- Synthesis, characterization and investigation of AChE and BuChE inhibitory activity of 1-alkyl-4-[(5,6-dimethoxy-1-indanone-2-yl)methylene]pyridinium halide derivatives
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Abstract: The design, synthesis and characterization of a series of 1-alkyl-4-[(5,6-dimethoxy-1-indanone-2-yl)methylene]pyridinium halide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors for the treatment of Alzheimer’s disease were reported. The strategy for this synthesis was based on aldol condensation reaction between 4-pyridinecarboxaldehyde with 5,6-dimethoxy-1-indanone in the presence of NaOH in EtOH-H2O solution as the first step and N-alkylation reaction of the produced 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone with various alkyl halides (R–X) in the second step. This reaction was carried out under reflux temperature in polar aprotic solvents such as acetone or acetonitrile. 1H and 13C NMR and FTIR spectroscopy along with CHN analysis were used to confirm the structure of our synthesized compounds. Biological activities including acetylcholinesterase and butyrylcholinesterase (BuChE) inhibitions for synthesized compounds were tested using the Ellman method. The results were compared with donepezil and galantamine, and among the synthesized compounds, the highest inhibitory activity with BuChE IC50 = 0.55?μM was observed. Graphic abstract: [Figure not available: see fulltext.]
- Farrokhi, Hanieh,Mozaffarnia, Sakineh,Rahimpour, Keshvar,Rashidi, Mohammad Reza,Teimuri-Mofrad, Reza
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- Synthesis method of donepezil hydrochloride
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The invention belongs to the technical field of medicine, and discloses a synthesis method of donepezil hydrochloride. 5,6-dimethoxyl-1-indanone and 4-pyridyl aldehyde are taken as the primary raw materials, a mixed catalyst is adopted to produce an intermediate (I), a hydrogen source is used to replace hydrogen gas to carry out catalytic transfer hydrogenation reactions, and the reaction productreacts with benzyl chloride to obtain donepezil hydrochloride. The adopted catalyst can be completely removed through filtering, the post treatment is simple, the reaction conditions are mild, moreover, the selectivity problem of hydrogen reduction in the prior art is solved, the yield and purity are high, and the synthesis method is suitable for industrial production.
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Paragraph 0037-0042; 0055-0062
(2019/05/15)
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- Synthesis and anticonvulsant activity of 3a,4-dihydro-3Hindeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues
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A series of fourteen 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues were synthesized and evaluated for anticonvulsant activity according to the Antiepileptic Drug Development Programme (ADD) protocol. Some of the synthesized compounds showed significant activity in minimal clonic seizure model (6 Hz psychomotor seizure test). 3-(4-Fluorophenyl)-N-(4-bromophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c] pyrazole-2-carboxamide (4c) was found to be the most active compound of the series showing 75% (3/4, 0.25-2.0 h) and 50% (2/4, 4.0 h) protection against minimal clonic seizure at 100 mg/kg without any toxicity. 3-(Pyridin-4-yl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4f) showed protection in maximal electroshock (MES) seizure and subcutaneous metrazol (scMET) seizure at 300 mg/kg.
- Ahsan, Mohamed Jawed,Khalilullah, Habibullah,Stables, James P.,Govindasamy, Jeyabalan
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p. 644 - 650
(2015/02/19)
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- Synthesis and anticonvulsant activity of 3a,4-dihydro-3H-indeno[1,2-c] pyrazole-2-carboxamide/carbothioamide analogues
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A series of fourteen 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/ carbothioamide analogues were synthesized and evaluated for anticonvulsant activity according to the Antiepileptic Drug Development Programme (ADD) protocol. Some of the synthesized compounds showed significant activity in minimal clonic seizure model (6 Hz psychomotor seizure test). 3-(4-Fluorophenyl)-N-(4-bromophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c] pyrazole-2-carboxamide (4c) was found to be the most active compound of the series showing 75% (3/4, 0.25-2.0 h) and 50% (2/4, 4.0 h) protection against minimal clonic seizure at 100 mg/kg without any toxicity. 3-(Pyridin-4-yl)-N-(4- chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4f) showed protection in maximal electroshock (MES) seizure and subcutaneous metrazol (scMET) seizure at 300 mg/kg.
- Ahsan, Mohamed Jawed,Khalilullah, Habibullah,Stables, James P.,Govindasamy, Jeyabalan
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p. 644 - 650
(2013/05/21)
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- A PROCESS FOR PREPARATION OF INTERMEDIATES OF DONEPEZIL HYDROCHLORIDE
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The present invention provides a process for the preparation of key intermediate for the synthesis 5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1-indanone hydrochloride (donepezil hydrochloride). The present invention particularly provides a process for the preparation of 5,6-dimethoxy-2-(4-pyridylmethylene)-1-indanone comprising condensation of 5,6-dimethoxy-1-indanone with 4- pyridinecarboxaldehyde using an alkali metal hydroxide as a mild base in the presence of demineralized water as a solvent at a temperature in the range of 15°C to 45°C to yield 5,6-dimethoxy-2-(4-pyridylmethylene)-1-indanone, which is subsequently benzylated using benzyl bromide in the presence of solvent at a reflux temperature to yield 1-benzyl-4-[(5,6-dimethoxy-1-indanone-2-yl)methylene]pyridinium bromide.
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Page/Page column 16
(2012/10/18)
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- POMA analyses as new efficient bioinformatics' platform to predict and optimise bioactivity of synthesized 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2- carboxamide/carbothioamide analogues
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A series of 43, 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/ carbothioamide analogues (D01-D43) were analysed using Petra, Osiris, Molinspiration and ALOGPS (POMA) to identify pharmacophore, toxicity prediction, lipophilicity and bioactivity. All the compounds were evaluated for anti-HIV activity. 3-(4-Chlorophenyl)-N-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H- indeno[1,2-c]pyrazole-2-carboxamide (D07) was found to be the most active with IC50 > 4.83 μM and CC50 4.83 μM. 3-(4-Fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c] pyrazole-2-carbothioamide (D41) was found to be the most active compound against bacterial strains with MIC of 4 μg/ml, comparable to the standard drug ciprofloxacin while 3-(4-methoxyphenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1, 2-c]pyrazole-2-carboxamide (D38) was found to be the most active compound against fungal strains with MIC 2-4 μg/ml, however less active than standard fluconazole. Toxicities prediction by Osiris were well supported and experimentally verified with exception of some compounds. In anticonvulsant screening, 3-(4-fluorophenyl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H- indeno[1,2-c]pyrazole-2-carboxamide (D09) showed maximum activity showing 100% (4/4, 0.25-0.5 h) and 75% (3/4, 1.0 h) protection against minimal clonic seizure test without any toxicity.
- Ahsan, Mohamed Jawed,Govindasamy, Jeyabalan,Khalilullah, Habibullah,Mohan, Govind,Stables, James P.,Pannecouque, Christophe,Clercq, Eric De
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p. 7029 - 7035,7
(2012/12/12)
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- Synthesis and antimycobacterial evaluation of 3a,4-dihydro-3H-indeno [1,2-c] pyrazole-2-carboxamide analogues
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In the present investigation, a series of 3a,4-dihydro-3H-indeno [1,2-c] pyrazole-2-carboxamide analogues were synthesized and were evaluated for antitubercular activity by two fold serial dilution technique. All the newly synthesized compounds showed low to good inhibitory activities against Mycobacterium tuberculosis H37Rv and multi-drug resistant M. tuberculosis (MDR-TB). 3-(4-fluorophenyl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4- dihydro-3H-indeno [1,2-c] pyrazole-2-carboxamide (4c) was found to be the most promising compound active against M. tuberculosis, H37Rv and MDR-TB with minimum inhibitory concentrations 0.83 μM and 3.32 μM respectively.
- Ahsan, Mohamed Jawed,Samy, Jeyabalan Govinda,Khalilullah, Habibullah,Bakht, Mohamed Afroz,Hassan, Mohd. Zaheen
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experimental part
p. 5694 - 5697
(2011/12/16)
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- A new commercially viable synthetic route for donepezil hydrochloride: Anti-Alzheimer's drug
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An economical new process has been developed for the synthesis of donepezil hydrochloride (1) an anti-Alzheimer's drug. The process involves Darzen reaction of pyridine-4-carboxaldehyde and 2-bromo-5,6-dimethoxy indanone affording epoxide 5,6-dimethoxy-3-(pyridine-4-yl)spiro[indene-2,2′-oxiran] -1(3H)-one (4) as a key intermediate. The one-pot deoxygenation of 4 and hydrogenation of the aryl moiety in high yield improved the overall yield of the process.
- Dubey, Shailendra Kumar,Kharbanda, Manita,Dubey, Sushil Kumar,Mathela, Chandra Shekhar
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experimental part
p. 1157 - 1160
(2010/11/18)
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- Process for preparation of donepezil
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An efficient process for preparation of donepezil is provided. In one embodiment, the process for preparation of donepezil includes suspending a catalyst, which is palladium metal on carbon and the compound of the structure in an alcoholic solvent and hydrogenating the suspension at the hydrogen pressure of from about 1 to about 5 and a temperature of from about 40 to about 90° C. till the hydrogenation reaction is substantially complete to obtain a compound of the formula (VI): which then converted to donepezil. The processes of the invention are believed to be simple, eco-friendly, and commercially viable.
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- PROCESS FOR THE PREPARATION OF DONEPEZIL AND DERIVATIVES THEREOF
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The invention relates to processes for the preparation of piperidylmethyl-indanones, and to the use of these compounds as intermediates for the preparation of benzyl-piperidylmethyl-indanones which are active compounds for the treatment of CNS disorders. The invention also relates to a process for the preparation of donepezil or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions that include the donepezil or a pharmaceutically acceptable salt thereof.
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Page/Page column 9
(2008/06/13)
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