- N-alkylpiperidine carbamates as potential anti-Alzheimer's agents
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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
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- Transition-Metal-Free Total Synthesis and Revision of the Absolute Configuration of Pipermethystine
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Starting from 3-hydroxy piperidines, a novel transition-metal-free strategy to 5-hydroxy-5,6-dihydro-2(1H)pyridones is reported. This unprecedented approach, which provides a practical, economical, and ecofriendly alternative to either the classical ring-closing metathesis of N-homoallyl-unsaturated amides or the dehydrogenation of amides, occurs by means of a triple C-H functionalization of three unreactive piperidine sp3 carbons. The completion of the total synthesis revealed that the natural levo-isomer possesses the R absolute configuration, not S.
- Quintero, Leticia,Rodr?guez-Molina, Braulio,Sartillo-Piscil, Fernando,Vázquez-Amaya, Laura Y.
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- A benidipine hydrochloride method for synthesizing intermediate
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The invention discloses a synthetic method for a benidipine hydrochloride intermediate. The synthetic method comprises performing a nucleophilic substitution reaction on 3-hydroxypyridine and a benzyl halide under a solvent refluxing condition, so as to generate 1-benzyl-3-hydroxypyridiniumhalide; taking an alcohol as a solvent and reducing 1-benzyl-3-hydroxypyridiniumhalide to generate 1-benzyl-3-piperidinol; then performing transesterification reaction on 1-benzyl-3-piperidinol and ethyl acetoacetate under a refluxing condition by taking toluene as a solvent in the presence/absence of a catalyst, and under the condition that less than 30% of the alcohol is left, performing normal-pressure distillation until the alcohol completely finishes reaction, so as to obtain the product. The synthetic method is simple and has the three-step total yield of 80% or more, and all employed materials are industrialized products and are cheap and easily obtained, and the quality is easily controlled.
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- Synthesis method of N-benzyl-3-hydroxypiperidine
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The invention discloses a synthesis method of N-benzyl-3-hydroxypiperidine, and belongs to the technical field of organic synthesis. In the absence of alkaline, and after 3-hydroxypiperidine is protected by halogenated benzyl, hexamethyldisilane is added to continue the reaction to obtain N-benzyl-3-trimethylsiloxidine, and then alcohols solvent or fluorine-containing ionicsalt is added for deprotection to obtain high-purity N-benzyl-3-hydroxypiperidine. According to the synthesis method of N-benzyl-3-hydroxypiperidine, the raw materials and reagents are cheap and easy to obtain, the reactioncondition is mild, continuous operation can be conducted, the product purity reaches up to 99.5% or above, and the method is suitable for enlarged production on a large scale.
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Paragraph 0026; 0029; 0032
(2018/03/26)
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- Stereo-complementary bioreduction of saturated N-heterocyclic ketones
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The asymmetric bioreduction of several saturated N-heterocyclic ketones is demonstrated in a stereo-complementary fashion using the ketoreductases READH and ChKRED20 for the production of (S)- and (R)-alcohols, respectively. The reaction accepts substrates with a five-, six- or seven-membered ring, and exhibits excellent stereoselectivity when using 2-propanol as both the ultimate reducing agent and cosolvent, achieve >99% ee in the majority of cases for both enantiomers.
- Li, Chao,Liu, Yan,Pei, Xiao-Qiong,Wu, Zhong-Liu
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- Efficient and chemoselective reduction of pyridines to tetrahydropyridines and piperidines via rhodium-catalyzed transfer hydrogenation
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Promoted by iodide anion the rhodium complex dimer, [Cp RhCl 2]2, catalyzes efficiently the transfer hydrogenation of various quaternary pyridinium salts under mild conditions, affording not only piperidines but also 1,2,3,6-tetrahydropyridines in a highly chemoselective fashion, depending on the substitution pattern at the pyridinium ring. The reduction is conducted in azeotropic formic acid/triethylamine (HCOOH-Et 3N) mixture at 40 °C, with catalyst loadings as low as 0.005mol% being feasible. Copyright
- Wu, Jianjun,Tang, Weijun,Pettman, Alan,Xiao, Jianliang
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- PYRIDINE-3-CARBOXYAMIDE DERIVATIVE
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To provide a novel JAK3 inhibitor that is useful as a preventive and/or therapeutic agent for rejection and graft versus host disease (GvHD) in organ transplantation, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Sj?gren syndrome, Behcet's disease, type I diabetes mellitus, autoimmune thyroiditis, idiopathic thrombocytopenic purpura, ulcerative colitis, Crohn's disease, asthma, allergic rhinitis, atopic dermatitis, contact dermatitis, urticaria, eczema, psoriasis, allergic conjunctivitis, uveitis, cancer, leukemia and the like. The pyridine-3-carboxyamide derivative represented by the general formula (1): or its salt or a solvate thereof.
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Page/Page column 112
(2011/10/12)
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- Enantioselective access to all-trans 5-alkylpiperidine-3,4-diols: Application to the asymmetric synthesis of the 1-n-iminosugar (+)-isofagomine
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Access to 3,4-disubstituted N-benzylprolinol derivatives is described that, after optimization of the ring-enlargement reaction conditions, could be efficiently transformed into the corresponding 3-hydroxypiperidines. This approach was applied to the asym
- Rives, Arnaud,Genisson, Yves,Faugeroux, Vanessa,Saffon, Nathalie,Baltas, Michel
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experimental part
p. 3251 - 3258
(2010/03/01)
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- QUINOLONE ANTIBACTERIAL AGENTS
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Compounds of formula (I, II, III, IV, V, and VI) and methods for their preparation are disclosed. Further disclosed are methods of making biologically active compounds of formula (I) as well as pharmaceutically acceptable compositions comprising compounds of formula (I). Compounds of formula (I) as disclosed herein can be used in a variety of applications including use as antibacterial agents.
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Page/Page column 98
(2010/02/11)
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- PENEM DERIVATIVES AND ANTIMICROBIAL AGENT CONTAINING THE SAME
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A penem derivative represented by the following formula (I): wherein R1represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkenylthio group, a substituted or unsubstituted aralkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic thio group, a substituted or unsubstituted acylthio group, a mercapto group or a hydrogen atom, and R2represents a hydrogen atom or a carboxyl-protecting group; or a pharmacologically acceptable salt thereof. The compound (I) exhibits strong antibacterial activities, and especially, shows strong activities against MRSA. It is therefore useful not only as a general antibacterial agent but also as an antibacterial agent for MRSA against which no general antibacterial agents are recognized to be effective.
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- Lipase-catalyzed practical synthesis of (R)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione and its related compounds
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A practical method for preparing (R)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione (1) was investigated by the use of the enzymatic hydrolysis of its acetate (2a). Among several hydrolases examined here, lipase PS from Pseudomonas cepacia gave the best result: In a mixed solvent (1:1 v/v) of dioxane and a phosphate buffer (pH 7), the hydrolysis took place smoothly with a high enantioselectivity (E > 3000). Several 3-alkanoyl derivatives of 1 were subjected to the lipase PS-catalyzed hydrolysis. The chain length of the alkanoyl does not noticeably influence the reaction rate or the enantioselectivity. In contrast, the hydrolysis of the 1-benzoyl derivative proceeded slowly with a low enantioselectivity (E = 19). The syntheses of optically active 3-hydroxypyrrolidines and 3-hydroxypiperidines were also achieved under the reaction conditions similar to the lipase PS-catalyzed hydrolysis of 2a.
- Tomori, Hiroshi,Shibutani, Kuniko,Ogura, Katsuyuki
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p. 207 - 215
(2007/10/03)
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- Novel 2-amino-1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive effects of 2-amino-1,4-dihydropyridine derivatives having N,N-dialkylaminoalkoxycarbonyl groups at 3- and/or 5-positions
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Novel 2-amino-1,4-dihydropyridine derivatives I, which contain N,N-dialkylaminoalkoxycarbonyl groups at the 3- and/or 5-position, were synthesized and their antihypertensive effects were evaluated in spontaneously hypertensive rats. Remarkably prolonged duration of antihypertensive action was observed when a tertiary amino group was introduced into either the 3- or 5-ester side-chain of the 1,4-dihydropyridine ring. In particular, the compounds containing cyclic amino moieties at the 3-position showed greater potency than those with acyclic amino moieties. Chemical modification studies indicated that the two ester side-chains of 1,4-dihydropyridine at the 3- and 5-position might function in a different manner in relation to the antihypertensive activities. 3-(1-Benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxyl ate, I-43 (CS-905), exhibited potent and long-lasting antihypertensive effects with gradual onset of action, and is a promising candidate as an antihypertensive drug.
- Kobayashi,Inoue,Nishino,Fujihara,Oizumi,Kimura
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p. 797 - 817
(2007/10/02)
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- Novel 2-amino-1,4-dihydropyridine calcium antagonists. I. Synthesis and antihypertensive effects of 2-amino-1,4-dihydropyridine derivatives having nitroxyalkoxycarbonyl groups at 3- and/or 5-position
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Novel 2-amino-1,4-dihydropyridine derivatives, which contain nitroxy-alkoxycarbonyl groups at the 3- and/or 5-position, were synthesized and their pharmaceutical effect was evaluated in spontaneously hypertensive rats. The structure-activity relationships are discussed in terms of potency, onset-rapidity, and duration of antihypertensive activity. Remarkably prolonged duration of antihypertensive action was observed when a tertiary amino group was introduced on either side of an ester chain.
- Kobayashi,Inoue,Kita,Yoshiya,Nishino,Oizumi,Kimura
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p. 788 - 796
(2007/10/02)
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- Piperidine derivatives
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The invention provides piperidine derivatives of the general formula STR1 or an acid-addition salt or metal salt complex thereof, in which R represents a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, arylcarbonyl, heterocyclyl or heterocyclyloxy group; R1 represents an optionally substituted alkyl, phenyl, benzyl or cycloalkyl group; R2 represents a hydrogen atom or an optionally substituted alkyl group; one of W and X represents --CH2 --, --CH2 CH2 -- or --O--, the other of W and X being --CH2 -- or --CH2 CH2 or X represents a single chemical bond; m is 0 or 1 and n represents an integer from 0 to 3; processes for their preparation; compositions containing such compounds and their use as fungicides.
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- 1,4-Dihydropyridine derivatives
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Compounds having coronary and vasodilator effects, a hypotensive effect, and useful as antianginal drugs and drugs for treating hypertension are represented by the following general formula: STR1 wherein R1 and R2 are the same or different groups and each represents a lower alkyl group, one of R3 and R4 represents a lower alkyl group and the other represents a group of the general formula: STR2 wherein R5 represents an aralkyl group or an acyl group and n represents 0 or an integer of 1-3; the pharmaceutically acceptable acid addition salts thereof are also effective therapeutic compounds.
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