- Koch-Haaf reaction of adamantanols in an acidtolerant hastelloy-made microreactor
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The Koch-Haaf reaction of adamantanols was successfully carried out in a microflow system at room temperature. By combining an acid-tolerant hastelloy-made micromixer, a PTFE tube, and a hastelloy-made microextraction unit, a packaged reaction-toworkup system was developed. By means of the present system, the multigram scale synthesis of 1-adamantanecarboxylic acid was achieved in ca. one hour operation.
- Fukuyama, Takahide,Mukai, Yu,Ryu, Ilhyong
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- Discovery and metabolic stabilization of potent and selective 2-amino-N-(adamant-2-yl) acetamide 11β-hydroxysteroid dehydrogenase type 1 inhibitors
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Starting from a rapidly metabolized adamantane 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (±)-22f, was discovered. Many of these compounds are potent inhibitors of 11β-HSD1 and are selective over 11β-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11β-HSD1 inhibition was confirmed with (±)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11β-HSD1 inhibitors has been discovered.
- Rohde, Jeffrey J.,Pliushchev, Marina A.,Sorensen, Bryan K.,Wodka, Dariusz,Shuai, Qi,Wang, Jiahong,Fung, Steven,Monzon, Katina M.,Chiou, William J.,Pan, Liping,Deng, Xiaoqing,Chovan, Linda E.,Ramaiya, Atul,Mullally, Mark,Henry, Rodger F.,Stolarik, DeAnne F.,Imade, Hovis M.,Marsh, Kennan C.,Beno, David W. A.,Fey, Thomas A.,Droz, Brian A.,Brune, Michael E.,Camp, Heidi S.,Sham, Hing L.,Frevert, Ernst Uli,Jacobson, Peer B.,Link
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- Synthesis of Substituted Bridged Carboxylic Acids of the Adamantane Series
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Abstract: A number of new 1,3,6- and 1,4,4-tri- and 1,3,6,6-tetrasubstituted polyfunctional derivatives were synthesized starting from bridged carboxylic acids of the adamantane series. The reactions were carried out in acidic media. A number of new amino acids were synthesized from 1-acetylamino- and 1,3-diacetylamino derivatives. The synthesized compounds can be considered as a molecular platform for the synthesis of new polymeric materials.
- Ivleva, E. A.,Klimochkin, Yu. N.,Morozova, A. I.,Shiryaev, A. K.,Suchilin, I. D.
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- New chemical agents based on adamantane-monoterpene conjugates against orthopoxvirus infections
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Currently, the spectrum of agents against orthopoxviruses, in particular smallpox, is very narrow. Despite the fact that smallpox is well controlled, there is, for many reasons, a real threat of epidemics associated with this or a similar virus. In order to search for new low molecular weight orthopoxvirus inhibitors, a series of amides combining adamantane and monoterpene moieties were synthesized using 1- and 2-adamantanecarboxylic acids as well as myrtenic, citronellic and camphorsulfonic acids as acid components. The produced compounds exhibited high activity against the vaccinia virus (an enveloped virus belonging to the poxvirus family), which was combined with low cytotoxicity. Some compounds had a selectivity index higher than that of the reference drug cidofovir; the highest SI = 1123 was exhibited by 1-adamantanecarboxylic acid amide containing the (-)-10-amino-2-pinene moiety. The produced compounds demonstrated inhibitory activity against other orthopoxviruses: cowpox virus (SI = 30-406) and ectromelia virus (mousepox virus, SI = 39-707). This journal is
- Agafonov, Alexander P.,Bormotov, Nikolay I.,Korchagina, Dina V.,Maksyutov, Rinat A.,Mozhaytsev, Evgenii S.,Salakhutdinov, Nariman F.,Serova, Olga A.,Shishkina, Larisa N.,Suslov, Evgenii V.,Volcho, Konstantin P.,Yarovaya, Olga I.
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p. 1185 - 1195
(2020/11/03)
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- INTRAESOPHAGEAL ADMINISTRATION OF TARGETED NITROXIDE AGENTS FOR PROTECTION AGAINST IONIZING IRRADIATION-INDUCED ESOPHAGITIS
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Provided herein are compositions and related methods useful for prevention or mitigation of ionizing radiation-induced esophagitis. The compositions comprise compounds comprising a nitroxide-containing group attached to a mitochondria-targeting group. The
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Paragraph 0152; 0164
(2019/07/23)
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- Ring-fused compound, pharmaceutical composition containing same and application of compound
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The invention discloses a ring-fused compound, a preparation method thereof, pharmaceutical composition containing the compound and an application of the compound. A polycyclic compound (I) as well asan isomer, a prodrug, a stable isotopic derivative or pharmacologically acceptable salt of the compound (I) has the following structure. The polycyclic compound has good IDO1 and/or TDO2 inhibition functions, can effectively treat, relieve and/or prevent various diseases which are related with IDO1 and/or TDO2, such as cancer, virus infection, autoimmune diseases or the like.
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Paragraph 0256; 0257; 0260
(2018/04/01)
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- FUSED-RING COMPOUNDS, PHARMACEUTICAL COMPOSITION AND USES THEREOF
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This disclosure is related to a fused-ring compound of formula (I) and/or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the fused ring compound of formula (I) and/or a pharmaceutically acceptable salt thereof, preparation methods thereof, and use thereof in modulating activity of indoleamine 2, 3-dioxygenase (IDO) and/or tryptophan 2, 3-dioxygenase (TDO). This disclosure further provides methods of treating IDO and/or TDO-associated diseases, including cancer, viral infection and autoimmune diseases.
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Paragraph 304; 305; 306; 307
(2016/09/15)
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- C H Bond Arylation of Diamondoids Catalyzed by Palladium(II) Acetate
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We have developed an effective approach to 1,2-disubstituted diamondoids by palladium(II) acetate catalyzed functionalization of C H bond. Selective mono-arylation of the adamantane framework was achieved using picolylamide as a directing group in yields up to 87 %. Kinetic studies in combination with deuterium labeling experiments, competitive experiments and mass spectrometry contribute to the mechanistic understanding of the arylation process of alkanes with number of C H bonds neighboring the directing group. Triflic anhydride promoted cyclization of the directing group generates imidazo[1,5-a]pyridine derivatives. Acid-mediated removal of the directing group provides access to 2-aryl diamondoid carboxylic acids, which are common precursors for the synthesis of various bioactive compounds (drug candidates). (Figure presented.) .
- Larrosa, Marta,Heiles, Sven,Becker, Jonathan,Spengler, Bernhard,Hrdina, Radim
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supporting information
p. 2163 - 2171
(2016/07/16)
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- Synthesis of analogs of the radiation mitigator JP4-039 and visualization of BODIPY derivatives in mitochondria
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JP4-039 is a lead structure in a series of nitroxide conjugates that are capable of accumulating in mitochondria and scavenging reactive oxygen species (ROS). To explore structure-activity relationships (SAR), new analogs with variable nitroxide moieties were prepared. Furthermore, fluorophore-tagged analogs were synthesized and provided the opportunity for visualization in mitochondria. All analogs were tested for radioprotective and radiomitigative effects in 32Dcl3 cells.
- Frantz, Marie-Céline,Skoda, Erin M.,Sacher, Joshua R.,Epperly, Michael W.,Goff, Julie P.,Greenberger, Joel S.,Wipf, Peter
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supporting information
p. 4147 - 4153
(2013/07/19)
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- Metal-free and copper-promoted single-pot hydrocarboxylation of cycloalkanes to carboxylic acids in aqueous medium
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A simple and effective method for the transformation, under mild conditions and in aqueous medium, of various cycloalkanes (cyclopentane, cyclohexane, methylcyclohexane, cis- and trans-1,2dimethylcyclohexane, cycloheptane, cyclooctane and adamantane) into the corresponding cycloalkanecarboxylic acids bearing one more carbon atom, is achieved. This method is characterized by a singlepot, low-temperature hydrocarboxylation reaction of the cycloalkane with carbon monoxide, water and potassium peroxodisulfate in water/acetonitrile medium, proceeding either in the absence or in the presence of a metal promoter. The influence of various reaction parameters, such as type and amount of metal promoter, solvent composition, temperature, time, carbon monoxide pressure, oxidant and cycloalkane, is investigated, leading to an optimization of the cyclohexane and cyclopentane carboxylations. The highest efficiency is observed in the systems promoted by a tetracopper(II) triethanolaminate-de rived complex, which also shows different bond and stereoselectivity parameters (compared to the metalfree systems) in the carboxylations of methylcyclohexane and stereoisomeric 1,2-dimethylcyclohexanes. A free radical mechanism is proposed for the carboxylation of cyclohexane as a model substrate, involving the formation of an acyl radical, its oxidation and consequent hydroxylation by water. Relevant features of the present hydrocarboxylation method, besides the operation in aqueous medium, include the exceptional metal-free and acid-solvent-free reaction conditions, a rare hydroxylating role of water, substrate versatility, low temperatures (ca. 50°C) and a rather high efficiency (up to 72% carboxylic acid yields based on cycloalkane).
- Kirillova, Marina V.,Kirillov, Alexander M.,Pombeiro, Armando J. L.
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experimental part
p. 2936 - 2948
(2010/04/03)
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- Enhanced enantio- and diastereoselectivity via confinement and cation binding: Yang photocyclization of 2-benzoyladamantane derivatives within zeolites
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Irradiation of 2-benzoyladamantane derivatives in zeolites yields the endo-cyclobutanols as the only photoproduct via a γ-hydrogen abstraction process. The cyclobutanols readily undergo retroaldol reaction to give δ-ketoesters. The enantiomeric excess (ee) in the endo-cyclobutanols is measured by monitoring the ee in the ketoesters. Whereas in solution the ee in the product ketoester is zero, within achiral NaY zeolite, in the presence of a chiral inductor such as pseudoephedrine, ee's up to 28% have been obtained. The influence of zeolite on several chiral esters of 2-benzoyladamantane-2-carboxylic acids has also been examined. Whereas in solution the diastereomeric excess is 15%, in zeolite the δ-ketoesters are obtained in 79% de (best examples). Ab initio computations suggest that enhancement of chiral induction within zeolites is likely to be due to cation complexation with the reactant ketone. Alkali ion-organic interaction, a powerful tool, is waiting to be fully exploited in photochemical and thermal reactions. In this context zeolites could be a useful medium as one could view them as a reservoir of "naked" alkali ions that are only partially coordinated to the zeolite walls.
- Natarajan, Arunkumar,Joy, Abraham,Kaanumalle, Lakshmi S.,Scheffer, John R.,Ramamurthy
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p. 8339 - 8350
(2007/10/03)
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- New coupling reactions of some acyl chlorides with samarium diiodide in the presence of samarium: Carbinols from three acyl units
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A mixture of samarium(II) iodide and samarium can induce a coupling reaction of three molecules of alkanoyl halide to give trialkylcarbinols of 2-hydroxy-1,3-diones. When aliphatic, unbranched alkanoyl chlorides are used, this new coupling reaction provides trimeric products as the main reaction products. Tetrahydropyran (THP) proved superior as the solvent because no ring-opening and subsequent reaction with the alkanoyl halides was observed under the reaction conditions, unlike when THF was used. Wiley-VCH Verlag GmbH, 2000.
- Clausen, Christian,Weidner, Ingo,Butenschoen, Holger
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p. 3799 - 3806
(2007/10/03)
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- Mechanism of esterification of 1,3-dimethylamino alcohols by N-acetylimidazole in acetonitrile and the influence of alkyl and geminal dialkyl substitution upon the rate
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3-(Dimethylamino)propan-1-ol and seven derivatives with alkyl substituents at the 2-position have been prepared by conventional methods, and second-order rate constants for their esterification by N-acetylimidazole in acetonitrile have been measured under pseudo-first-order conditions both by 1H NMR spectroscopy at a single temperature (23°C) and by a UV spectroscopic method over the temperature range 25-65°C. Evidence is presented that the intermolecular esterifications proceed via an initial rate-determining intramolecular general base catalysed formation of a cyclic tetrahedral intermediate. Effective molarities compared with the third-order reactions of simpler alcohols with acetylimidazole catalysed by triethylamine are estimated to be 13-14 mol dm-3, but alkyl substitution at the 2-position of the amino alcohol has only a modest effect upon reaction rates. All reactions have substantial negative entropies of activation and only modest enthalpies of activation as expected for concerted bimolecular reactions with highly ordered transition structures. Three structurally related carbocyclic amino alcohols constitute a short isokinetic series with the isokinetic temperature very close to the experimental range. Along this series, decreasing enthalpies of activation are almost exactly balanced in their contributions to the overall free energy of activation near room temperature by increasingly negative entropies of activation.
- Madder, Annemieke,Sebastian, Sonny,Van Haver, Dirk,De Clercq, Pierre J.,Maskill, Howard
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p. 2787 - 2793
(2007/10/03)
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- The carboxylation of saturated hydrocarbons by Gif systems. (FeIII trispicolinate/P(OMe)3/CO/H2O2 in pyridine-acetic acid)
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Saturated hydrocarbons are transformed into the corresponding homologous carboxylic acids by treatment with Fe(Pa)3/P(OMe)3/CO/H2O2 in pyridine-acetic acid. Optimisation of the reaction conditions and mechanistics studies are reported.
- Barton, Derek H. R.,Beck, Albert H.,Delanghe, Nathalie C.
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p. 1555 - 1558
(2007/10/03)
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- The conversion of saturated hydrocarbons into carboxylic acids using Fe(CO)5-H2O2 oxidation
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Saturated hydrocarbons are transformed into their corresponding homologous carboxylic acids by treatment with iron pentacarbonyl and hydrogen peroxide in pyridine-acetic acid. A mechanism for this reaction is proposed. Attention is also directed to a new and convenient procedure for the determination of carbon monoxide.
- Barton, Derek H. R.,Delanghe, Nathalie C.
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p. 8137 - 8140
(2007/10/03)
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- Face Selection in Claisen Rearrangements
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An investigation is reported of the stereochemistry of the Claisen rearrangement of 2-(5-phenyl-2-adamantylidene)ethyl vinyl ether (1-Ph) and of allyl (5-fluoro-2-adamatylidene)methyl ether (2-F).Both ethers undergo the rearrangement principally with the
- Mukherjee, Ashis,Wu, Qianhong,Noble, William J. le
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p. 3270 - 3274
(2007/10/02)
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- The carboxylation of saturated hydrocarbons by Gif systems (Fe0/CO/O2 and Cu0/CO/O2 in pyridine-acetic acid)
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Saturated hydrocarbons are transformed into the corresponding homologous carboxylic acid by treatment with Fe0/CO/O2 or Cu0/CO/O2 in pyridine/acetic acid. Mechanistic studies support a reaction pathway involving the insertion of CO into a carbon-iron or carbon-copper bond.
- Barton,Csuhai,Doller
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p. 4389 - 4392
(2007/10/02)
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- 3-BUTENYL ESTERS AS CONVENIENT PROTECTING GROUPS FOR CARBOXYLIC ACIDS
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Carboxylic acids were protected as their corresponding 3-butenyl esters.Deprotection was carried out via ozonolysis and β-elimination of the resultant 3-acyloxypropanal.
- Barrett, Anthony G.M.,Lebold, Suzanne A.,Zhang, Xiao-an
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p. 7317 - 7320
(2007/10/02)
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- Adamantane-2-spiro-3'-diazirine in reactions with protic and aprotic acids
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During the action of strong protic acids on adamantane-2-spiro-3'-diazirine addition of the proton is accompanied by the elimination of a molecule of nitrogen and the formation of the intermediate 2-adamantyl cation.In the presence of nucleophiles the latter is converted into the corresponding 2-substituted derivatives of adamantane.Lewis acids promote isomerization of the cyclic diazirine to the linear diazo compound, and the main reaction product is adamantanone azine.Trifluoroacetic acid and bromine react by both mechanisms simultaneously. (In the latter case Br+ plays the role of the proton in the first stage.)
- Isaev, S. D.,Zhalnina, G. G.,Murzinova, Z. N.,Lastovenko, S. I.,Yurchenko, A. G.
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p. 126 - 131
(2007/10/02)
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- Formation of Cage-Structure Organomagnesium Compounds. Influence of the Degree of Adsorption of the Transient Species at the Metal Surface
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Secondary and tertiary adamantyl organomagnesium compounds have been synthesized with yields of ca. 60percent by means of an original static procedure.By condensing Grignard reagents of adamantane over benzaldehyde, 70percent and 72percent yields of alcohol are obtained; the 1- and 2-adamantanecarboxylic acid chlorides give 40percent and 50percent yields of 1,1- and 2,2-diadamantyl ketone, respectively.Competition between the various reactions occuring either at the metal-solution interface (formation of the organomagnesium compound and of the dimerization hydrocarbon) or in the medium (formation of the solvent-attack products) is studied in terms of the stirring, the nature of the halogen, the basicity of the solvent, and the ratio of the magnesium surface to the halide.The kinetic study of the formation of these organomagnesium compounds demonstrates the essential role of the anion radical (RX) and of radical pair (RMgX), whose degrees of adsorption at the metal surface, i.e., electrostatic interaction between the transient species at the metal surface, after the single electron transfer (SET), determine the competition between the various reaction pathways.These degrees of adsorption are highly dependent on the nature of the cage structure of the radical.An XPS analysis at different depths of the deposit at the metal surface provides invaluable information on the phenomena occuring at the metal-solution interface when 1-bromoadamantane attacks the magnesium.This makes it possible to retrace the history of the reaction in its initial phase.
- Molle, G.,Bauer, P.,Dubois, J. E.
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p. 4120 - 4128
(2007/10/02)
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- Adamantylene compounds
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Substituted diphenyl adamantylidene methanes. Examples of substituents on the para positions of the phenyl groups are propoxy and acetyloxy. The compounds have estrogenic activities.
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