-BuLi followed by addition of catalytic amount of Pd(OAc) 2 and PPh 3 in THF and 3 equiv of an organic halide as discussed by the authors.
40 citations
TL;DR: In this article, a vibrating-tube densimeter and a Picker flow microcalorimeter were used to measure the excess molar heat capacity of binary liquid mixtures.
Abstract: Excess molar volumes V
E
and excess molar heat capacities C
/
at constant pressure have been obtained, as a function of mole fraction x1, for several binary liquid mixtures belonging either to series I: pyridine+n-alkane (ClH2l+2), with l=7, 10, 14, 16, or series II: piperidine+n-alkane, with l=7, 8, 10, 12, 14. The instruments used were a vibrating-tube densimeter and a Picker flow microcalorimeter, respectively. V
E
of pyridine+n-heptane shows a S-shaped composition dependence with a small negative part in the region rich in pyridine (x1>0.90). All the other systems show positive V
E
only. The excess volumes increase with increasing chain length l of the n-alkane. The excess molar heat capacities of the mixtures belonging to series II are all negative, except for a small positive part for piperidine+n-heptane in the region rich in piperidine (x1>0.87). The C
/
at the respective minima, C
/
(x1,min
), become more negative with increasing l, and the x1,min
values range from about 0.26 (l=7) to 0.39 (l=14). Most interestingly, mixtures of series I exhibit curves of C
/
against x1 with two minima and one maximum, the so-called W-shape curves.
40 citations
Patent•
26 May 1992
38 citations
TL;DR: The (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG, and is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.
Abstract: The synthesis of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones is described [cyclopentyl (1), cyclohexyl (2)]. The enantiomers of 2 were separated either by using HPLC on optically active sorbent or by crystallization of the brucine salt of the phthalamic acid of 2. The absolute configuration of the (+)- and (-)-enantiomers of 2 were assigned as S and R, respectively, by comparing the CD spectra to those of the enantiomers of aminoglutethimide (AG, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The compounds were tested in vitro for inhibition of human placental aromatase, the cytochrome P450-dependent enzyme which is responsible for the conversion of androgens to estrogens. Compounds 1 and 2 inhibited aromatase by 50% at 1.2 and 0.3 microM, respectively (IC50 AG = 37 microM). According to the findings with AG, the (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG. On the other hand, (+)-2 displayed a strongly reduced inhibition of desmolase (cholesterol side-chain cleavage enzyme) compared to AG (relative activity = 0.3). Thus (+)-2 is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.
TL;DR: The unnatural enantiomer (-)-euphococcinine (2) and the natural enantiomers of (-)-adaline (3), two homotropane alkaloids, were each prepared in three steps from chiral (-)-2-cyano-6-oxazolopiperidine synthon 8 by CN(R,S) method.
Abstract: The unnatural enantiomer (-)-euphococcinine (2) and the natural enantiomer of (-)-adaline (3), two homotropane alkaloids, were each prepared in three steps from chiral (-)-2-cyano-6-oxazolopiperidine synthon 8 by CN(R,S) method. The key steps of these syntheses are the formation of a chiral quaternary center α to the piperidine nitrogen with complete stereocontrol and a subsequent intramolecular Mannich reaction. The previously unknown absolute configuration of natural (+)-euphococcinine was deduced from the the synthesis of its enantiomer (-)-2
TL;DR: The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]-2- [(alkylamino)methyl]piperidines and their activities as kappa-opioid receptor agonists are described and selected structural modifications are made to the basic moiety and at the 2, 3, 4, 5, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated.
Abstract: The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]-2- [(alkylamino)methyl]piperidines and their activities as kappa-opioid receptor agonists are described. Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated. As a result, some highly potent and selective kappa-receptor agonists have been identified. In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain. Thus, 1-[(3,4-dichlorophenyl)acetyl]- 2-[[1-(3-oxopyrrolidinyl)]methyl]piperidine (10) possesses high activity in the rabbit vas deferens (LVD, kappa-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc). The spirocyclic analogue 8-[(3,4-dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dio xa-8- azaspirol4.5]decane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc. Both 10 and 39 displayed high selectivity for kappa-opioid receptors over both mu- and delta-opioid receptor subtypes.
TL;DR: Two new piperidine alkaloids, piperoctadecalidine and pipereicosalidine have been isolated from the fruits of Piper retrofractum (Piperaceae) along with two known piperine and pipernonaline as discussed by the authors.
TL;DR: The title compounds 5a-c and 7a-m have been prepared by Vilsmeier formylation of 4-aminocoumarins 1 yielding aldehydes 2, and subsequent condensation of 2 with C-H acids in the presence of piperidine as mentioned in this paper.
TL;DR: A facile method of synthesizing enantiomerically pure piperidine alkaloids, (R)-(−)-coniine and (2R,6S)-dihydropinidine, has been explored by employing the highly diastereoselective reaction of a 1,3-oxazolidine with Grignard reagents as mentioned in this paper.
Abstract: A facile method of synthesizing enantiomerically pure piperidine alkaloids, (R)-(−)-coniine and (2R,6S)-(−)-dihydropinidine, has been explored by employing the highly diastereoselective reaction of a 1,3-oxazolidine with Grignard reagents
TL;DR: In this paper, the asymmetric intramolecular Michael reaction of acyclic compounds was investigated under a variety of conditions, and the pyrrolidine ethyl (4-acetyl-1-benzylpyrrolidin-3-yl)acetate was obtained in moderato to excellent optical yield.
Abstract: The asymmetric intramolecular Michael reaction of acyclic compounds ethyl (E)-4-[benzyl-(3-oxobutyl)amino]but-2-enoate 9, and ethyl (E)-5-[benzyl-(3-oxobutyl)amino]pent-2-enoate 10 was investigated under a variety of conditions, and the pyrrolidine ethyl (4-acetyl-1-benzylpyrrolidin-3-yl)acetate 11 and piperidine ethyl (3-acetyl-1-benzylpiperidin-4-yl)acetate 12, versatile chiral building blocks for alkaloid synthesis, were obtained in moderato to excellent optical yield. Cyclization of the aforementioned but- and pent-2-enoate using (R)-1-phenylethylamine in THF in the presence of molecular sieves 5 A gave tha (+)-pyrrolidine derivative (+)-11 and the (–)-piperidine dsrivative (–)-12 in 60 and 90% ee., respectively. When (S)-1-phenylethylamine was used, pyrrolidine (–)-11 and piperidine derivatives (+)-12 Were obtained in similar optical yields, respectively. The ee of (–)-and (+)-piperidine derivatives increased up to 98% upon recrystallization of their hydrobromide salts.
Patent•
02 Apr 1992
TL;DR: In this article, a piperidine derivative of general formula (I) is defined, where R represents a hydrogen atom, a linear or branched (C1-6)alkyl group or a cyclo(C3-8) group, X represents an oxygen atom or a sulphur atom.
Abstract: A compound which is a piperidine derivative of general formula (I) ##STR1## in which R1 represents a hydrogen atom, a linear or branched (C1-6)alkyl group or a cyclo(C3-8)alkyl group, X represents an oxygen atom, a sulphur atom or a group of general formula N--R3 in which R3 is a hydrogen atom, or a linear or branched (C1-8)alkyl, cyclo(C3-6)alkyl, cyclo(C3-6)alkylmethyl, (C1-4)alkoxy-(C1-4)alkyl, phenyl, pyridin-4-yl, pyridin-3-yl, pyridin-4-ylmethyl or pyridin-3-ylmethyl group and Z represents a hydrogen or fluorine atom and acid addition salts thereof with pharmaceutically acceptable acids, can be used for the treatment and prevention of disorders in which 5-HT receptors are involved.
TL;DR: The structure of pseudodistomin B, a piperidine alkaloid, has been revised to 1a on the bases of the degradation reaction and the first total synthesis of (±)-pseudodistsomin B acetate (1b ) was reported in this article.
TL;DR: Phenyl-substituted etoxadrol analogues were compared to similarly substituted PCP analogues and distinct differences were found in their structure-activity relationships suggesting that the aromatic rings in these two drug classes interact differently with the PCP binding sites.
Abstract: A series of dioxolane analogues based on dexoxadrol ((4S,6S)-2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane) and etoxadrol ((2S,4S,6S)-2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane) were prepared and tested for their ability to displace [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine) from PCP (1-(1-phenylcyclohexyl)piperidine) binding sites in rat brain tissue homogenates. Qualitative structure-activity relationships within this series were explored through modifications of the three major structural units of dexoxadrol, the piperidine, 1,3-dioxolane, and aromatic rings of the molecule. N-Alkyl derivatives of dexoxadrol were found to be inactive, as were those analogues where the dioxolane ring was modified. Phenyl-substituted etoxadrol analogues were compared to similarly substituted PCP analogues and distinct differences were found in their structure-activity relationships suggesting that the aromatic rings in these two drug classes interact differently with the PCP binding sites. The replacement of the phenyl ring in etoxadrol by either a 2- or 3-thienyl ring led to compounds with affinity comparable to etoxadrol, and the replacement of the ethyl moiety on etoxadrol's dioxolane ring with propyl (7) or isopropyl (8) led to compounds which were more potent than etoxadrol or PCP. The most potent compound was (2S,4S,6S)-2-ethyl- 2-(1-chlorophenyl)-4-(2-piperidyl)-1,3-dioxolane (11), where a chlorine moiety was placed in the ortho position in the aromatic ring of etoxadrol. Its potency was comparable with TCP in vitro.
TL;DR: In this paper, a variable temperature nmr study of the positions of equilibria was conducted to compare the ring inversion equilibrium in carbomethoxycyclohexane, 2-cyanotetrahydropyran and 2-cyclopiperidine, and the trend in ΔH° values was consistent with the expected increase in stabilising endo-anomeric effect along the series C, O, N.
TL;DR: In this article, butyl (R)-3-(hydroxymethyl)-1piperidinecarboxylate was prepared with lipase P in up to 98 % ee by means of enanti-selective esterification of the racemic alcohol as well as by enantioselective hydrolysis of the corresponding butyryl ester.
Abstract: t-Butyl (R)-3-(hydroxymethyl)-1-piperidinecarboxylate was prepared with lipase P in up to 98 % ee by means of enantioselective esterification of the racemic alcohol as well as by enantioselective hydrolysis of the corresponding butyryl ester and subsequent chemical hydrolysis of the retained (R)-ester A work-up procedure feasible on the kg-scale is described
TL;DR: Three of the most active compounds, 1-acyl-4-cyano-4-(4-pyridylcyanomethyl)piperazine, 100, 114, and 115 have been selected for further pharmacological development.
Abstract: A series of (pyridylcyanomethyl)piperazines was prepared and evaluated for PAF-antagonist activity. Compounds were tested in vitro in a PAF-induced platelet aggregation assay and in vivo in a PAF-induced hypotension test in normotensive rats. Oral activity was ascertained through a PAF-induced mortality test in mice. The main structure-activity trends of the series were established. Activity was mainly found in four skeletons: 1-acyl-4-(3-pyridylcyanomethyl)piperazine, 1-acyl-4-(4-pyridylcyanomethyl)piperazine, 1-acyl-4-(3-pyridylcyanomethyl)piperidine, and 1-acyl-4-cyano-4-(3-pyridylamino)piperidine. The acyl substituents, diphenylacetyl and 3,3-diphenylpropionyl, provided the most active compounds, and the introduction of an amine or hydroxy group in the 3,3-diphenylpropionyl substituent led to further improvement in oral activity. As a result, three of the most active compounds (100, 114, and 115) have been selected for further pharmacological development.
TL;DR: In this paper, the chemistry of hydrodenitrogenation catalysis is discussed with special attention being focused on the nature of the catalytic sites active for piperidine hydrogenolysis and the mechanism operative in the C-N bond cleavage during pidine conversion.
Abstract: The chemistry of hydrodenitrogenation catalysis is discussed with special attention being focused on the nature of the catalytic sites active for piperidine hydrogenolysis and the mechanism operative in the C-N bond cleavage during piperidine conversion. Reactions such as hydrogenolysis, alkylation, cyclization, cleavage, dehydrogenation, and hydrogenation occurred when piperidine was hydrogenated over a sulfided CoMo commercial hydrocracking catalyst. Reaction mechanisms are proposed to account for the formation of the identified products from these reactions. Both acidic (Bronsted or Lewis) and basic sites are proposed to participate in the amine (such as piperidine) denitrogenation reactions
TL;DR: Both enantiomers of the homochiral 3-oxygenated 2,6-cis-disubstituted piperidine1 were synyhesized by starting with lipase-catalyzed transesterification or hydrolysis of the meso glycol or its diacetate in the conjoined twin Piperidine system as discussed by the authors.
TL;DR: The first synthesis of tetrahydroacetate of pseudodistomin, a novel antineoplastic piperidine alkaloid, was achieved via the route involving the reductive photcyclization of enamide and α-acylamino radical allylation as mentioned in this paper.
TL;DR: In this article, a new polymerizable stabilizer 4-(hex-5-enyl)-2,2,6,6-tetramethylpiperidine is prepared, copolymerized with propylene over a fourth generation TiCl4/MgCl2 Ziegler-Natta catalyst, using Al(C2H5)3 as cocatalyst and diphenyldimethoxysilane, DMS, as external electron donor.
Abstract: A new polymerizable stabilizer 4-(hex-5-enyl)-2,2,6,6-tetramethylpiperidine is prepared. This sterically hindered piperidine was copolymerized with propylene over a fourth generation TiCl4/MgCl2 Ziegler–Natta catalyst, using Al(C2H5)3 as cocatalyst and diphenyldimethoxysilane, DMS, as external electron donor. The copolymer exhibited high thermo-oxidative stability even after exhaustive extraction with n-heptane.