Cyclic Amide Derivatives Research Articles

Coordination Chemistry of Actinide Nitrates with Cyclic Amide Derivatives for the Development of the Nuclear Fuel Materials Selective Precipitation (NUMAP) Reprocessing Method

Nuclear fuel recycling is one of promising options to resolve current issues arising from energy security and nuclear wastes. Chemical separation called reprocessing aims to recover recyclable nuclear fuel materials from spent fuels, and also to reduce the volume of high‐level radioactive wastes. Even today, solvent extraction is extensively employed as a principal method for reprocessing, while there are also several safety and security concerns arising from use of large amount of organic solvents and potential isolation of highly purified (namely “decontaminated”) Pu. To resolve these issues, we propose selective precipitation of nuclear fuel materials as an alternative principle for the spent fuel reprocessing. In this minireview, we outlined history of our development of precipitation‐based reprocessing methods for spent nuclear fuels from serendipitous discovery of N‐cyclohexyl‐2‐pyrrolidone to current status reaching our simple and versatile reprocessing concept, NUclear fuel MAterials selective Precipitation (NUMAP).

ChemInform Abstract: Sulfamic Acid‐Mediated, Efficient, One‐Pot Synthesis of Novel 5‐Substituted 1,3,4‐Thiadiazol‐2‐ylcarbamoyl Aliphatic Amide Acid Derivatives and Facile Synthesis of Cyclic Amides.

Abstract Convenient and efficient one-pot syntheses of 5-substituted-1,3,4-thiadiazol-2-ylcarbamoyl aliphatic amide acid derivatives were described and developed using sulfamic acid catalyst. Thiosemicarbazide and substituted triethylorthoester and cyclic/alicyclic anhydride were efficiently condensed using sulfamic acid to furnish 5-disubstituted-1,3,4-thiadiazol-2-ylcarbamoyl aliphatic acid and amide derivatives in fair to good yield, which exclusively get cyclized to new cyclic amide derivatives. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

Sulfamic Acid–Mediated, Efficient, One-Pot Synthesis of Novel 5-Substituted 1,3,4-Thiadiazol-2-ylcarbamoyl Aliphatic Amide Acid Derivatives and Facile Synthesis of Cyclic Amides

Convenient and efficient one-pot syntheses of 5-substituted-1,3,4-thiadiazol-2-ylcarbamoyl aliphatic amide acid derivatives were described and developed using sulfamic acid catalyst. Thiosemicarbazide and substituted triethylorthoester and cyclic/alicyclic anhydride were efficiently condensed using sulfamic acid to furnish 5-disubstituted-1,3,4-thiadiazol-2-ylcarbamoyl aliphatic acid and amide derivatives in fair to good yield, which exclusively get cyclized to new cyclic amide derivatives. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

Discovery of novel 7-membered cyclic amide derivatives that inhibit 11beta-hydroxysteroid dehydrogenase type 1

A series of novel 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27, which furthermore showed the potent efficacy in in vivo studies.

Pharmacokinetic considerations in the design of better and safer new antiepileptic drugs

Valproic acid (VPA) is one of the major antiepileptic drugs. However, its anticonvulsant potency is less than the other three major antiepileptic drugs. Furthermore, VPA causes two rare but severe side effects: teratogenicity and hepatotoxicity. We utilized pharmacokinetic considerations in designing various amide derivatives of VPA which are more potent as anticonvulsants than VPA and have the potential to be nonteratogenic and nonhepatotoxic. The following three groups of VPA derivatives were designed and evaluated: (1) Isomers of valpromide (VPD) in order to explore the structural requirements for metabolically stable VPD isomers. Two chiral amides, valnoctamide and propylisopropyl acetamide, have emerged from a stereospecific study as the optimal compounds; (2) Cyclic amide derivatives of VPD. N-Methyl 2,2,3,3-tetramethylcyclopropane carboxamide (M-TMCD) was found to be the optimal compound in this series. M-TMCD is a stable achiral VPD analogue acid which is nonteratogenic. Since M-TMCD contains four methyl substituents it cannot form a metabolite with a terminal double bond, and thus has the potential to be a nonhepatotoxic compound; (3) Conjugation products of VPA and γ-amino butyric acid (GABA) or glycine. N-valproyl glycinamide (VGD) emerged as the best compound out of this group and is currently undergoing phase II clinical trials. VGD is mainly metabolized to N-valproyl glycine by a nonoxidative hydrolytic metabolic pathway. It did not operate as chemical drug delivery systems of VPA and glycine or GABA, but acted rather as a drug on its own.

Cyclic amide derivatives as potential prodrugs II: N-hydroxymethylsuccinimide- / isatin esters of some NSAIDs as prodrugs with an improved therapeutic index

Ester prodrugs of aspirin 1a, ibuprofen 1b, naproxen 1c and indomethacin 1d were synthesized using N-Hydroxymethylsuccinimide (HMSI) 3 and N-hydroxymethylisatin (HMIS) 4 as promoieties to reduce their gastrointestinal toxicity and improve bioavailability. Additionally, the kinetics of hydrolysis of the synthesized prodrugs 5a–d and 6a–d were studied at 37 °C in non-enzymatic simulated gastric fluid (SGF; hydrochloric acid buffer pH = 1.2); 0.02 M phosphate buffer (pH = 7.4); 80% human plasma and 10% rat liver homogenate. The results indicate higher chemical stability of the ester prodrugs in non-enzymatic SGF (t 1/2 ≅ 6.5–18.6 h) and rapid conversion to the parent drugs in 80% human plasma (t 1/2 ≅ 11.4–235 min) as well as in 10% rat liver homogenates (t 1/2 ≅ 12.0–90.0 min). As a general pattern, the HMSI esters 5a–d revealed higher chemical stability than the corresponding HMIS analogues 6a–d. The pH-rate profile of 5c and 6a indicated maximum stability of the former at pH = 1.2–8.0 and of the latter at pH = 1.2–4.0. The distribution coefficient (D 7.4) values of the prodrugs 5a–d, 6a–d and the parent drugs 1a–d in an n-octanol/phosphate buffer (pH = 7.4) system indicated enhanced lipophilic properties of the prodrugs. Furthermore, the HMIS ester prodrugs 6a–d are more lipophilic than the corresponding HMSI derivatives 5a–d. In vivo ulcerogenicity studies using scanning electron microscopy on stomach specimens of rats treated with an oral dose for 4 d revealed that the synthesized ester prodrugs are significantly less irritating to gastric mucosa than the parent drugs. These results suggested HMSI and/or HMIS esters possess good potential as prodrugs with an improved therapeutic index for oral delivery of NSAIDs.

ChemInform Abstract: Cyclic Amide Derivatives as Potential Prodrugs. Synthesis and Evaluation of N‐Hydroxymethylphthalimide Esters of Some Non‐Steroidal Antiinflammatory Carboxylic Acid Drugs.

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Cyclic amide derivatives as potential prodrugs. Synthesis and evaluation of N-hydroxymethylphthalimide esters of some non-steroidal anti-inflammatory carboxylic acid drugs

N-Hydroxymethylphthalimide (HMPhI) esters 5a-d of some nonsteroidal anti-inflammatory drugs were synthesized and evaluated as potential prodrugs with the aim of depressing the gastrotoxicity of the parent drugs by temporarily masking the carboxylic acid function. The ester prodrugs were synthesized through condensation of N -hydroxymethylphthalimide and the mixed carboxylic-carbonic anhydride intermediate or the corresponding acid chloride of the parent acid. Their structures were confirmed by 1H-NMR spectra and the purity has been assessed by TLC and elemental analyses. An HPLC method has been developed for investigation of the hydrolysis kinetics in aqueous buffer solutions and in 80% rabbit plasma. The lipophilicity parameters log P and log k′ were determined and showed that the prodrugs were found to be more lipophilic (log P > 2) than the parent drugs. A considerable chemical stability of all compounds ( t 1/2 = 4.7–21.9 h) has been observed in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3), while at pH 7.4 only prodrugs 5b-d are sufficiently stable ( t 1/2 ~ 3–5 h). Meanwhile, rapid conversion to the parent drugs 3a-d was observed in 80% rabbit plasma ( t 1/2 ~ 1.0–11.5 min). Potential ulcerogenicity on rat stomach mucosa of the prodrugs and the parent drugs after oral administration for 4 days was studied using a scanning electron microscope. Gross observations and scanning electro-micrographs showed that the prodrugs are significantly less irritating to gastric mucosa than the parent NSAIDs. This result suggests that N-hydroxymethylphthalimide esters may be useful as nonulcerogenic prodrug forms for acidic NSAIDs.

1,2,3‐Triazolodiazepines. I. Preparation and benzodiazepine receptor binding of 1‐benzyl‐ and 1‐phenethyl‐1,2,3‐triazolo‐[4,5‐b][1,4]diazepines

AbstractSeveral new 1,2,3‐triazolo[4,5‐b][1,4]diazepines were prepared starting from 1‐benzyl‐1 and 1‐phenethyl‐4,5‐diamino‐1,2,3‐triazole 2 (Scheme 1), by condensation reactions with β‐diketones (Scheme 2), β‐ketoesters (Scheme 3), and diethyl malonates (Scheme 4). In the first case we obtained compounds 3 and 4 with basic properties, while the ester function condensations gave cyclic amide derivatives 7, 8, 10, 12 and 13 with acid properties. Some N‐methyl derivatives 11, 14 and 15 were obtained from the cyclic amide compounds. Most of compounds were tested for their ability to displace [3H]flunitrazepam from bovine brain membranes but no compound showed benzodiazepine receptor binding affinity.

Structural Elucidation of Long‐Chain Fatty Acids and Alcohols by Mass Spectrometry of their Cyclic Amide Derivatives

AbstractSeveral deuterium‐labelled normal‐chain carboxylic acids and alcohols, their unlabelled analogues and several unlabelled methyl‐branched chain fatty acids and alcohols have been investigated by mass spectrometry — at different electron energies — of their respective N‐acyl 2‐methylaziridine and pyrrolidine and N‐alkyl 2‐pyrrolidone and 2‐piperidone derivatives. The result shows that these kinds of amides and lactams are among the best derivatives of fatty acids and alcohols for structural elucidation by mass spectrometry.

Reaction of sulfonyl chlorides and chlorophosphates with 1,3,2-diheterophospholanes

1. The reactions of benzenesulfonyl chloride with linear and cyclic amide derivatives of trivalent phosphorus are accompanied by oxidation at the phosphorus atom. 2. The reactions of trivalent phosphorus amides with diethyl chlorophosphate proceed with splitting of the P-N bond and lead to exchange products of the amine group at P atom for Cl. Several diphosphorylated derivatives of methylaminoethanol were synthesized, and their thermal stability was studied.