Showing papers on "Piperidine published in 2006"
TL;DR: In this paper, the capability of neutral titanium complexes to catalyze intramolecular hydroamination reactions of alkenes has been investigated and the corresponding pyrrolidine and piperidine products are formed in yields up to 97%%.
77 citations
TL;DR: Testing two hypotheses derived from modeling and mutant cycle results support the hypothesis that it is the carboxamide oxygen of the C-3 substituent of 1 that engages in a hydrogen bond with K3.28(192) in WT CB1.
Abstract: The biarylpyrazole, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 1) has been shown to act as an inverse agonist/antagonist at the cannabinoid CB1 receptor. Our previous mutant cycle study suggested that K3.28(192) is involved in a direct interaction with the C-3 substituent of 1 in wild-type (WT) CB1.1 However, these results did not establish what part of the C-3 substituent of 1 is involved in the K3.28(192) hydrogen bond, the carboxamide oxygen or the piperidine nitrogen. Furthermore, our previous calcium channel assay results for 5-(4- chlorophenyl)-3-[(E)-2-cyclohexylethenyl]-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole (VCHSR; 2) (an analogue of 1 that lacks hydrogen-bonding capability in its C-3 substituent) showed that this compound acts as a neutral antagonist, a result that is in contrast to 1, which acts as an inverse agonist in this same assay.1 These results suggested a relationship between biarylpyrazole interaction with K3.28(192)...
77 citations
TL;DR: Second-order rate constants have been determined spectrophotometrically for the reactions of 2,4-dinitrophenyl X-substituted benzoates with a series of alicyclic secondary amines in MeCN and a concerted mechanism is proposed for the aminolysis of 1 a-f in Me CN.
Abstract: Second-order rate constants (k(N)) have been determined spectrophotometrically for the reactions of 2,4-dinitrophenyl X-substituted benzoates (1 a-f) and Y-substituted phenyl benzoates (2 a-h) with a series of alicyclic secondary amines in MeCN at 25.0 +/- 0.1 degrees C. The k(N) values are only slightly larger in MeCN than in H2O, although the amines studied are approximately 8 pK(a) units more basic in the aprotic solvent than in H2O. The Yukawa-Tsuno plot for the aminolysis of 1 a-f is linear, indicating that the electronic nature of the substituent X in the nonleaving group does not affect the rate-determining step (RDS) or reaction mechanism. The Hammett correlation with sigma- constants also exhibits good linearity with a large slope (rho(Y) = 3.54) for the reactions of 2 a-h with piperidine, implying that the leaving-group departure occurs at the rate-determining step. Aminolysis of 2,4-dinitrophenyl benzoate (1 c) results in a linear Bronsted-type plot with a beta(nuc) value of 0.40, suggesting that bond formation between the attacking amine and the carbonyl carbon atom of 1 c is little advanced in the transition state (TS). A concerted mechanism is proposed for the aminolysis of 1 a-f in MeCN. The medium change from H2O to MeCN appears to force the reaction to proceed concertedly by decreasing the stability of the zwitterionic tetrahedral intermediate (T+/-) in aprotic solvent.
76 citations
TL;DR: 4-Methylpiperidine is fully equivalent to piperidine in removal of Fmoc protecting group in solid phase synthesis.
Abstract: 4-Methylpiperidine is fully equivalent to piperidine in removal of Fmoc protecting group in solid phase synthesis This reagent is not a controlled substance and its use does not require any paperwork
61 citations
TL;DR: 27 derivatives of an achiral piperidine trioxolane were synthesized; most were potent antimalarial peroxides with IC(50)s ranging from 0.20 to 7.0 ng/mL, and the oral efficacies of two of these were superior to artesunate and comparable to artemether.
57 citations
TL;DR: Using competition experiments between a range of ligands and (-)-sparteine, a reactivity series for N-Boc pyrrolidine lithiation using s-BuLi/diamines has been constructed; the results indicate that the s- BuLi/(+)- sparteine surrogate complex is more reactive than s-buLi/(-)-spartenine and this has been exploited in the selection of ligand pairs.
54 citations
TL;DR: Stereocontrolled synthesis of 2,4,6-trisubstituted piperidine diastereomers has been realized from common intermediates, obtained by a one-pot azaelectrocyclization protocol.
47 citations
TL;DR: Some spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3' H)-ones 3 and spiro:[1,2,4]triazolo[1,5-c]quinazolines 4 were synthesized and evaluated as ligands of the nociceptin receptor.
Abstract: Some spiro[piperidine-4,2′(1′H)-quinazolin]-4′(3′H)-ones 3 and spiro[piperidine-4,5′(6′H)-[1,2,4]triazolo[1,5-c]quinazolines] 4 were synthesized and evaluated as ligands of the nociceptin receptor. The examined compounds showed partial agonistic activity, except compounds 3, 4n that proved to be pure antagonists.
44 citations
TL;DR: In this paper, the condensation of benzaldehyde and different substituted benzaldehydes, such as 2-nitrobenzaldehyde, 3-nitrogen-benzinzaldehyde and 2,4-dichlorobenzaldehyde, with ethyl cyanoacetate was carried out using two alkaline carbons (Na-Norit and Cs-norit) as catalysts in the absence of solvent.
44 citations
TL;DR: Experimental observations indicated that the direct photocatalytic oxidation of HTMP followed by reaction with O2 is the dominant process in the formation of TEMPOL radicals.
Abstract: A sterically hindered cyclic amine, 4-hydroxy-2,2,6,6-tetramethylpiperidine (HTMP), is converted to the corresponding aminoxyl radical (nitroxide radical), 4-hydroxy-2,2,6,6-tetramethyl piperidine 1-oxyl (TEMPOL radical) as a result of a photocatalytic reaction in TiO2 aqueous suspension. The time profile of the radical formation and the effect of additives, such as SCN-, I-, methanol, and H2O2, on the initial formation rate were measured in order to elucidate the reaction mechanism. The experimental observations indicated that the direct photocatalytic oxidation of HTMP followed by reaction with O2 is the dominant process in the formation of TEMPOL radicals. Electrochemical measurements showed that HTMP is oxidized at 0.7 V (vs NHE), which is consistent with the proposed mechanism. The possibility of other processes, involving reactions with singlet molecular oxygen, superoxide radical, and hydroxyl radical, were excluded from the reaction mechanism.
43 citations
TL;DR: In this paper, the rate constants for reaction of 4-substituted 1-chloro-2,6-dinitrobenzenes and corresponding 1-phenoxy derivatives with n-butylamine, pyrrolidine and piperidine in acetonitrile as solvent were reported.
TL;DR: The synthesis of two enantiomerically pure iminosugars, analogues of 1-L-deoxynojirimycin (l-DNJ) and 1-D-deoxymannojirimYcin (DMJ) was achieved using cyclic sulfate substituted isoxazoline derivatives, resulting in six new nitrogen analogs of salacinol.
Abstract: The synthesis of two enantiomerically pure iminosugars, analogues of 1-L-deoxynojirimycin (l-DNJ) and 1-D-deoxymannojirimycin (DMJ), was achieved using cyclic sulfate substituted isoxazoline derivatives. The piperidine ring was formed via the reduction of an isoxazoline into an amine which underwent a spontaneous intramolecular cyclization by reaction with the cyclic sulfate moiety. The nucleophilic attack of these two trisubstituted piperidines and morpholine on L- and D-erythritol-1,3-cyclic sulfates gave six new nitrogen analogues of salacinol. The inhibitory properties of the synthesized salacinol analogues were evaluated on several commercial glycosidases.
Patent•
11 Dec 2006
TL;DR: In this paper, the ERK inhibitors of formula 1.0 and the pharmaceutically acceptable salts and solvates thereof are discussed and the methods of treating cancer using the compounds of formula1.0 are presented.
Abstract: Disclosed are the ERK inhibitors of formula 1.0 and the pharmaceutically acceptable salts and solvates thereof. Q is a piperidine or piperazine ring that can have a bridge or a fused ring. The piperidine ring can have a double bond in the ring. All other substitutents are as defined herein. Also disclosed are methods of treating cancer using the compounds of formula 1.0.
TL;DR: The asymmetric synthesis of the 2,3,6-trisubstituted piperidine core of the antitumor Nuphar alkaloids was readily achieved by using the intramolecular Mannich reaction and a sulfinimine-derived beta-amino ketone.
Abstract: The asymmetric synthesis of the 2,3,6-trisubstituted piperidine core of the antitumor Nuphar alkaloids was readily achieved by using the intramolecular Mannich reaction and a sulfinimine-derived beta-amino ketone.
TL;DR: It is shown that the use of 5% acetonitrile or propionitrile in dichloromethane functions to increase the beta-selectivity of a number of L-rhamnopyranosylation reactions conducted by the thioglycoside method with activation by the 1-benzenesulfinyl piperidine/trifluoromethanesulfonic anhydride couple.
TL;DR: The enhancement in diastereoselectivity results from the selective rearrangement of the minor stereoisomer through a cascade process involving radical cyclization to the piperidine radical, 1,5-radical translocation, and attack of the translocated radical onto the sulfonamide with extrusion of SO2 in a Smiles-type rearrangements.
Abstract: A novel approach to 2,4-disubstituted piperidines is reported, involving the radical cyclization of 7-substituted-6-aza-8-bromooct-2-enoates. Cyclization with tributyltin hydride affords the trans piperidines with trans/cis diastereomeric ratios ranging typically from 3:1 to 6:1. Cyclization with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99:1 in certain cases. The enhancement in diastereoselectivity results from the selective rearrangement of the minor stereoisomer through a cascade process involving radical cyclization to the piperidine radical, 1,5-radical translocation, and attack of the translocated radical onto the sulfonamide with extrusion of SO2 in a Smiles-type rearrangement. Slower trapping of the piperidine radical by tris(trimethylsilyl)silane compared to tributyltin hydride accounts for the occurrence of the rearrangement cascade in the former case.
Patent•
22 Nov 2006TL;DR: In this article, the authors describe substituted piperidine derivatives of formula (I) wherein R1, R2, R3, R4, R5, R6, R7 and X are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof.
Abstract: The invention is concerned with novel substituted piperidine derivatives of formula (I) wherein R1, R2, R3, R4, R5, R6, R7 and X are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds inhibit L- CPT1 and can be used as medicaments.
TL;DR: This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships about the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines.
Abstract: The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical mu-opioid antagonist in this series. In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high affinity toward the mu-opioid receptor. Compound 6 was found to be a mu-opioid antagonist, whereas the constrained analogue 9 displayed potent mu-agonist activity in vitro. This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships.
TL;DR: Mechanistic studies suggest that the cyclizations proceed via a mechanism with significant carbocationic character, with the cis carbocation being more stable than the trans carbocation, and the cis piperidine is also the favored product from cyclization through a more concerted mechanism.
Abstract: A novel approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 4a-e catalyzed by MeAlCl(2) in refluxing chloroform afforded the trans piperidines 7a-e with diastereomeric ratios of up to 93:7, while aldehyde 4f afforded solely the cis product 6f, which was resistant to isomerization to the trans isomer. It was demonstrated for 4a that the cyclization catalyzed by a variety of Lewis acids at low temperature proceeded under kinetic control to afford predominantly the cis piperidine 6a, and this isomerized to the thermodynamically more stable trans piperidine 7a on warming. In contrast, Prins cyclization of 4a-e catalyzed by concentrated hydrochloric acid in CH2Cl2 at low temperature afforded cis piperidines 6a-e with diastereomeric ratios of up to >98:2. The yield and diastereoselectivity of these cyclizations could be improved by using HCl-saturated CH2Cl2 to form the corresponding chloride, followed by elimination of HCl effected by ammonia. Aldehydes 4f and 4galso cyclized in good yield under the latter conditions. Mechanistic studies supported by DFT calculations (B3LYP/6-31G(d)) suggest that the cyclizations proceed via a mechanism with significant carbocationic character, with the cis carbocation being more stable than the trans carbocation. DFT calculations (B3LYP/6-31G(d)) of the transition state energies for concerted cyclization show that the cis piperidine is also the favored product from cyclization through a more concerted mechanism.
TL;DR: In this paper, the secondary amine SA (dimethylamine DMA, diethylamine DEA, pyrrolidine Pyr, piperidine Pip, morpholine Mor) to pentafluoropropene PFP gives rise to generation of mixtures of two products (1-dialkylamine-1, 3,3,3-3, 3-tetrafluorOPropene and N,N-dialkyl-1.
TL;DR: In this paper, the authors explored the scope and limitations of the system with respect to nucleophile, leaving group, and substituents within the substrate backbone, and explored the limitation of the Pyrrolidine and piperidine systems with memory of stereochemistry.
TL;DR: In this paper, ortho-lithiated tert-Bu N-aryl carbamates (i.e., BOC-protected anilines) with N-(trifluoroacetyl)piperidine were treated.
TL;DR: In this paper, a possible reaction mechanism for the formation of 3, 4 and 5 was presented, and the structures of new compounds were determined by spectral methods, microanalysis and X-ray diffraction analysis.
TL;DR: A series of novel substituted thiopyrano[2,3-b]quinolines 4a-e, 5a-, 6a-, and 6e were prepared from substituted 3-formyl-2-mercapto quinolines 2a-,e, on reaction with ethyl acetoacetate, diethyl malonate, and ethyl cyanoacetate 3a-c by microwave irradiation in the presence of piperidine.
Abstract: A series of novel substituted thiopyrano[2,3-b]quinolines 4a–e , 5a–e , and 6a–e were prepared from substituted 3-formyl-2-mercapto quinolines 2a–e , on reaction with ethyl acetoacetate, diethyl malonate, and ethyl cyanoacetate 3a–c by microwave irradiation in the presence of piperidine. Synthesized compounds were evaluated for antimicrobial activities. Among the compounds tested, 7-chloro-2-oxo-2H-thiopyrano[2,3-b]quinoline-3-carbonitrile 6d and 7-nitro-2-oxo-2H-thiopyrano[2,3-b]quinoline-3-carbonitrile 6e were highly active against S. aureus and M. roseus.
TL;DR: In this paper, the highly diastereoselective synthesis of five trifluoro-substituted analogues of mono-, di-, and trisubstitized piperidine alkaloids was accomplished in two to four steps from 2-trifluoromethyl keto-protected 4-piperidones, prepared by an intramolecular Mannich-type reaction methodology.
TL;DR: In this article, a one-pot reductive amination of aldehydes and ketones using N-methyl piperidine zinc borohydride as a new and stable reducing agent is described.
Abstract: A one-pot reductive amination of aldehydes and ketones using N-methyl piperidine zinc borohydride as a new and stable reducing agent is described. The reaction has been carried out in methanol at room temperature under neutral conditions.
TL;DR: A novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester 1 was prepared by the double asymmetric allylboration of glutaldehyde followed by an aminocyclization and carbamation.
Abstract: A novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester 1 was prepared by the double asymmetric allylboration of glutaldehyde followed by an aminocyclization and carbamation. On the basis of desymmetrization of 1 using iodocarbamation, one allyl group of 1 was protected and monofunctionalizations of the resulting oxazolidinone 11 were performed. The reaction of the N-methoxycarbonyl piperidine 25 employing decarbamation reagent (n-PrSLi or TMSI) as a key step gave oxazolidinone 26 or 17 including an intramolecular ring formation, which was transformed in a few steps into (−)-porantheridine (2) and (−)-2-epi-porantheridine (3), respectively. In addition, the expedient synthesis of (+)-epi-dihydropinidine (4), (2R,6R)-trans-solenopsin A (5), and precoccinelline (6), starting from 11 is described.
Patent•
16 Feb 2006
TL;DR: In this article, the authors described formulas of formula (I) and their pharmaceutically acceptable salts: formula(I), processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections.
Abstract: Compounds of formula (I) and their pharmaceutically acceptable salts are described: Formula (I). Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.
TL;DR: The combination of the pH-metric and NMR studies is used to examine the stabilities and coordination modes as well as related structural aspects of zinc(II), magnesium(II) and calcium( II) complexation to piperyd-1-yl-methane-1,1-diphosphonic acid and its derivatives containing a topologically modified piperidine ring.