- In situ silane activation enables catalytic reduction of carboxylic acids
-
We describe a catalytic system for the conversion of carboxylic acids into alcohols using substoichiometric zinc acetate and N-methyl morpholine, in combination with phenylsilane as the nominal terminal reductant. Reaction monitoring by19F NMR spectroscopy demonstrates that the reaction proceeds by mutual activation of the carboxylic acid and silane through the in situ generation of silyl ester intermediates.
- Barber, Thomas,Denton, Ross M.,Hirst, David J.,Stoll, Emma L.
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supporting information
p. 3509 - 3512
(2022/03/31)
-
- First synthesis of racemic trans propargylamino-donepezil, a pleiotrope agent able to both inhibit AChE and MAO-B, with potential interest against Alzheimer’s disease
-
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 μM) and (h)MAO-B (IC50 = 6.4 μM).
- Guieu, Benjamin,Lecoutey, Cedric,Legay, Rémi,Davis, Audrey,De Oliveira Santos, Jana Sopkova,Altomare, Cosimo Damiano,Catto, Marco,Rochais, Christophe,Dallemagne, Patrick
-
-
- Cobalt-Catalyzed Remote Hydroboration of Alkenyl Amines
-
We here present a generally applicable cobalt-catalyzed remote hydroboration of alkenyl amines, providing a practical strategy for the preparation of borylamines and aminoalcohols. This method shows broad substrate scope and good functional group tolerance, tolerating a series of alkenyl amines, including alkyl-alkyl amines, alkyl-aryl amines, aryl-aryl amines, and amides. Of note, this protocol is also compatible with a variety of natural products and drug derivatives. Preliminary mechanistic studies suggest that this transformation involves an iterative chain walking and hydroboration sequence.
- Lei, Yaqin,Huang, Jiaxin,Zhao, Wanxiang
-
p. 7797 - 7802
(2021/10/20)
-
- Synthesis and Bio-Evaluation of N-Benzylpiperidine-8-Hydroxyquinoline Derivatives as Potential Cholinesterase Inhibitors, Metal Ion Chelators and Calcium Channel Blockers
-
Abstract: A new series of N-benzylpiperidine 8-hydroxyquinoline derivatives were synthesized and evaluated as cholinesterase inhibitors, metal ion chelators and calcium channel blockers. It was found that the ethyl cholinesterase inhibition activity could be improved when the linker between N-benzylpiperidine and 8?hydroxyquinoline groups were extended. Among all derivatives, compound (XIIId) showed best acetyl cholinesterase inhibition activity with an IC50 value of 0.24 ± 0.03 μM. It also showed metal ion chelating activity with a metal-compound ratio of 1 : 2 on copper or zinc ions. The calcium channel blocking property of select compounds were tested and compared by patching clamp on HEK293 cell expressing Cav1.2 calcium channel. Among tested compounds, cholinesterase inhibitor 8c showed mild calcium channel blockade activity with the inhibition ratio of calcium channel of 24.56 ± 2.44% (10 μM). This result suggested that the potential neuroprotective ability of this cholinesterase inhibitor might be partially related to the calcium channel blocking property.
- Xiu, Fan,Xu, Siqi,Zhang, Chun,Wang, Li
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p. 524 - 534
(2021/05/03)
-
- Synthesis method of N-benzyl-4-piperidine formaldehyde
-
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of N-benzyl-4-piperidine formaldehyde. According to the invention, 4-piperidinecarboxylic acid is used as a raw material; an esterification reaction is carried out to generate 4-methyl piperidinecarboxylate hydrochloride; an alkylation reaction is carried out on N-benzyl-4-methyl piperidinecarboxylate hydrochloride to generate N-benzyl-4-methyl piperidinecarboxylate; n-benzyl-4-methyl piperidinecarboxylate is hydrolyzed to obtain N-benzyl-4-piperidinecarboxylic acid, N-benzyl-4-piperidinecarboxylic acid is subjected to an acylation reaction to generate N-benzyl-4-piperidinecarboxamide, N-benzyl-4-piperidinecarboxamide is dehydrated to obtain 1-benzylpiperidine-4-nitrile, and 1-benzylpiperidine-4-nitrile is subjected to a reduction reaction to generate N-benzyl-4-piperidineformaldehyde. The method is mild in reaction condition, simple in aftertreatment and high in yield, N-benzyl-4-piperidinecarboxaldehyde can be obtained at the high yield at the temperature of 0 DEG C, column chromatography is not needed, and repeatability is high.
- -
-
-
- Functional Group Interconversion of Alkylidenemalononitriles to Primary Alcohols by a Cooperative Redox Operation
-
Functional group interconversions are essential chemical processes enabling synthesis. In this report, we describe a strategy to convert alkylidenemalononitriles into primary alcohols in one step. The reaction relies on a choreographed redox process invol
- Emmetiere, Fabien,Grenning, Alexander J.
-
p. 3077 - 3085
(2020/08/10)
-
- N-alkylpiperidine carbamates as potential anti-Alzheimer's agents
-
Compounds capable of interacting with single or multiple targets involved in Alzheimer's disease (AD) pathogenesis are potential anti-Alzheimer's agents. In our aim to develop new anti-Alzheimer's agents, a series of 36 new N-alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoamine oxidases [monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B)]. Four compounds are very promising: multiple AChE (IC50 = 7.31 μM), BChE (IC50 = 0.56 μM) and MAO-B (IC50 = 26.1 μM) inhibitor 10, dual AChE (IC50 = 2.25 μM) and BChE (IC50 = 0.81 μM) inhibitor 22, selective BChE (IC50 = 0.06 μM) inhibitor 13, and selective MAO-B (IC50 = 0.18 μM) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10, 13, and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N-propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N-benzylpiperidine 10 is reversible. Additionally, compounds 10, 13, 16, and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid β1–42 (Aβ1–42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Aβ1–42 anti-aggregation effects.
- Brazzolotto, Xavier,Gobec, Stanislav,Knez, Damijan,Kos, Janko,Nachon, Florian,?akelj, Simon,Juki?, Marko,Ko?ak, Urban,Pi?lar, Anja,Stra?ek, Nika,Zahirovi?, Abida
-
supporting information
(2020/05/06)
-
- Industrially scalable synthesis of anti-alzheimer drug donepezil
-
This paper describes a simple, efficient and industrially scalable total synthesis of donepezil hydrochloride. The article also reported the X-ray studies of the 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one, an intermediate in the synthesis of donepezil. The crystal structure analysis of 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one shows that it crystallizes in monoclinic class under the space group P121/c1 with cell parameters, a = 17.2992(7) ?, b = 10.1999(4) ?, c = 11.9539(5) ?, β = 103.450(2)°, V = 2051.42(15) ?3 and Z = 4.
- Gaonkar, Santosh L.,Nadaf,Bilehal, Dinesh,Shetty, Nitinkumar S.
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p. 1999 - 2004
(2017/07/27)
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- Compounding method for N-ethyl carbazole
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The invention provides a compounding method for N-ethyl carbazole and relates to N-ethyl carbazole. The method comprises the following steps: performing salt-forming reaction on carbazole and proton-removing agent in an N-methyl pyrrolidone solvent, thereby generating carbazole salt; continuing introducing acetylene and reacting, thereby acquiring N-vinyl carbazole; adding a Pd catalyst into the organic solvent of the generated N-vinyl carbazole and performing hydrogenation reaction in the additives, thereby acquiring N-ethyl carbazole. A series of special catalysts are optimized, a catalytic hydrogenation technology is adopted for effectively realizing the green synthesis of N-ethyl carbazole and three-waste emission is reduced. In a hydrogenation process, the catalyst is reusable and the cost is lowered. The quality of the N-ethyl carbazole product prepared according to the hydrogenation process is higher. The traditional alkylate reagent (diethyl sulfate, ethyl carbonate, halothane, and the like) or the toxic organic solvent is not required, no waste liquid is emitted and the compounding method is a green and clean production technology.
- -
-
Paragraph 0023-0035
(2018/03/24)
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- Novel method for preparing donepezil
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The present invention relates to a method for preparing Donepezil, comprising the steps of: (a) making 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carbonitrile represented by chemical formula 3 react with a benzylpiperidine compound represented by chemical formula 4 to provide 2-((1-benzylpiperidine-4-yl)methyl)-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carbonitrile represented by chemical formula 2; and (b) subjecting 2-((1-benzylpiperidine-4-yl)methyl)-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carbonitrile represented by chemical formula 2 to decyanation reaction, thereby providing Donepezil represented by chemical formula 1.COPYRIGHT KIPO 2017
- -
-
Paragraph 0084-0086
(2017/06/19)
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- Isolation and Characterization of Regioisomers of Pyrazole-Based Palladacycles and Their Use in α-Alkylation of Ketones Using Alcohols
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Regioisomers of 3,5-diphenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-based palladacycles (1 and 2) were synthesized by the aromatic C-H bond activation of N/3-aryl ring. The application of these regioisomers as catalysts to enable the formation of α-alkylated ketones or quinolines with alcohols using a hydrogen borrowing process is evaluated. Experimental results reveal that palladacycle 2 is superior over palladacycle 1 to catalyze the reaction under similar reaction conditions. The reaction mechanisms for the palladacycles 1 and 2 catalyzed α-alkylation of acetophenone were studied using density functional theoretical (DFT) methods. The DFT studies indicate that palladacycle 2 has an energy barrier lower than that of palladacycle 1 for the alkylation reaction, consistent with the better catalytic activity of palladacycle 2 seen in the experiments. The palladacycle-phosphine system was found to tolerate a wide range of functional groups and serves as an efficient protocol for the synthesis of α-alkylated products under solvent-free conditions. In addition, the synthetic protocol was successfully applied to prepare donepezil, a drug for Alzheimer's disease, from simple starting materials.
- Mamidala, Ramesh,Samser, Shaikh,Sharma, Nishant,Lourderaj, Upakarasamy,Venkatasubbaiah, Krishnan
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supporting information
p. 3343 - 3351
(2017/09/18)
-
- NOVEL COMPOUNDS AS GPR119 AGONISTS
-
The present invention relates to novel compounds of formula (I) as GPR119 agonist, composition compositions containing such compounds and method of preparation thereof.
- -
-
Paragraph 0277-0279
(2017/10/26)
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- Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease
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A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In?vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity f
- Dias, Kris Simone T.,de Paula, Cynthia T.,dos Santos, Thiago,Souza, Isis N.O.,Boni, Marina S.,Guimar?es, Marcos J.R.,da Silva, Fernanda M.R.,Castro, Newton G.,Neves, Gilda A.,Veloso, Clarice C.,Coelho, Márcio M.,de Melo, Ivo Souza F.,Giusti, Fabiana C.V.,Giusti-Paiva, Alexandre,da Silva, Marcelo L.,Dardenne, Laurent E.,Guedes, Isabella A.,Pruccoli, Letizia,Morroni, Fabiana,Tarozzi, Andrea,Viegas, Claudio
-
p. 440 - 457
(2017/03/11)
-
- Preparation method of 1-benzyl-4-piperidine formaldehyde
-
The invention discloses a preparation method of 1-benzyl-4-piperidine formaldehyde. The preparation method comprises the following steps of carrying out a partial reduction reaction on 1-benzyl-4-piperidine methyl formate or 1-benzyl-4-piperidine ethyl formate and a vitride complex in a solvent; then collecting the 1-benzyl-4-piperidine formaldehyde from a reaction product. According to the preparation method of the 1-benzyl-4-piperidine formaldehyde, disclosed by the invention, 1-benzyl-4-piperidine formic acid esters are used as raw materials, the vitride complex is used as a reducing agent, the raw materials are easy to prepare, the operation is simple and convenient, the yield is high, the product purity is good, and the preparation method is suitable for industrial production.
- -
-
Paragraph 0074; 0075
(2016/10/08)
-
- Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase
-
The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.
- McHardy, Stanton F.,Bohmann, Jonathan A.,Corbett, Michael R.,Campos, Bismarck,Tidwell, Michael W.,Thompson, Paul Marty,Bemben, Chris J.,Menchaca, Tony A.,Reeves, Tony E.,Cantrell Jr., William R.,Bauta, William E.,Lopez, Ambrosio,Maxwell, Donald M.,Brecht, Karen M.,Sweeney, Richard E.,McDonough, John
-
supporting information
p. 1711 - 1714
(2014/04/17)
-
- Part I: The development of the catalytic wittig reaction
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We have developed the first catalytic (in phosphane) Wittig reaction (CWR). The utilization of an organosilane was pivotal for success as it allowed for the chemoselective reduction of a phosphane oxide. Protocol optimization evaluated the phosphane oxide precatalyst structure, loading, organosilane, temperature, solvent, and base. These studies demonstrated that to maintain viable catalytic performance it was necessary to employ cyclic phosphane oxide precatalysts of type 1. Initial substrate studies utilized sodium carbonate as a base, and further experimentation identified N,N-diisopropylethylamine (DIPEA) as a soluble alternative. The use of DIPEA improved the ease of use, broadened the substrate scope, and decreased the precatalyst loading. The optimized protocols were compatible with alkyl, aryl, and heterocyclic (furyl, indolyl, pyridyl, pyrrolyl, and thienyl) aldehydes to produce both di- and trisubstituted olefins in moderate-to-high yields (60-96 %) by using a precatalyst loading of 4-10 mol %. Kinetic E/Z selectivity was generally 66:34; complete E selectivity for disubstituted α,β-unsaturated products was achieved through a phosphane-mediated isomerization event. The CWR was applied to the synthesis of 54, a known precursor to the anti-Alzheimer drug donepezil hydrochloride, on a multigram scale (12.2 g, 74 % yield). In addition, to our knowledge, the described CWR is the only transition-/heavy-metal-free catalytic olefination process, excluding proton-catalyzed elimination reactions. A point of difference: By utilizing an organosilane to chemoselectively reduce a phosphane oxide precatalyst to a phosphane (see scheme), the first catalytic (in phosphane) Wittig reaction has been developed. The methodology has been applied to the synthesis of 22 disubstituted and 24 trisubstituted olefins, including a multigram synthesis of a precursor to the anti-Alzheimer drug donepezil hydrochloride.
- O'Brien, Christopher J.,Nixon, Zachary S.,Holohan, Andrew J.,Kunkel, Stephen R.,Tellez, Jennifer L.,Doonan, Bryan J.,Coyle, Emma E.,Lavigne, Florie,Kang, Lauren J.,Przeworski, Katherine C.
-
supporting information
p. 15281 - 15289
(2013/11/06)
-
- Polymeric bimetallic catalyst-promoted in-water dehydrative alkylation of ammonia and amines with alcohols
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A dehydrative alkylation with three kinds of Ir/B heterobimetallic polymeric catalysts in water is reported. The polymeric heterobimetallic catalysts were readily prepared by ionic convolution of a poly(catechol borate) and iridium complexes. The N-alkylation of ammonia and amines with alcohols, as alkylating agents, was carried out with a heterogeneous catalyst (1 mol% Ir) at 100 °C without the use of organic solvents under aerobic and aqueous conditions to afford the corresponding alkylated amines in high yield. Georg Thieme Verlag Stuttgart New York.
- Yamada, Yoichim. A.,Ohta, Hidetoshi,Yuyama, Yoshinari,Uozumi, Yasuhiro
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p. 2093 - 2100
(2013/08/23)
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- In-water dehydrative alkylation of ammonia and amines with alcohols by a polymeric bimetallic catalyst
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An in-water dehydrative alkylation with a novel heterobimetallic polymeric catalyst is described. Thus, a boron-iridium heterobimetallic polymeric catalyst was prepared by ionic convolution of a poly(catechol borate) and an iridium complex. The alkylation of ammonia and amines with alcohols, alkylating agents, was performed with 1 mol % Ir of the heterogeneous catalyst in water without the use of organic solvents under aerobic conditions to give the corresponding alkylated amines.
- Ohta, Hidetoshi,Yuyama, Yoshinari,Uozumi, Yasuhiro,Yamada, Yoichi M. A.
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supporting information; scheme or table
p. 3892 - 3895
(2011/10/09)
-
- COMPOUND WITH SEROTONINERGIC ACTIVITY, PROCESS FOR PREPARING IT AND PHARMACEUTICAL COMPOSITION COMPRISING IT
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Compound of formula (I) in which R1, R2 and R3 are defined in the following description, and the pharmaceutically acceptable acid-addition or base-addition salts thereof. The invention also relates to a process and an intermediate for preparing it, and to a pharmaceutical composition comprising it. The invention also relates to the use of a novel 2H-pyrrolo[3,4-c]quinoline compound for preparing a pharmaceutical composition that is active in the treatment of disturbances of the serotoninergic system.
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Page/Page column 28-29
(2010/04/03)
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- Enantioselective synthesis of a chiral fluoropiperidine via asymmetric hydrogenation of a vinyl fluoride
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Asymmetric hydrogenation of a vinyl fluoride derivative gives efficient access to enantioenriched 1,3,4-trisubstituted piperidine 1 with a stereogenic alkyl fluoride center. Extensive catalyst screening across transition metals and chiral ligands identifi
- Krska, Shane W.,Mitten, Jeffrey V.,Dormer, Peter G.,Mowrey, Dale,Machrouhi, Fouzia,Sun, Yongkui,Nelson, Todd D.
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scheme or table
p. 8987 - 8994
(2009/12/22)
-
- Compounds IV
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The present application relates to new compounds of formula (I), to pharmaceutical compositions comprising the compounds, to processes for their preparation, and to the use of the compounds as leptin receptor modulator mimetics in the preparation of medic
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Page/Page column 8
(2009/08/18)
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- An improved and efficient process for the production of donepezil hydrochloride: Substitution of sodium hydroxide for n-butyl lithium via phase transfer catalysis
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A simple, efficient and highly economic process for the production of donepezil hydrochloride (1), an anti-Alzheimer drug is reported. The process relies upon improved and large-scale synthesis of a key intermediate: 1-benzylpiperidine-4-carboxaldehyde (2), and the introduction of operationally simple chemistry at the penultimate stage wherein 2 is reacted with 5,6-dimethoxy indanone (3) in the presence of sodium hydroxide and a phase transfer catalyst (PTC) in a biphasic solvent to furnish the intermediate 4, which is reduced and directly treated with hydrochloric acid to furnish highly pure donepezil hydrochloride with desired polymorphic form. The improved process provides donepezil hydrochloride at considerably lower cost and allows the omission of hazardous chemicals.
- Niphade, Navanath,Mali, Anil,Jagtap, Kunal,Ojha, Ramesh Chandra,Vankawala, Pravinchandra J.,Mathad, Vijayavitthal T.
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p. 731 - 735
(2013/01/03)
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- Development of two diastereoselective routes towards trans-4-aminomethyl-piperidin-3-ol building blocks
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Two diastereoselective, scaleable routes towards trans-3,4-disubstituted piperidines with a 4-hydroxymethyl-3-hydroxy or 4-aminomethyl-3-hydroxy substitution pattern are being described. In the first route, the 3,4-trans configuration was introduced regio- and diastereoselectively via a hydroboration/oxidation sequence starting from 4-hydroxymethylpyridine. In the second route, regioselective epoxide ring opening of N-benzyl-3,4-epoxy-piperidine was achieved with LiCN, in situ generated from acetocyanohydrin and LiNH2. The regioselectivity of both the hydroboration and the epoxide ring opening was positively influenced by the presence of the basic piperidine nitrogen. Both routes have been optimized to be performed at large scale.
- Gijsen, Harrie J.M.,De Cleyn, Michel J.A.,Love, Christopher J.,Surkyn, Michel,Van Brandt, Sven F.A.,Verdonck, Marc G.C.,Moens, Luc,Cuypers, Jef,Bosmans, Jean-Paul R.M.A.
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p. 2456 - 2464
(2008/09/18)
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- 5-HTX MODULATORS
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This invention relates to compounds which bind to serotonin receptors inside or outside the central nervous system, in particular compounds which bind to the 5-HT2 or 5-HT7 receptors, their preparation and use, compositions containing them, and methods of treatment using them.
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Page/Page column 33-34
(2008/06/13)
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- A practical and efficient procedure for reduction of carboxylic acids and their derivatives: use of KBH4-MgCl2
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The use of KBH4-MgCl2 to reduce carboxylic acids and their derivatives to the corresponding alcohols or the respective reduced products is described. Methyl (S)-3,4-O-isopropylidene-3,4-dihydroxy butanoate 2 used as a reference substrate was reduced with KBH4 and MgCl2 in 1:1 mol ratio to (S)-1,2-O-isopropylidene-1,2,4-butanetriol 1.
- Qiu, You-Chun,Zhang, Fu-Li,Zhang, Chun-Nian
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p. 7595 - 7598
(2008/03/14)
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- MODULATORS OF PERIPHERAL 5-HT RECEPTORS
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Novel modulators of 5-HT4 receptors have been developed which have a selectivity for peripheral receptors rather than those of the central nervous systems. Theses include novel derivatives of known modulators as well as entirely novel entities. Surprisingly, the derivatised compounds of the known modulators maintain a high binding affinity to 5-HT4 receptors, despite the presence of an acidic moiety at the end of an optional chain. The entirely novel entities also exhibit good binding affinity to 5-HT4 receptors. All of the compounds of the invention have a common motif which includes a basic nitrogen moiety and an acidic moiety. The compounds of the invention, due at least in part to their high ionisation potential at physiological pH, have the unique properties of selectively for peripheral 5HT4 receptors over those of the CNS, good binding affinity, and selectively of 5HT4 receptors over other serotonin receptors.
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Page/Page column 38
(2010/02/12)
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- (4-PIPERIDINYL)-1H-2-BENZOPYRAN DERIVATIVES USEFUL AS ANTIPSYCHOTIC AGENTS
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The present invention comprises (4-Piperidinyl)-1H-2-Benzopyran derivatives useful as antipsychotic agents, their intermediates, pharmaceutical compositions and methods of making these compounds. These compounds are useful in treating psychosis.
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- 1-Benzyl-4-chloromethylpiperidine: A building block in the synthesis of compounds of pharmacological interest
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The first synthesis of 1-benzyl-4-(chloromethyl)piperidine (1) is described, together with its application in the synthesis of potential pharmaceuticals. Reaction of 1 with several purines in basic medium proceed through the initial formation of 1-benzyl-1-azoniabicyclo[2.2.1]heptane system, which then undergoes nucleophilic attack at two different carbons, yielding N-benzylpiperidine and N-benzylpyrrolidine derivatives.
- Rodríguez-Franco, María Isabel,Fernández-Bachiller, María Isabel
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p. 911 - 915
(2007/10/03)
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- Large scale synthesis of N-benzyl-4-formylpiperidine through partial reduction of esters using aluminum hydride reagents modified with pyrrolidine
-
The modification of sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) with pyrrolidine provided a highly selective reducing agent to transform N-benzyl-4-ethoxycarbonylpiperidine into N-benzyl-4-formylpiperidine 1 under mild conditions. However, this simple modification led to a significant amount of N-benzyl-4-(pyrrolidin-1-ylmethyl)piperidine 4 due to overreduction of an intermediate. Our extensive research revealed that an alkaline base such as potassium tert-butoxide could suppress the formation of the by-product to give the desired aldehyde, enabling us to establish a viable synthetic process for a key intermediate of donepezil hydrochloride. The potential applications of this reagent are also described.
- Abe,Haga,Negi,Morita,Takayanagi,Hamamura
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p. 2701 - 2710
(2007/10/03)
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- Synthesis and preliminary pharmacological results on new naphthalene derivatives as 5-HT4 receptor ligands
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The indole derivative GR 113808 is currently used as the reference ligand for labelling the 5-HT4 serotoninergic receptors. Previous works in our laboratories established the bioisosteric equivalency of the indole heterocycle and naphthalene in a series of melatonin receptor ligands. Based on this knowledge we designed new analogues of GR 113808 by introducing two bioisosteric modifications: firstly, the indole ring was replaced by a naphthalene one and secondly, the ester linkage was replaced by an amide group. Compound 8 emerged within this novel series as it displayed high and selective affinity at 5-HT4 receptors (Ki 5-HT4 = 6 nM, Ki 5-HT3 = 100 nM, Ki values at other 5-HT receptors were higher than 1 000 nM). Compound 8 is currently undergoing further pharmacological evaluation. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Diouf, Ousmane,Depreux, Patrick,Chavatte, Philippe,Poupaert, Jacques Henri
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p. 699 - 706
(2007/10/03)
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- (4-PIPERIDINYL)-1H-2-BENZOPYRAN DERIVATIVES USEFUL AS ANTIPSYCHOTIC AGENTS
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The present invention comprises (4-Piperidinyl)-1H-2-Benzopyran derivatives useful as antipsychotic agents, their intermediates, pharmaceutical compositions and methods of making these compounds. These compounds are useful in treating psychosis.
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- Exploring the structure-activity relationships of [1-(4-(4- tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), a high-affinity and selective δ-opioid receptor nonpeptide agonist ligand
-
SL-3111 [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4- benzylpiperazine] is a de novo designed, high-affinity and selective nonpeptide peptidomimetic agonist of the δ-opioid receptor. In a previous report we had described the unique biological characteristics of this ligand and also a need for further structural evaluation. To pursue this, we have introduced a completely different heterocyclic template (2 and 3), which, based on molecular modeling studies, may present the required structural features to properly orient the pharmacophore groups. We also have made more subtle changes to the original piperazine scaffold (5 and 11). The biological activities of these compounds revealed an important participation of the scaffold in the ligand-receptor interaction. To further explore functional diversity on the scaffold, we have maintained the original piperazine ring and introduced four different functionalities at position 2 of the heterocyclic ring (15a-d; a = CH2-O-CH2-Ph; b = Me; c = CH2Ph; d = CH2OH). The biological activities observed for these compounds showed a very interesting trend in terms of the steric effects of the groups introduced at this position. A decrease of almost 2000-fold in affinity and potency at the δ- receptor was observed for 15c compared with 15b. This difference may be explained if we postulate that the bioactive conformation of these peptidomimetics is close to the minimal energy conformations calculated in our study. On the basis of these findings we have realized the importance of this position to further explore and simplify the structure of future generations of peptidomimetic ligands.
- Alfaro-Lopez, Josue,Okayama, Toru,Hosohata, Keiko,Davis, Peg,Porreca, Frank,Yamamura, Henry I.,Hruby, Victor J.
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p. 5359 - 5368
(2007/10/03)
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- CONDENSED INDOLE DERIVATIVES AS 5HT4-RECEPTOR ANTAGONISTS
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Compounds of formula (I) and pharmaceutically acceptable salts thereof: STR1 and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
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- Benzyl-piperidine derivatives
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Benzly-piperidine derivatives of formula I and their pharmaceutically acceptable salts are used in the control of psychotic disorders which are caused by damage to the dopamine system, especially schizophrenia. STR1 A is STR2 B is STR3 R 1, R 2 and R 3 are independently hydrogen, amino, nitro, halogen, lower-alkly or lower-alkoxy. R 4, R 5 and R 6 are independently hydrogen, nitro, halogen, lower-alkyl, lower-alkoxy, cyano, trifluoromethyl, amino, lower-alkylamino or di-lower-alkylamino. R 7, R 2 and R 9 are independently hydrogen, amino or nitro.
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- Condensed indole derivatives as 5HT4 -receptor antagonists
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Compounds of formula (I) and pharmaceutically acceptable salts thereof: STR1 and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.
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- Structure-activity relationship studies of novel 4-[2-[bis(4- fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine analogs: Synthesis and biological evaluation at the dopamine and serotonin transporter sites
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Several analogs of the potent dopamine (DA) transporter ligand 4-[2- [bis(4-fluorophenyl)-methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, were made and biologically evaluated for their binding at the DA and serotonin (5HT) transporters in rat striatal membranes. Different alkyl chain lengths and substitutions were introduced in these molecules to generate an optimum activity and selectivity for the DA transporter. In general, unsubstituted and fluoro-substituted compounds were the most active and selective for the DA transporter. The compound 4-[2(diphenylmethoxy)ethyl]-1-benzylpiperidine, 9a, showed high potency and was the most selective for the DA transporter (5HT/DA = 49) in this series of compounds. Some of these novel analogs were found to be more selective in binding at the DA transporter than the original GBR 12909 molecule, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperidine.
- Dutta,Xu,Reith
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p. 749 - 756
(2007/10/03)
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- ETHER DERIVATIVES OF ALKYL PIPERIDINES AND PYRROLIDINES AS ANTIPSYCHOTIC AGAENTS
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Novel unsaturated ether derivatives of alkyl piperidine and pyrrolidine compounds, pharmaceutical compositions containing them, methods of preparation and methods of using these compounds as antipsychotic agents are disclosed.
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- Novel piperidine σ receptor ligands as potential antipsychotic drugs
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σ receptor ligands represent a new class of potential antipsychotic drugs. This paper presents the structure-activity relationships leading to novel disubstituted piperidine σ ligands, which have little or no affinity for dopamine D2 receptors. Selectivity for σ sites over dopamine D2 or serotonin 5-HT2 receptors appears to be governed by the chemical nature of the piperidine nitrogen substituent, its distance from the basic nitrogen, and its orientation relative to the other piperidine substituent. Several of these compounds have good oral potency in some animal models used to evaluate potential antipsychotic drugs. The N-cyclopropylmethyl ketones and ethers (e.g. 6i (DuP 734), 6q, 18a, and 18n) have the best in vivo potency. Compounds 6i (DuP 734) and 6q did not cause catalepsy in the rat, even at very high doses. On the basis of the pharmacology profiles of these σ ligands, we propose these compounds may be effective antipsychotic drugs, which do not induce extrapyramidal side effects or tardive dyskinesia.
- Gilligan,Cain,Christos,Cook,Drummond,Johnson,Kergaye,McElroy,Rohrbach,Schmidt,Tam
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p. 4344 - 4361
(2007/10/02)
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