Abstract:A series of erythro- and threo-2-(aryloxy)-1-(2-piperidyl)ethanol derivatives (3) was synthesized from 2-(2-oxiranyl)pyridine for evaluation as beta-antagonists. Most compounds displayed high competitive beta-blocking potency, but they lacked significant beta 1/beta 2 selectivity. The 1-naphthoxy derivative erythro-3b was 17 (beta 1) and 33 (beta 2) times more potent than its open-chain analogue, propranolol. Within the whole series, erythro-3 diastereomers were more potent beta-blockers than the threo-3 isome… Show more
“…We are unaware of other general methods for this ring system. Accordingly, we adopted the Dieckmann route − and first coupled it with a more recent procedure for the synthesis of 2,5-disubstituted piperidines from the corresponding pyridine − (Scheme ). 1 Synthesis of Aza-Bridged [3.3.1]-Bicyclic Amines…”
Section: Resultsmentioning
confidence: 99%
“…Several pyridine-reductive methods have been reported. − , For C(2) substituted methylene pyridines, piperidine formation is accompanied by competitive reduction of the C(2) methylene substituent. We examined several methods and found, for 12c and 12e , that PtO 2 , H 2 , and acid 12-14 provided the desired piperidines.…”
Section: Resultsmentioning
confidence: 99%
“…The combined yields for these two steps ranged from 13 to 51%. For the preparation of 13a, we used commercially available ethyl 3-piperidinecarboxylate (14) rather than reduce ethyl nicotinate (12a). For 12c, nearly 50% of the product mixture consisted of the byproduct 15 (C(2) reduction) after treatment with ethyl acrylate.…”
Expedient syntheses of C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones are reported to begin with 2,5-disubstituted pyridines. Catalytic reduction of the pyridine to the piperidine followed by treatment with ethyl acrylate and Dieckmann cyclization gave diastereomeric mixtures of C(8) substituted 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes, which were separable by chromatography. We found that the catalytic reduction (PtO2, H2) procedure provided the cis-substituted piperidine but that pyridine reduction was accompanied by competitive cleavage of the C(2) pyridyl substituent. Accordingly, an alternative route was devised that afforded a diastereomeric mixture of the cis- and trans-2,5-disubstituted piperidine. Treatment of the substituted pyridine with m-CPBA gave the pyridine N-oxide, which was reduced to the piperidine by sequential reduction with ammonium formate in the presence of Pd-C followed by NaBH3CN. Addition of ethyl acrylate completed the synthesis of the substituted piperidine. The overall four-step reaction gave higher yields (57%) than the two-step procedure (13%) with little cleavage of the C(2) pyridyl substituent. Acid decarboxylation of the bicyclo[3.3.1]non-3-enes provided the C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones. Structural studies revealed diagnostic 13C NMR signals that permit assignment of the orientation of the C(8) substituent. Pharmacological investigations documented that 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes efficiently bind to the human M1-M5 muscarinic receptors and function as antagonists. We observed that exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene (3) displayed the highest affinity, exhibiting Ki values at all five muscarinic receptors that were approximately 10-50 times lower than carbachol and approximately 30-230 times lower than arecoline. Receptor selectivity was observed for 3. Compound 3 contained two different pharmacophores found in many muscarinic receptor ligands, and preliminary findings indicated the importance of both structural elements for maximal activity. Compound 3 serves as a novel lead compound for further drug development.
“…We are unaware of other general methods for this ring system. Accordingly, we adopted the Dieckmann route − and first coupled it with a more recent procedure for the synthesis of 2,5-disubstituted piperidines from the corresponding pyridine − (Scheme ). 1 Synthesis of Aza-Bridged [3.3.1]-Bicyclic Amines…”
Section: Resultsmentioning
confidence: 99%
“…Several pyridine-reductive methods have been reported. − , For C(2) substituted methylene pyridines, piperidine formation is accompanied by competitive reduction of the C(2) methylene substituent. We examined several methods and found, for 12c and 12e , that PtO 2 , H 2 , and acid 12-14 provided the desired piperidines.…”
Section: Resultsmentioning
confidence: 99%
“…The combined yields for these two steps ranged from 13 to 51%. For the preparation of 13a, we used commercially available ethyl 3-piperidinecarboxylate (14) rather than reduce ethyl nicotinate (12a). For 12c, nearly 50% of the product mixture consisted of the byproduct 15 (C(2) reduction) after treatment with ethyl acrylate.…”
Expedient syntheses of C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones are reported to begin with 2,5-disubstituted pyridines. Catalytic reduction of the pyridine to the piperidine followed by treatment with ethyl acrylate and Dieckmann cyclization gave diastereomeric mixtures of C(8) substituted 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes, which were separable by chromatography. We found that the catalytic reduction (PtO2, H2) procedure provided the cis-substituted piperidine but that pyridine reduction was accompanied by competitive cleavage of the C(2) pyridyl substituent. Accordingly, an alternative route was devised that afforded a diastereomeric mixture of the cis- and trans-2,5-disubstituted piperidine. Treatment of the substituted pyridine with m-CPBA gave the pyridine N-oxide, which was reduced to the piperidine by sequential reduction with ammonium formate in the presence of Pd-C followed by NaBH3CN. Addition of ethyl acrylate completed the synthesis of the substituted piperidine. The overall four-step reaction gave higher yields (57%) than the two-step procedure (13%) with little cleavage of the C(2) pyridyl substituent. Acid decarboxylation of the bicyclo[3.3.1]non-3-enes provided the C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones. Structural studies revealed diagnostic 13C NMR signals that permit assignment of the orientation of the C(8) substituent. Pharmacological investigations documented that 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes efficiently bind to the human M1-M5 muscarinic receptors and function as antagonists. We observed that exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene (3) displayed the highest affinity, exhibiting Ki values at all five muscarinic receptors that were approximately 10-50 times lower than carbachol and approximately 30-230 times lower than arecoline. Receptor selectivity was observed for 3. Compound 3 contained two different pharmacophores found in many muscarinic receptor ligands, and preliminary findings indicated the importance of both structural elements for maximal activity. Compound 3 serves as a novel lead compound for further drug development.
“…Isometric force was recorded from the preparations by a force−displacement transducer coupled to an Omni-Scribe recorder. A constant level of tone was induced by the addition of a 5 × 10 -7 M carbachol chloride solution to the bath to obtain after 15 min a control concentration−response curve for each agonist. , The tracheal chain was washed thoroughly with the Krebs solution for 30 min, and then, a 10 -4 M solution of the antagonist (8-PT, DMPX, CSC, and alloxazine) was added to the bath and allowed to act for 30 min. During the last 15 min of the antagonist incubation, the carbachol chloride solution was added to the bath and the cumulative concentration−response curve for each agonist was determined by measuring the maximal relaxation produced by different concentrations of the agonist (compound 1 , 3 × 10 -8 to 10 -3 M; compound 2 , 3 × 10 -7 to 10 -3 M; compound 4 , 3 × 10 -8 to 3 × 10 -4 M; compound 7 , 10 -6 to 3 × 10 -4 M; adenosine, 3 × 10 -6 to 10 -2 M; and NECA, 3 × 10 -7 to 10 -3 M).…”
New adenosine derivatives have been synthesized and tested as putative agonists of adenosine receptors. Compounds 2-6 derive from the introduction of several types of substituents (electron donating, electron withdrawing, and halogens) in the para-position of the phenyl ring of the parent compound 1, and compound 7 lacks the hydroxyl group of amino alcohol 1. In radioligand binding assays using recombinant human A(1), A(2A), A(2B), and A(3) receptors, all compounds showed very low or negligible affinity for A(1) and A(2B) receptors but compounds 3, 5, and 7 displayed a remarkably potent affinity for the A(2A) receptor with K(i) values of 1-5 nM. Bromo derivative 3 displayed a selectivity A(1)/A(2A) = 62 and A(3)/A(2A) = 16 whereas the presence of a hydroxyl group (compound 5) improved the selectivity of A(1)/A(2A) and A(3)/A(2A) to 120- and 28-fold, respectively. When the methoxy derivative 4 lacks the hydroxyl group on the side chain (compound 7), the binding affinity for A(2A) is increased to 1 nM, improving selectivity ratios to 356- and 100-fold against A(1) and A(3), respectively. In Chinese hamster ovary cells transfected with human A(2A) and A(2B) receptors, most compounds showed a remarkable activity for the A(2A) receptor, except chloro derivative 2, with EC(50) values ranging from 1.4 to 8.8 nM. The compounds behaved as good A(2A) agonists, and all were more selective than 5'-(N-ethylcarboxamino)adenosine (NECA), with A(2B)/A(2A) ratios of cAMP accumulation ranging from 48 for compound 2 to 666 for compound 7 while the corresponding A(2B)/A(2A) ratio for NECA was only 9. Compounds 1, 3, 5, and 7 also displayed higher selectivities than NECA up to 100-fold in isolated aortas of rat and guinea pig. In guinea pig tracheal rings precontracted by carbachol, compounds 2 and 4 were more potent than adenosine (100-fold) and NECA (10-fold), whereas compounds 1 and 7 displayed similar effects to NECA. Pretreatment of the tracheal rings with A(2), A(2A), and A(2B) receptor antagonists 3,7-dimethyl-l-propargylxanthine, 8-(3-chlorostyryl)caffeine, and alloxazine produced a marked inhibition of the tracheal relaxations induced by compounds 1, 2, and 4, but none of the compounds showed selectivity toward any of the adenosine receptors.
“…The organic layer was washed to neutral with saturated NaCl solution, dried with anhydrous sodium sulfate, and concentrated in vacuo. Purification by column chromatography on silica gel afforded epoxy compounds 5a-c [29,30].…”
Section: General Procedures For the Synthesis Of Dnj Derivativesmentioning
Thirteen 1-deoxynojirimycin (DNJ) derivatives of five different skeletal structures were designed and synthesized. The newly synthesized compounds were evaluated using an in vitro α-glucosidase assay, and kinetic parameters (Ki, IC 50 ) were measured. Some DNJ derivatives showed weak α-glucosidase inhibitory activities, and the compounds 1-(3-benzyloxy-2-hydroxypropyl)-2-hydroxymethyl-piperidine-3,4,5-triol (2a) and 1-{3-[1-(4-fluorophenyl)-1H-[1,2,3]triazol-4-ylmethoxy]-2-hydroxypropyl}-2-hydroxymethyl-piperidine-3,4,5-triol (13d) showed activities comparable to that of DNJ. While 2a was found to be a reversible, non-competitive inhibitor of α-glucosidase with a Ki value of 1.56 × 10 −4 M and an IC 50 value of 3.07 × 10 −4 M, 13d was a reversible, competitive inhibitor of α-glucosidase with a Ki value of 2.08 × 10 −4 M and an IC 50 value of 3.31 × 10 −4 M.
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