- Oxidative study of gabapentin by alkaline hexacyanoferrate(III) in room temperature in presence of catalytic amount of Ru(III) - a mechanistic approach
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The kinetics of oxidation of gabapentin by hexacyanoferrate(III) in aqueous alkaline medium at a constant ionic strength of 0.5 mol dm-3 was studied spectrophotometrically. The reaction is of first order in [HCF(III)] and of less than unit order in [alkali]. The reaction rate is independent upon [gabapentin]. Effects of added products, ionic strength and dielectric constant of the reaction medium have been investigated. Oxidative product of gabapentin was identified. A suitable mechanism has been proposed. The reaction constants involved in the different steps of mechanism are calculated. The activation parameters of the mechanism are computed and discussed.
- Jose, Timy P.,Angadi, Mahantesh A.,Salunke, Manjalee S.,Tuwar, Suresh M.
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- Synthesis of spiro[cycloalkane-pyridazinones] with high Fsp3 character
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Background: Nowadays, in course of the drug design and discovery much attention is paid to the physicochemical parameters of a drug candidate, in addition to their biological activity. Disadvantageous physicochemical parameters can hinder the success of a drug candidate. Objective: Lovering et al. introduced the Fsp3 character as a measure of carbon bond saturation, which is related to the physicochemical paramethers of the drug. The pharmaceutical research focuses on the synthesis of compounds with high Fsp3 character. Method: To improve the physicochemical properties (clogP, solubility, more advantageous ADME profile, etc.) of drug-candidate molecules one possibility is the replacement of all-carbon aromatic systems with bioisoster heteroaromatic moieties, e.g. with one or two nitrogen atom containing systems, such as pyridines and pyridazines, etc. The other option is to increase the Fsp3 character of the drug candidates. Both of these aspects were considered in the design the new spiro[cycloalkanepyridazinones], the synthesis of which is described in the present study. Results: Starting from 2-oxaspiro[4.5]decane-1,3-dione or 2-oxaspiro[4.4]nonane-1,3-dione, the corresponding ketocarboxylic acids were obtained by Friedel-Crafts reaction with anisole or veratrole. The ketocarboxylic acids were treated by hydrazine, methylhydrazine or phenylhydrazine to form the pyridazinone ring. N-Alkylation reaction of the pyridazinones resulted in the formation of further derivatives with high Fsp3 character. Conclusion: A small compound library was obtained incorporating compounds with high Fsp3 characters, which predicts advantageous physico-chemical parameters (LogP, ClogP and TPSA) for potential applications in medicinal chemistry.
- Für, Csilla Sepsey,Riszter, Gergo,Gerencsér, János,Szigetvári, áron,Dékány, Miklós,Hazai, László,Keglevich, Gy?rgy,B?lcskei, Hedvig
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p. 731 - 744
(2020/06/22)
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- Kinetics of oxidation of gabapentin (neurontin) by chloramine-T in perchloric acid medium
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A kinetic study of oxidation of gabapentin (neurontin) by chloramine-T has been carried out in HClO4 medium at 303 K. The reaction rate is first order dependence on [CAT]o, fractional order on [GP]o and an inverse fractional order on [H+]. Effects of added p-toluenesulfonamide and halide ions, and varying ionic strength of the medium have been investigated and the activation parameters evaluated. The reaction fails to initiate polymerization of acrylonitrile. The reaction stoichiometry and oxidation products have been identified and a suitable mechanism has been proposed.
- Mohan,Jagadeesh
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experimental part
p. 1226 - 1229
(2009/03/11)
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- Antiarthritic and suppressor cell inducing activity of azaspiranes: Structure-function relationships of a novel class of immunomodulatory agents
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Spirogermanium (1;8,8-diethyl-N,N-dimethyl-2-aza-8-germaspiro[4.5]decane-2-propanamin e dihydrochloride) is a potent cytotoxic agent in vitro which has demonstrated limited activity in experimental animal tumor models. Subsequently, it has been reported that spirogermanium has antiarthritic and suppressor cell-inducing activity. We have synthesized a series of substituted 8-hetero-2-azaspiro[4.5]decane and 9-hetero-3-azaspiro[5.5]undecane analogues of spirogermanium to identify the heteroatom requirements for in vivo antiarthritic and suppressor cell-inducing activity. This structure-activity relationship study has identified that appropriately substituted silicon and carbon analogues of spirogermanium retain both antiarthritic and immunosuppressive activity, with the 8,8-dipropyl (carbon) analogue being among the most active. Following the identification of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine dihydrochloride (9) as more active analogue than spirogermanium, a series of 8,8-dipropyl analogues with various amine substituents were synthesized. A number of these analogues had activity similar to that of 9. A correlation between activity in the adjuvant arthritic rat and the ability to induce suppressor cells (r = 0.894, p0.001) suggests an association between the two pharmacologic effects. While the precise biochemical mechanism(s) for the pharmacological activity is unclear, these data suggest that compounds within this series, e.g., N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine dihydrochloride, may provide effective therapy in diseases of autoimmune origin and/or the prevention of rejection in tissue transplantation.
- Badger,Schwartz,Picker,Dorman,Bradley,Cheeseman,DiMartino,Hanna,Mirabelli
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p. 2963 - 2970
(2007/10/02)
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- Superoxide Anion Radical (O2-anionradical) Mediated Base Catalyzed Autooxidation of α-Keto Enols
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Eight 4,4-disubstituted 2-hydroxycyclohexa-2,5-dien-1-ones were prepared by the base-catalysed autooxidation (BCA) of the corresponding 4,4- or 5,5-disubstituted cyclohex-2-en-1-ones.Upon reaction with superoxide anion radical (O2-anionradical, generated from KO2/18-crown-6) in inert nonpolar aprotic media at room temperature, α-keto enols 3a-g undergo initial deprotonation of the enol hydrogen followed by BCA at C3 of the resulting enolate.Aqueous acid workup of the reaction mixture yields lactols 4, while methyl iodide quenching generates methoxy lactones 5.Lactols 4 can be readily converted to their acetoxy analogues 8, opened to aldehydo methyl esters 6, or reduced to the related lactones 7.The latter suggests a convenient one-pot synthesis of 2,3-unsaturated δ-valerolactones from the corresponding cyclohex-2-en-1-ones. 4,4-Diphenyl enol 3h, by contrast, resists BCA (whether mediated by O2-anionradical or t-C4H9O-anion) to the corresponding lactol yielding instead a variety of oxidative cleavage products 13-18. 2-Hydroxyspirodec-1-en-3-one (21) also underwent O2-anionradical-mediated BCA, yielding diacids 22 and 26 as well as lactol 30.The synthetic applications of these results are also discussed.
- Frimer, Aryeh A.,Gilinsky-Sharon, Pessia,Aljadeff, Gladis,Marks, Vered,Rosental, Zilpa
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p. 4866 - 4872
(2007/10/02)
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- Spiro[4,5] and spiro[4,6] carboxylic acids: Cyclic analogues of valproic acid. Synthesis and anticonvulsant evaluation
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Spiro[4,5]decane-2-carboxylic acid, spiro[4,5]decane-2,2-dicarboxylic acid, spiro[4,6]undecane-2-carboxylic acid (12b), spiro[4,6]undecane-2,2-dicarboxylic acid, and spiro[4,6]undecane-2-acetic acid were synthesized by an improved method and evaluated for anticonvulsant activity. These analogues were synthesized to evaluate the role of the carboxylic acid group as an essential substituent in valproic acid (di-n-propylacetic acid, 1). Carbocyclic spiranes are known to resist metabolic alteration so that any activity elicited by these compounds would be due to the carboxylic acid function and not to any metabolic change. Spiro[4,6]undecane-2-carboxylic acid (12b) was the most active analogue tested and the pentylenetetrazol and picrotoxin evaluations of 12b compared favorably to 1. However, 12b failed to provide adequate protection against maximal electroshock seizures, bicuculline, or strychnine in mice. Possible reasons for these results are discussed.
- Scott,Moore,Zalucky,Nicholson,Lee,Hinko
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p. 413 - 417
(2007/10/02)
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- Composes heterocycliques spiranniques. V. Synthese et etude configurationnelle dans la serie de l'oxa-2 spirodecane
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The 8-t-butyl-2-oxaspirodecan-3-one, 8-t-butyl-2-oxaspirodecane and its 3-methylated derivatives were synthesized by different routes starting from methyl 4-t-butylcyclohexanecarboxylate, 4-t-butylmethylenecyclohexane and methyl 4-t-butylcyclohexylidenecyanoacetate.The cis (-CH2O axial) and trans (-CH2O equatorial) isomers were isolated by preparative HPLC ; their configurations were established from (1) the known stereoselectivity of the reaction involved in the cis/trans ratio controlling step (2) their proton and 13C nmr spectra.
- Picard, Philippe,Moulines, Jean,Lecoustre, Max
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- Evaluation of various N-substituted azaspiranedione derivatives as potential antimicrobial agents
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A series of N-substituted hydrazines were condensed with various spiro[4,5] and [5,5]anhydrides and the resultant N-substituted azaspiranediones were evaluated for antimicrobial activity. None displayed any significant activity in a variety of organisms tested.
- Scott,Kennedy,Kemp,Telang,Matthews
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p. 183 - 186
(2007/10/02)
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