- An efficient approach to diarylethene-amino acid photochromic fluorescent hybrids
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An effective approach to the synthesis of diarylethene-amino acid hybrids DE-Gly, DE-AABA and DE-DAA (5a-d - 7-a-d) was developed via condensation of furan-2,5-dione-based diarylethenes (DE) and ethyl esters of glycine (Gly), α-aminobutyric acid (AABA) and D-aspartic acid (DAA) with moderate to good yields. According to X-ray diffraction data, DE-Gly hybrid 5a exists in an antiparallel conformation with a distance of 4.549 ? between the reactive carbon atoms C(1)-C(11), potentially capable of forming a single bond, which is suitable for the conrotatory photocyclization reaction allowed by the Woodward-Hoffman rules. The structures of the obtained compounds were proved by 1H, COZY, HSQC, HMBC and 13C NMR spectroscopy. The hybrids DE-Gly, DE-AABA and DE-DAA absorb at 443–456 nm, which corresponds to their existence in a ring-open form O, and display fluorescence at 531–612 nm. Irradiation with light of 436 nm results in their rearrangement into ring-closed colored nonfluorescent isomers C. Backwards re-opening occurs under the action of visible light (λ > 500 nm). Spectral kinetic investigation of 5a,c revealed that the efficiency of photocyclization, as well as the emission quantum yield, decreases with the growth of solvent polarity. The ring-closed isomer C of sterically hindered 5a (R2 = R3 = Me) is stable at room temperature, whereas for 5c (R3 = H), ring opening readily occurs with the speed increasing with the polarity of the solvent. The internal emission of sterically hindered hybrids 5a, 6a and 7a (R2 = R3 = Me) is reversibly modulated in a binary response with good fatigue resistance under successive irradiation with light of 436 and 540 nm.
- Bren, Vladimir A.,Dubonosov, Alexander D.,Kuzmina, Lyudmila G.,Minkin, Vladimir I.,Podshibyakin, Vitaly А.,Shepelenko, Еvgenii N.,Yu. Karlutova, Olga
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Read Online
- Copper-induced ammonia N-H functionalization
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The activation of ammonia has been achieved with the aid of the TpMsCu core (TpMs = hydrotris(3-mesityl-pyrazolyl)borate). Complexes of the general composition TpMsCu(amine) (1-4) including the ammonia adduct TpMsCu(NH3) (1) have been synthesized and fully spectroscopical- and structurally characterized. Coordinated ammonia in 1 has been reacted with Ph3CPF6 yielding TpMsCu(NH2CPh3) (5) as a result of N-H cleavage and N-C bond formation. In a parallel manner the catalytic functionalization of ammonia with ethyl diazoacetate leading to glycinate derivatives has been developed with TpMsCu(THF) as the catalyst, in the first example of this transformation with ammonia and a copper-based system.
- álvarez, María,álvarez, Eleuterio,Fructos, Manuel R.,Urbano, Juan,Pérez, Pedro J.
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Read Online
- Functionalized 5-Amino-4-cyanoxazoles, their Hetero- and Macrocyclic Derivatives: Preparation and Synthetic Applications
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An approach to a series of new 5-amino-4-cyanoxazoles is described. Synthesis of the title compounds relied on a two-step sequence including heterocyclization of 2-amido-3,3-dichloroacrylonitriles with aliphatic secondary amines (dimethylamine, morpholine), primary aliphatic amines with active functional groups (2-aminoethanol and glycine ethyl ester), and aniline. An efficient and straightforward protocol introduces a carboxylate group at the C-2 position of 5-amino-4-cyanoxazoles, connected to the heterocycle directly or through an aliphatic linker. This carboxylic group is an attractive motif that can be found in a variety of drug-relevant compounds and also used for further modifications. Furthermore, efficient transformations of selected trisubstituted compounds were used to demonstrate their rich synthetic potential – e. g., as precursors to 2-(4-cyano-5-(dimethylamino)oxazol-2-yl)acetamides, oxazole-containing macrocyclic structures, 2-(oxazol-2-yl)acetamides, amino pyrazoles, 3-(4-cyano-5-aminoxazol-2-yl)coumarins, and oxazole amino acids.
- Merzhyievskyi, Danylo O.,Shablykin, Oleh V.,Shablykina, Olga V.,Kozytskiy, Andriy V.,Rusanov, Eduard B.,Moskvina, Viktoriia S.,Brovarets, Volodymyr S.
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Read Online
- Synthesis of some new 5-arylidene-2,4-thiazolidinedione esters
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Compounds containing the 1,3-thiazolidine-2,4-dione scaffold are gaining increasing scientific interest as potential interventional agents for a variety of disease states. A four-step synthesis of ethyl-(2-(5-arylidine-2,4- dioxothiazolidin-3-yl)acetyl)glycinates, alaninates, butanoates, valinates and norvalinates is described. The synthesis began by converting 1,3-thiazolidine-2,4-dione into its potassium salt, which was treated with ethyl (2-chloroacetamido)glycinates, alaninates, butanoates, valinates and norvalinates, respectively, to obtain the penultimate products. These products were then subjected to a Knoevenagel condensation reaction with different aldehydes to obtain the desired products in low to excellent yields.
- Tshiluka, Ndivhuwo R.,Bvumbi, Mpelegeng V.,Ramaite, Isaiah I.,Mnyakeni-Moleele, Simon S.
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p. 161 - 175
(2021/03/17)
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- Stereospecific Synthesis of 3,4-Dihydro-2 H-naphtho-1,4-oxazin-2-ones by Unification of Benzoxepine-4-carboxylates with Chiral Amino Acid Ethyl Esters
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A novel and efficient stereocontrolled method has been developed for the preparation of chiral 3,4-dihydro-2H-naphtho[1,2-b][1,4]oxazin-2-ones by the reaction of benzoxepine-4-carboxylates with chiral amino acid ethyl esters for the first time. The chiral 3,4-dihydro-2H-naphtho-1,4-oxazinones have been achieved in one step by the formation of C-N, C-C, and C-O bonds.
- Bhimapaka, China Raju,Kasagani, Veera Prasad,Kurma, Siva Hariprasad
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supporting information
p. 2976 - 2983
(2020/03/23)
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- Design, synthesis and biological evaluation of novel 2-(5-aryl-1H-imidazol-1-yl) derivatives as potential inhibitors of the HIV-1 Vpu and host BST-2 protein interaction
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Novel ethyl 2-(5-aryl-1H-imidazol-1-yl)-acetates 17 and propionates 18, together with their acetic acid 19 and acetohydrazide 20 derivatives, were designed and synthesized using TosMIC chemistry. Biological evaluation of these newly synthesized scaffolds in the HIV-1 Vpu- Host BST-2 ELISA assay identified seven hits (17a, 17b, 17c, 17g, 18a, 20f and 20g) with greater than 50% inhibitory activity. These hits were validated in the HIV-1 Vpu- Host BST-2 AlphaScreen and six of the seven compounds were found to have comparable percentage inhibitory activities to those of the ELISA assay. Compounds 17b and 20g, with consistent percentage inhibitory activities across the two assays, had IC50 values of 11.6 ± 1.1 μM and 17.6 ± 0.9 μM in a dose response AlphaScreen assay. In a cell-based HIV-1 antiviral assay, compound 17b exhibited an EC50 = 6.3 ± 0.7 μM at non-toxic concentrations (CC50 = 184.5 ± 0.8 μM), whereas compound 20g displayed antiviral activity roughly equivalent to its toxicity (CC50 = 159.5 ± 0.9 μM). This data suggests that compound 17b, active in both cell-based and biochemical assays, provides a good starting point for the design of possible lead compounds for prevention of HIV-1 Vpu and host BST-2 protein binding in new anti-HIV therapeutics.
- Bode, Moira L.,Coyanis, E. Mabel,Mosebi, Salerwe,Njengele, Zikhona,Rashamuse, Thompho J.,Sayed, Yasien
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- Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma
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Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e–7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.
- Zhou, Ruolan,Fang, Shaoyu,Zhang, Minmin,Zhang, Qingsen,Hu, Jian,Wang, Mingping,Wang, Chongqing,Zhu, Ju,Shen, Aijun,Chen, Xin,Zheng, Canhui
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supporting information
p. 349 - 352
(2019/01/04)
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- Amide pyridine derivative and application thereof
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The invention belongs to the technical field of medicine and relates to an amide pyridine derivative which is shown as a general formula I. The invention further relates to stereoisomer and pharmaceutically-acceptable salt, hydrate, solvate or prodrug of the amide pyridine derivative. The definitions of substituent groups of Ar, M, R and Py are given out in an instruction book. The invention further relates to a method for preparing the compound shown in the general formula I, pharmaceutical composition containing the compound and application of the compound and the pharmaceutical compositionin preparing medicine for treating and preventing superficial-layer fungal diseases and deep-layer fungal diseases.
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Paragraph 0083; 0084
(2019/02/06)
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- A α-cycloalanine on the preparation method
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The invention relates to a method for synthesizing alpha-cycloalanine. The method comprises the steps of performing esterification on glycine serving as a raw material, synthesizing esterified product from the former step with p-benzene sulfonyl chloride, performing alkylation reaction on the synthesized product from the former step and 1,2-dibromoethane, and finally hydrolyzing to obtain a product. The method has the advantages of low process pollution, high yield, good purity, low cost and the like, is simple to operate and is a process suitable for industrialized production.
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Paragraph 0015; 0017-0019
(2017/04/29)
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- One-pot synthesis of pyrroles using a titanium-catalyzed multicomponent coupling procedure
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A simple one-pot procedure for the production of 2-carboxylpyrroles with 4-alkyl, 5-alkyl, 4-aryl, 4-aryl-5-alkyl, or 3,4-diaryl substitution patterns is presented. The procedure involves the titanium-catalyzed multicomponent coupling of alkynes, primary amines and isonitriles to give 1,3-diimines in situ; the multicomponent product is then treated with the ethyl ester of glycine hydrochloride to give the NH-pyrrole. The reaction can be carried out with the neutralized glycine ester or with the hydrochloride salt using DBU as a base. Yields of pyrrole based on starting alkyne varied from 25 to 65% over the one pot procedure, and in most cases only one regioisomer of the product is observed. Further, it is proposed that the regioselectivities of the reactions are a result of rate-determining ring closure after relatively fast transimination with glycine ethyl ester.
- Pasko, Cody M.,Dissanayake, Amila A.,Billow, Brennan S.,Odom, Aaron L.
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p. 1168 - 1176
(2016/02/16)
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- Integrated Heterogeneous Metal/Enzymatic Multiple Relay Catalysis for Eco-Friendly and Asymmetric Synthesis
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Organic synthesis is in general performed using stepwise transformations where isolation and purification of key intermediates is often required prior to further reactions. Herein we disclose the concept of integrated heterogeneous metal/enzymatic multiple relay catalysis for eco-friendly and asymmetric synthesis of valuable molecules (e.g., amines and amides) in one-pot using a combination of heterogeneous metal and enzyme catalysts. Here reagents, catalysts, and different conditions can be introduced throughout the one-pot procedure involving multistep catalytic tandem operations. Several novel cocatalytic relay sequences (reductive amination/amidation, aerobic oxidation/reductive amination/amidation, reductive amination/kinetic resolution and reductive amination/dynamic kinetic resolution) were developed. They were next applied to the direct synthesis of various biologically and optically active amines or amides in one-pot from simple aldehydes, ketones, or alcohols, respectively.
- Palo-Nieto, Carlos,Afewerki, Samson,Anderson, Mattias,Tai, Cheuk-Wai,Berglund, Per,Córdova, Armando
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p. 3932 - 3940
(2016/07/06)
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- SYNTHESIS OF AMIDES AND AMINES FROM ALDEHYDES OR KETONES BY HETEROGENEOUS METAL CATALYSIS
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This invention concerns the first mild and efficient synthesis of primary amines and amides from aldehydes or ketones using a heterogeneous metal catalystand amine donor. The initial heterogeneous metal- catalyzed reaction between the carbonyl and the amine donor components is followed up with the addition of a suitable acylating agent component in one-pot. Hence, the present invention provides a novel catalytic one-pot three-component synthesis of amides. Moreover, the integration of enzyme catalysis allows for eco-friendly one-pot co-catalytic synthesis ofamides from aldehyde and ketone substrates, respectively. The process can be applied to the co-catalytic one-pot three-component synthesis of capsaicin and its analogues from vanillin or vanillyl alcohol. It can also be applied for asymmetric synthesis. In the present invention, a novel co-catalytic reductive amination/dynamic kinetic resolution (dkr) relay sequence for the asymmetric synthesis of optically active amides from ketones is disclosed. Moreover, implementation of a catalytic reductive amination/kinetic resolution (kr) relay sequence produces the corresponding optically active amide product and optical active primary amine product with the opposite stereochemistry from the starting ketones.
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Page/Page column 17
(2016/07/05)
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- Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of Azomethine Ylides with Methacrylonitrile
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Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.
- Walton, Mary C.,Yang, Yun-Fang,Hong, Xin,Houk,Overman, Larry E.
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supporting information
p. 6166 - 6169
(2016/01/09)
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- 4-HYDROXY-2-OXO-1-PYRROLIDINEACETAMIDE RACEMATE CRYSTAL FORM I AND PREPARATION METHOD THEREFOR
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A crystal form I of the racemate of 4-hydroxy-2-oxo-1-pyrrolidine acetamide is prepared by the following steps: dissolving crude racemate of 4-hydroxy-2-oxo-1-pyrrolidine acetamide in a small molecular alcohol solvent to reach supersaturation; heating and stirring overnight at 38-42°C to obtain an suspended sediment; filtering and drying to obtain a crystal. The crystal form I of the racemate of 4-hydroxy-2-oxo-1-pyrrolidine acetamide in the present invention has a high purity which can reach 99.5%.
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Page/Page column
(2014/07/07)
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- Friedel-Crafts alkylation of natural amino acid-derived pyrroles with CF3-substituted cyclic imines
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Natural amino acid-derived ethyl 2-(1-pyrrolyl)alkanoates react with 2-trifluoromethyl-1-azacycloalkenes selectivity at the β-position of the pyrrole moiety to afford ethyl 2-[3-(1-trifluoromethyl-2-azacycloalkyl)pyrrol-1- yl]alkanoates.
- Shmatova, Olga I.,Shevchenko, Nikolay E.,Balenkova, Elizabeth S.,R?schenthaler, Gerd-Volker,Nenajdenko, Valentine G.
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- Practical asymmetric synthesis of a chiral piperazinone derivative
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A practical asymmetric route to a chiral piperazinone derivative, a fragment of MK-3207, is reported. The amine-bearing benzylic stereocenter is introduced via an asymmetric Pd-catalyzed hydrogenation of a cyclic sulfimidate in the presence of a chiral phosphine ligand. An efficient synthesis of the hydrogenation substrate is described, together with process development of the hydrogenation step and elaboration of the resulting cyclic sulfamate product to the desired piperazinone.
- McLaughlin, Mark,Belyk, Kevin,Chen, Cheng-Yi,Linghu, Xin,Pan, Jun,Qian, Gang,Reamer, Robert A.,Xu, Yingju
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p. 1052 - 1060
(2013/09/12)
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- Equimolar CO2 capture by N-substituted amino acid salts and subsequent conversion
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Steric bulk controls CO2 absorption: N-substituted amino acid salts in poly(ethylene glycol) reversibly absorb CO2 in nearly 1:1 stoichiometry. Carbamic acid is thought to be the absorbed form of CO 2; this was supported by NMR and in situ IR spectroscopy, and DFT calculations. The captured CO2 could be converted directly into oxazolidinones and thus CO2 desorption could be sidestepped. Copyright
- Liu, An-Hua,Ma, Ran,Song, Chan,Yang, Zhen-Zhen,Yu, Ao,Cai, Yu,He, Liang-Nian,Zhao, Ya-Nan,Yu, Bing,Song, Qing-Wen
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supporting information
p. 11306 - 11310
(2013/01/15)
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- Synthesis, glucose uptake activity and structure-activity relationships of some novel glitazones incorporated with glycine, aromatic and alicyclic amine moieties via two carbon acyl linker
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Three series of novel glitazones were designed and prepared by using appropriate synthetic schemes to incorporate glycine, aromatic and alicyclic amines via two carbon linker. Compounds were synthesized both under conventional and microwave methods. Nineteen out of twenty four synthesized compounds were evaluated for their in vitro glucose uptake activity using isolated rat hemi-diaphragm. Compounds, 6, 9a, 13a, 13b, 13c, 13f and 13h exhibited significant glucose uptake activity. Illustration about their synthesis and in vitro glucose uptake activity is described along with the structure-activity relationships.
- Kumar, B.R. Prashantha,Soni, Mukesh,Kumar, S. Santhosh,Singh, Kuldeep,Patil, Mohan,Baig, R.B. Nasir,Adhikary, Laxmi
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experimental part
p. 835 - 844
(2011/04/16)
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- PROCESS FOR MAKING CGRP RECEPTOR ANTAGONIST
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The invention encompasses a novel process for making 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide, which is a CGRP receptor antagonist useful for the treatment of migraine, using an asymmetric phase-transfer catalysis route. The invention also encompasses an efficient and practical synthesis of the (R)-acid intermediate, and generates the benzylic stereocenter in an enantioselective manner.
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Page/Page column 70
(2011/02/24)
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- Polyphosphazenes containing vitamin substituents: Synthesis, characterization, and hydrolytic sensitivity
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Novel polyphosphazenes containing various vitamin substituents were synthesized and characterized, and their sensitivity to hydrolysis and pH behavior was investigated. Vitamins L1, E, and B6 were used because of their biocompatibility, their importance in a variety of biological functions, and their potential to increase the mechanical properties of the resulting polymers, thus making these materials promising candidates for hard tissue engineering scaffolds. Chlorine replacement reactions were carried out initially with the small molecule, hexachlorocyclotriphosphazene, as a model for high polymeric poly(dichlorophosphazene). Because of the steric hindrance generated by vitamin E as a substituent, co-substituted polymers were synthesized with either glycine ethyl ester or sodium ethoxide as the second substituent. Similarly, vitamin B6 was co-substituted with glycine ethyl ester or phenylalanine ethyl ester to favor biodegradability. To prevent cross-linking via multifunctional reagents, the hydroxyl groups in vitamin B6 were protected and subsequently deprotected under acidic conditions after side group linkage to the polymer backbone. The glass transition temperatures of the polymers ranged from -24.0 to 44.0 °C. Hydrolysis of the polymers in deionized water at 37 °C was used as an initial estimate of their hydrolytic sensitivity. Different solid polymers underwent 10-100% weight loss in 6 weeks with the generation of a broad pH range of ~2.5-9. The weight loss during preliminary hydrolysis experiments was attributed to cleavage of the polymer backbone and/or the polymers becoming soluble in the aqueous media during hydrolytic reactions.
- Morozowich, Nicole L.,Weikel, Arlin L.,Nichol, Jessica L.,Chen, Chen,Nair, Lakshmi S.,Laurencin, Cato T.,Allcock, Harry R.
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experimental part
p. 1355 - 1364
(2011/10/09)
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- Mild approach to the deprotection of Troc from protected amines using mischmetal and TMSCl
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The 2,2,2-trichloroethoxycarbonyl (Troc) protecting group was efficiently removed from Troc-protected aliphatic and aromatic amines and also some Troc, Tos- and Troc, Ac-protected amines using activated mischmetal (MM). All reactions were performed by ref
- Vellemaee, Eerold,Stepanov, Vladimir,Maeorg, Uno
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experimental part
p. 3397 - 3404
(2011/01/04)
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- Heterocyclic Compounds Useful as RAF Kinase Inhibitors
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The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
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Page/Page column 43
(2009/01/24)
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- COMPOUNDS USEFUL AS RAF KINASE INHIBITORS
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The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
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Page/Page column 88
(2009/03/07)
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- First and convergent synthesis of hybrid sulfonophosphinopeptides
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Figure Presented Hybrid sulfonophosphinopeptides were first and convergently synthesized in satisfactory to good yields via the Mannich-type reaction of N-protected 2-aminoalkanesulfonamides, aromatic aldehydes, and aryldichlorophosphines and subsequent aminolysis with amino esters.
- He, Fengdan,Meng, Fanhua,Song, Xiuqing,Hu, Wenxiang,Xu, Jiaxi
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supporting information; experimental part
p. 3922 - 3925
(2009/12/05)
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- Synthesis, characterization and pharmacological evaluation of amide prodrugs of ketorolac
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Ketorolac (KC) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of KC were synthesized by amidation with ethyl esters of amino acids, namely, glycine, l-phenylalanine, l-tryptophan, l-valine, l-isoleucine, l-alanine, l-leucine, l-glutamic acid, l-aspartic acid and β-alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for biopharmaceutical studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, anti-inflammatory activities were obtained in all cases as compared to KC. Among synthesized prodrugs, viz. AR-11, AR-19 and AR-20 showed excellent pharmacological response and encouraging hydrolysis rate both in SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent showed enhanced partition coefficient but diminished dissolution and hydrolysis rates. Such prodrugs can be considered for sustained release purpose.
- Mishra, Ashutosh,Veerasamy, Ravichandran,Jain, Prateek Kumar,Dixit, Vinod Kumar,Agrawal, Ram Kishor
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body text
p. 2464 - 2472
(2009/04/07)
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- On the mechanism of the thermal retrocycloaddition of pyrrolidinofullerenes (retro-prato reaction)
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In contrast to N-methyl or N-unsubstituted pyrrolidinofullerenes, which efficiently undergo the retrocycloaddition reaction to quantitatively afford pristine fullerene, N-benzoyl derivatives do not give this reaction under the same experimental conditions. To unravel the mechanism of the retrocycloaddition process, trapping experiments of the in-situ thermally generated azomethine ylides, with an efficient dipolarophile were conducted. These experiments afforded the respective cycloadducts as an endolexo iso-meric mixture. Theoretical calculations carried out at the DFT level and by using the two-layered ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) approach underpin the experimental findings and predict that the presence of the dienophile is not a basic requirement for the azomethine ylide to be able to leave the fullerene surface under thermal conditions. Once the 1,3-dipole is generated in the reaction medium, it is efficiently trapped by the dipolarophile (maleic anhydride or N-phenylmaleimide). However, for N-unsubstituted pyrrolidinofullerenes, the participation of the dipolarophile in assisting the 1,3-dipole to leave the fullerene surface throughout the whole reaction pathway is also a plausible mechanism that cannot be ruled out.
- Filippone, Salvatore,Barroso, Marta Izquierdo,Martin-Domenech, Angel,Osuna, Silvia,Sola, Miquel,Martin, Nazario
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supporting information; experimental part
p. 5198 - 5206
(2009/05/27)
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- ALPHA-GALACTOSYLCERAMIDE ANALOGS, THEIR METHODS OF MANUFACTURE, INTERMEDIATE COMPOUNDS USEFUL IN THESE METHODS, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The invention relates to α-galactoceramide analogs, their methods of manufacture, intermediate compounds useful in these methods. It also relates to pharmaceutical compositions containing the α-galactoceramide analogs. The methods of manufacture of the invention involve the use of unsaturated intermediate compounds which enable to synthesize α-galactoceramide analogs by a mere metathesis reaction. The α-galactoceramide analogs of the invention are useful as active ingredients of pharmaceutical compositions, particularly in pharmaceutical compositions having anti-cancerous properties.
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Page/Page column 42
(2008/12/05)
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- 1,2-Diarylacetylene Derivatives of Acyltryptophanols
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The present invention relates to acyltryptophanols of the general formula I, in which Q, W, R1, R2, R3, R4, R5, R6, R7 and R8 have the meaning as defined in the description. The compounds according to the invention are effective FSH antagonists and can be used for example for fertility control in men or in women, or for the prevention and/or treatment of osteoporosis.
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Page/Page column 45
(2008/12/06)
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- Light-sensitive protecting groups for amines and alcohols: The photosolvolysis of n-substituted 7-nitroindolines
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Representative examples of primary and secondary amines were protected as urea derivatives 4 of 5-bromo-7-nitroindoline and even more efficiently as ureas 8 derived from 5,7-dinitroindoline, via high-yield reactions with carbamoyl chlorides 3 and 7, respectively. Deprotection of 4 or 8 was achieved in high yields by UV irradiation at room temperature in Pyrex vessels under neutral conditions and exclusion of air. In a similar manner the dinitroindolines serve as protecting groups for alcohols and phenols; the derived carbamates 5 and 9 can likewise be deprotected photochemically in high yields. Georg Thieme Verlag Stuttgart.
- Hassner, Alfred,Yagudayev, Diana,Pradhan, Tarun K.,Nudelman, Abraham,Amit, Boaz
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p. 2405 - 2409
(2008/03/27)
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- NOVEL CONDENSED IMIDAZOLE DERIVATIVE
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Disclosed is a compound represented by the formula (1) below which has a high DPP-IV inhibitory activity and is improved in safety, toxicity and the like. Also disclosed is a prodrug of such a compound and pharmaceutically acceptable salts of them. (In the formula, R1 represents a hydrogen atom, an optionally substituted alkyl group or the like; R2 and R3 independently represent a hydrogen atom, an optionally substituted alkyl group or the like; R4 and R5 independently represent a hydrogen atom, an optionally substituted alkyl group or the like: R6 represents a hydrogen atom, an optionally substituted aryl group or the like; and -Y-NH2, represents a group represented by the following formula (A): (wherein m is 0, 1 or 2; and R7 may not exist or one or two R7 may exist and independently represent an optionally substituted alkyl group or the like) or the like.]
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Page/Page column 124-125
(2010/11/23)
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- Iron porphyrins catalyze the synthesis of non-protected amino acid esters from ammonia and diazoacetates
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Iron complexes of porphyrins (and corroles to a lesser extent) are the first catalysts to utilize ammonia for the synthesis of N-free amino acid esters. The Royal Society of Chemistry 2006.
- Aviv, Iris,Gross, Zeev
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p. 4477 - 4479
(2008/09/19)
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- Process for preparing amino acid esters and their acid addition salts
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The invention provides a process for preparing amino acid esters and/or their acid addition salts from monomeric or polymeric amino acids, peptides, proteins and alcohols, which comprises carrying out the reaction in supercritical alcohols, preferably at pressures and temperatures which are at least 5% above the critical parameters, the alcohols serving both as the solvent and as reactants.
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Page/Page column 3
(2008/06/13)
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- Process for the preparation of amino acid esters and their acid addition salts
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Preparation of amino acids, peptide esters and/or their acid addition salts of monomers or polymers amino acids, peptides, proteins or alcohols (I), where the reaction is carried out in supercritical alcohols.
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Page/Page column 5
(2008/06/13)
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- New insights into the palladium-mediated selective hydrolysis of the His18-Thr19 peptide bond in cytochrome c: 1H NMR and density functional theory investigation for model compounds
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The peptides, CH3CO-Met-His-GlyH, CH3CO-CysMe-His-GlyH, CH3CO-CysMe-His-Gly-OEt and its imidazole derivatives, Nτ-benzyl, Nτ-tosyl, N-benzyl-Nπ-phenacyl, have been synthesized and used as model compounds for the mechanistic study of the selective cleavage of cytochrome c promoted by Pd(II) complexes. The peptide bond cleavage of these substrates by cis-[Pd(en)(solvent)2]2+ (solvent: D2O or CD3OD) was monitored by 1H NMR spectroscopy. The results showed that the methionine-containing tripeptide differs from the S-methylcysteine-containing tripeptides in the mode of coordination to Pd(II). The former coordinates to Pd(II) through a sulfur atom, an amide nitrogen of methionine and an Nπ atom of imidazole, forming a polycyclic chelate, and is resistant to hydrolysis. The latter, as a model compound for cleavage of the His18-Thr19 bond in cytochrome c with Pd(II) complexes, coordinates to Pd(II) via a sulfur atom, an amide nitrogen and a carbonyl oxygen of histidine to form a polycyclic chelate in which the His-Gly peptide bond is cleaved. Kinetic studies showed that protonation of the Nπ atom of imidazole in the S-methylcysteine-containing tripeptides is one of the key factors in controlling the cleavage of the His-Gly bond. In order to obtain theoretical guidance on the cleavage reaction, the geometries of a representative Nπ protonated tripeptide cation of CH3CO-CysMe-His-GlyNMe and its Pd(II) complex with and without ancillary water molecules are optimized at the B3LYP density functional theory level using 3-21G, 6-31G(d) and LanL2DZ basis sets. Based on the experimental and theoretical results obtained from the model compounds, a mechanism is proposed for the first time to explain the nature of selective cleavage of the His18-Thr19 bond in cytochrome c promoted by Pd(II) complexes. Coordination of Pd(II) to the carbonyl oxygen of histidine and hydrogen bond formed between the C=O and ancillary dimer water weaken and polarize the C=O double bond of histidine, giving rise to cleavage of the peptide bond.
- Sun, Xiao-Juan,Zhang, Lin,Zhang, Yu,Yang, Gao-Sheng,Guo, Zi-Jian,Zhu, Long-Gen
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p. 818 - 822
(2007/10/03)
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- Synthesis, stability and in vitro dermal evaluation of aminocarbonyloxymethyl esters as prodrugs of carboxylic acid agents
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Aminocarbonyloxymethyl esters 3 based on (S)-amino acid carriers were synthesised and evaluated as potential prodrugs of carboxylic acid agents. In addition, the compounds were evaluated as topical prodrugs with the aim of improving the dermal delivery of two non-steroidal anti-inflammatory agents: naproxen and flufenamic acid. The lipophilicities of these compounds were determined and their hydrolyses in aqueous solutions and in human plasma were examined. Compounds 3 containing a secondary carbamate group were hydrolysed at pH 7.4 by two different routes: (i) direct nucleophilic attack at the ester carbonyl carbon leading to the release of the parent carboxylic acid and (ii) intramolecular rearrangement involving an O → N acyl migration, leading to the formation of the corresponding amide. The rearrangement pathway is highly dependent on the size of the carboxylic acid and amino acid substituents, being eliminated when the amino acid is valine or leucine. In contrast, compounds 3 decomposed in plasma exclusively through ester hydrolysis, most releasing the parent carboxylic acid quantitatively with half-lives shorter than 5 min. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. All prodrugs evaluated exhibited a lower flux than the corresponding parent carboxylic acid. The poor skin permeation observed for compounds 3 is most probably due to their low aqueous solubility and high partition coefficient.
- Mendes, Eduarda,Furtado, Tania,Neres, Jo?o,Iley, Jim,Jarvinen, Tomi,Rautio, Jarkko,Moreira, Rui
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p. 809 - 816
(2007/10/03)
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- Perfluoro-tagged benzyloxycarbonyl protecting group and its application in fluorous biphasic systems
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The synthesis of a new perfluoro-tagged benzyloxycarbonyl protecting group is reported, as well as its application in the parallel protection of amines. Isolation of the protected amines was performed by simple liquid-liquid extraction between perfluorinated and organic solvents. Deprotection was achieved by standard hydrogenolysis. The novel protecting group was also applied to cyclization protocols leading to quinazoline-2,4-diones. These products were isolated by simple extraction procedures.
- Schwinn, Dominik,Bannwarth, Willi
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p. 255 - 264
(2007/10/03)
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- Quinazolines, pharmaceutical compositions containing these compounds, their use and processes for preparing them
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Quinazolines of the formula having an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
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- Synthesis and anticholinesterase activity of some benzo-1,3,2-dioxaphospholene, oxazaphospholine and diazaphospholine 2-ones containing 2-amino acid substitution
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Synthesis of the titled compounds has been described. 1H NMR, IR band frequencies and MS fragmentation and rearrangement peaks were analyzed and discussed in detail. Studying the inhibitory effect of these compounds on acetylcholinesterase (AChE) showed that dioxaphospholenes were stronger inhibitors than oxazaphospholines and diazaphospholines. This was explained by increasing the number of nitrogen atoms around the phosphorus atom in the later two series, which reduces the electrophilic character of the phosphorus atom by the overlapping between the dπ - pπ orbitals of the phosphorus and the neighboring nitrogen atoms, and hence reducing the electrophilic attack of the phosphorus atom on a nucleophilic center at the esteratic site of the enzyme. Steric factor of the amino acid moiety showed stronger effect than the electronic factor on the inhibition activity, the observed order was glycine > glutamic > methaionine > phenylalanine > alanine.
- Ali, Hussein M.
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p. 157 - 166
(2007/10/03)
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- Hydrogenation of cyanophosphonate derivatives in the presence of a glycine derivative
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A process for preparing N-phosphonomethylglycine or an N-phosphonomethylglycine derivative involves the hydrogenation of cyanophosphonate derivatives in the presence of a glycine derivative and a catalyst to produce N-phosphonomethylglycine.
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- URICOSURIC AGENT
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A remedy for hyperuricemia which comprises a hydantoin derivative represented by general formula (I) or a salt thereof as the active ingredient, wherein Q represents cyclohexyl, cycloheptyl, cyclooctyl, 2,5-dimethylthien-3-yl, indan-2-yl or 2,5-dichlorophenyl. The uricosuric agent exerts a potent uricosuric effect on an animal experiment model while sustaining or gradually increasing the urine volume. Further, it has a low toxicity. Thus it is useful in the treatment of hyperuricemia or in the treatment and prevention of gout. It is expected that the effect of the uricosuric agent of sustaining or gradually increasing the urine volume would relieve the load on a patient of taking a large amount of water.
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- Kinetics of reversible carbon deprotonation of 2-nitroethanol and 2-nitro-1,3-propanediol by hydroxide ion, water, amines, and carboxylate ions. A normal br?nsted α despite an imbalanced transition state
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Rates of reversible carbon deprotonation of 2-nitroethanol (2) and 2-nitro-1,3-propanediol (3) by hydroxide ion, water, amines, and carboxylate ions and pKa values for the ionization at carbon (pKaCH) and oxygen (pKaOH) and ionization of the aci-forms (pKaNOH) were determined in aqueous solution at 25 °C. The pKaCH values for 2 and 3 are 8.60 and 7.68, respectively, as compared to 10.22 for CH3NO2. The acidifying effect of the CH2OH groups is attributed to a combination of inductive electron withdrawal and hyperconjugative stabilization of the respective nitronate ions, possibly coupled with intramolecular hydrogen bonding stabilization of this ion. The higher acidity of 2-nitroethanol compared to nitromethane is reflected in higher rates of proton transfer from 2-nitroethanol, implying a "normal" Br?nsted α between 0 and 1. This contrasts with the negative α value based on the reaction of OH- with nitromethane, nitroethane, and 2-nitropropane (Kresge, A. J. Can. J. Chem. 1974, 52, 1897). Reasons why a normal α value is observed in the current system are discussed.
- Bernasconi, Claude F.,Panda, Markandeswar,Stronach, Michael W.
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p. 9206 - 9212
(2007/10/03)
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- Oxime derivatives of the intermediary oncostatic metabolites of cyclophosphamide and ifosfamide: Synthesis and deuterium labeling for applications to metabolite quantification
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There is ongoing interest in the selective, quantitative analysis of the cyclophosphamide metabolites 4-hydroxycyclophosphamide (2a) and aldophosphamide (3a) because these tautomers are generally believed to play a key role in oncostatic selectivity and metabolite transport. O-(2,3,4,5,6- Pentafluorobenzyl)hydroxylamine (C6F5CH2ONH2, 1 equiv) provided for the complete conversion (by 31P NMR, 60% reaction within 15 min at 20 °C) of 2a/3a (17 mM in H2O/CH3OH) to E/Z-aldophosphamide O-(2,3,4,5,6- pentafluorobenzyl)oxime [C6F5CH2ON=CHCH2CH2OP-(O)(NH2)N(CH2CH2Cl)2; E:Z = 54:46 (±3% average deviation)]. Under these conditions, the oxime exhibited little (6%) decomposition over 3 weeks. Parallel studies showed that 4-hydroxyifosfamide/aldoifosfamide reacted completely to give the analogous aldoifosfamide oxime [C6F5- CH2ON=CHCH2CH2OP(O)(NHCH2CH2Cl)2; E:Z = 52:48 (±1% average deviation)] with 50% reaction within 15 min at 20 °C with no product decomposition over 3 weeks. In aqueous methanol and with 2 equiv C6F5CH2ONH2, clinically useful 4-hydroperoxycyclophosphamide (10 mM; τ = 10 min, 37 °C) and its isomer 4-hydroperoxyifosfamide (10 mM; τ = 25 min, 20 °C) underwent complete conversion to the corresponding aldehyde oximes. Each oxime was synthesized with deuterium in the chloroethyl moieties for use as internal standards in GC/MS applications.
- Ludeman,Shulman-Roskes,Wong,Han,Anderson,Strong,Colvin
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p. 393 - 398
(2007/10/02)
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- Reduction of azides to amines with borohydride exchange resin - Nickel acetate
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Borohydride exchange resin (BER) - nickel acetate system in methanol readily reduces both aliphatic and aromatic azides to the corresponding amines in excellent yields.
- Yoon,Choi,Shon
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p. 3047 - 3053
(2007/10/02)
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- Highly Sterically hindered Carbon Acids: The Intrinsic Reactivity of 5,5',5''-Trimethyl- and 3,3',3'',5,5',5''-Hexamethyl-2,2',2'',4,4',4''-Hexanitrotriphenylmethanes
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Rate constants (kpB,kpBH) for the reversible deprotonation of 5,5',5''-trimethyl- and 3,3',3'',5,5',5''-hexamethyl-2,2',2'',4,4',4''-hexanitrotriphenylmethanes (2 and 3) by primary aliphatic amines, piperidine and morpholine as well as by phenoxide anions and hydroxide anion have been measured in H2O-Me2SO (20:80) at 25 deg C.Comparison of the results obtained with those for 2,2',2'',4,4',4''-hexanitrotriphenylmethane (1a) shows that the introduction of methyl groups in positions adjacent to the nitro groups decreases markedly the thermodynamic acidity of theexocyclic CH group: ΔpK2a1a = 1.68; ΔpK3a1a = 6.48.It is suggested that these decreases are very likely the reflection of a twisting of the nitro groups out of their attached aromatic planes and therefore of a reduced resonance stabilization of the conjugated carbanions C-2 and C-3.Other important steric effects are operating in the ionization of 2 and 3.These arise from the accumulation of ortho-nitro groups in the triphenylmethane system which makes the approach of the base reagents from the exocyclic carbon of 2 and 3 very difficult.The finding of extremely low intrinsic reactivities for 2 and 3 and the observation of a much greater catalytic efficiency of primary amines than of secondary amines in assisting the proton transfers are the two most striking manifestations of these F-strain effects.
- Terrier, Francois,Xiao, Lan,Farrell, Patrick G.,Moskowitz, Danielle
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p. 1259 - 1263
(2007/10/02)
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- Cleavable bifunctional coupling agents
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A bifunctional coupling agent for joining a sulfhydryl containing protein or peptide and a metallic radionuclide comprising a sulfhydryl selective electrophile, a chelator containing at least one protected thiol and a organic linking radical containing at least one cleavable site which serves to join said electrophile and said chelator is disclosed. A radiodiagnostic or radiotherapeutic precursor comprising an antibody or antibody fragment and the specified bifunctional coupling agent bound to a sulfhydryl group on the antibody or antibody fragment and a radiodiagnostic or radiotherapeutic agent comprising such precursor having a metallic radionuclide bound thereto are also disclosed.
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- Kinetics of Amine Addition to Benzylidenemalonodialdehyde in 50percent Me2SO-50percent water
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The kinetics of the reaction of benzylidenemalonodialdehyde with piperidine, morpholine, n-butylamine, 2-methoxyethylamine, glycinamide, glycine ethyl ester, cyanomethylamine, and semicarbazide have been determined in 50percent aqueous Me2SO at 20 deg C.The reaction leads to a zwitterionic adduct, PhCH(RR'NH(1+))C(CHO)2(1-) (TA(+/-)), that is in fast acid-base equilibrium with the anionic adduct, PhCH(RR'N)C(CHO)2(1-) (TA(1-)).With strongly basic amines at high pH there is also attack of the amine on one of the carbonyl groups, which acts as a rapid preequilibrium.Rate constants for the formation of TA(+/-) (k1) and its reverse (k-1), as well as equilibrium constants (K1 = k1/k-1) and the pKa of TA(+/-) were determined for all the amines.Intrinsic rate constants (k0 = k1 = k-1 when K1 = 1) were calculated.The intrinsic rate constants are lower than those for amine addition to benzylidene Meldrum's acid.This is consistent with the greater role played by resonance in stabilizing TA(+/-) derived from benzylidenemalonodialdehyde.However, k0 for piperidine/morpholine addition to benzylidenemalonodialdehyde is much higher than for the reaction of benzylideneacetylacetone with the same amines, indicating that the rate-depressing effect of intramolecular hydrogen bonding in TA(+/-) derived from benzylidenemalonodialdehyde is much smaller than that in TA(+/-) derived from benzylideneacetylacetone.Even though semicarbazide is an α-effect nucleophile, no enhancement of k1 was observed, but K1, estimated on the basis of a structure-reactivity relationship, is larger than expected based on the pKa of the amine.This result is attributed to a low νnucn value.
- Bernasconi, Claude F.,Stronach, Michael W.
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p. 1993 - 2001
(2007/10/02)
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- A Convenient Synthesis of Primary Amines Using Sodium Diformylamide as A Modified Gabriel Reagent
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Sodium diformylamide (1) was used as a convenient substitute for phthalimide in the Gabriel synthesis of primary amines.Reagent 1 undergoes smooth N-alkylation with alkyl halides or p-toluenesulfonates 2 in acetonitrile or dimethylformamide to give the corresponding N,N-diformylalkylamines 3 in good yields, except with alkylating agents which are susceptible to base-catalyzed elimination.The formyl group of 3 can be easily removed by hydrochloric acid to give the corresponding alkylamine hydrochlorides 5 or free alkylamines 4.
- Yinglin, Han,Hongwen, Hu
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p. 122 - 124
(2007/10/02)
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- 1-carboalkoxyalkyl-3-alkoxy-4-(2'-carboxyphenyl)-azet-2-ones as plant growth regulators and selective herbicides
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Compounds of the formula: STR1 wherein R1 is lower alkyl of 1 to 6 carbon atoms lower alkenyl of 2 to 6 carbon atoms or benzyl; R2 is lower alkoxy of 1 to 6 carbon atoms, benzyloxy or the group STR2 where R4 is lower alkoxy of 1 to 4 carbon atoms; and R3 is hydrogen, lower alkyl of 1 to 6 carbon atoms, lower alkyl of 1 to 6 carbon atoms substituted with 1 to 3 trihalomethyl groups, lower haloalkyl of 1 to 6 carbon atoms substituted with 1 to 6 halogen atoms, lower alkenyl of 2 to 6 carbon atoms, arylalkyl of 7 to 12 carbon atoms, lower alkoxyalkyl of 2 to 6 carbon atoms, lower alkylthioalkyl of 2 to 6 carbon atoms, or lower cycloalkyl of 3 to 8 carbon atoms are active as plant growth regulators. Certain of these compounds also show activity as selective herbicides.
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