- Conformationally constrained analogues of (Z)-5-decenyl acetate, a pheromone component of Agrotis segetum
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Conformationally constrained analogues of (Z)-5-decenyl acetate (1), a pheromone component of the turnip moth. Agrotis segetum, have been synthesized and tested by using electrophysiological single-cell recordings. In the constrained analogues the terminal alkyl chain in 1 has been incorporated in a six-membered (3 and 4) or five-membered (6) ring system. These cyclic compounds are also conformationally constrained analogues of the previously deduced bioactive conformations of the corresponding chain-elongated analogues 2 and 5. The electrophysiological activities of the constrained analogues are found to be significantly lower than that of the natural pheromone component 1, most probably due to steric repulsive interactions between the analogue and the receptor, and also lower than the activities of the corresponding chain-elongated analogues of 1. It is concluded that the flexibility of the terminal chains in 2 and 5 is essential for the possibility of the receptor to accommodate these parts of the chain-elongated analogues in their bioactive conformations.
- Joensson, Stig,Hansson, Bill S.,Liljefors, Tommy
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Read Online
- Alkyl Ether and Enol Ether Analogs of (Z)-5-Decenyl Acetate, a Pheromone Component of the Turnip Moth, Agrotis segetum: Probing a Proposed Bioactive Conformation for Chain-Elongated Analogs
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In order to test a previous conclusion that chain-elongated analogs of (Z)-5-decenyl acetate (1), a pheromone component of the turnip moth, Agrotis segetum, adopt a loop conformation of the terminal alkyl chain in the bioactive conformation, a series of alkyl ether and enol ether analogs of 1 and (Z)-5-dodecenyl acetate (2) have been synthesized and tested using single-cell electrophysiology. In these analogs a methylene group in positions 7 and 9 of 1 and in positions 7 and 11 in 2 have been replaced by an oxygen atom in order to energetically facilitate the formation of a loop conformation in the chain-elongated analogs. The electrophysiological results in combination with molecular mechanics (MM2 and MM3) calculated conformational energies show that the activity decreases of the chain-elongated ether analogs are significantly smaller than that for 2 and that these activity decreases parallel the conformational energies for a loop formation of the terminal chains in the analogs. The results support our previous conclusion that the terminal chain of chain-elongated analogs of 1 adopts a loop conformation in their bioactive conformations.
- Gustavsson, Anna-Lena,Liljefors, Tommy,Hansson, Bill S.
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Read Online
- Acid-Catalyzed Intramolecular Ring-Opening Reactions of Cyclopropanated Oxabenzonorbornadienes with Carboxylic Acid Nucleophiles
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The present work demonstrates the ability of carboxylic acid tethered cyclopropanated oxabenzonorbornadienes (CPOBDs) to undergo ring-opening reactions in mild acidic conditions. The optimized reaction conditions involve the use of pTsOH in DCE at 90 °C. Two regioisomers are formed but the reactions are highly regioselective towards type 3 ring-opened products. It was observed that substitution at the C5 and aryl positions of CPOBD significantly hinders the ring-opening reactions leading to decreased yields of ring-opened products, although high regioselectivity for the Type 3 ring-opened products is still maintained. Herein, the first examples of acid-catalyzed intramolecular ring-opening reactions of CPOBD with carboxylic acid nucleophiles are reported.
- Carlson, Emily,Ho, Angel,Koh, Samuel,Macleod, Matthew P.,Pounder, Austin,Tam, William
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- Design, synthesis and evaluation of phthalide alkyl tertiary amine derivatives as promising acetylcholinesterase inhibitors with high potency and selectivity against Alzheimer's disease
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A series of phthalide alkyl tertiary amine derivatives were designed, synthesized and evaluated as potential multi-target agents against Alzheimer's disease (AD). The results indicated that almost all the compounds displayed significant AChE inhibitory and selective activities. Besides, most of the derivatives exhibited increased self-induced Aβ1-42 aggregation inhibitory activity compared to the lead compound DL-NBP, and some compounds also exerted good antioxidant activity. Specifically, compound I-8 showed the highest inhibitory potency toward AChE (IC50 = 2.66 nM), which was significantly better than Donepezil (IC50 = 26.4 nM). Moreover, molecular docking studies revealed that compound I-8 could bind to both the catalytic active site and peripheral anionic site of AChE. Furthermore, compound I-8 displayed excellent BBB permeability in vitro. Importantly, the step-down passive avoidance test indicated that I-8 significantly reversed scopolamine-induced memory deficit in mice. Collectively, these results suggested that I-8 might be a potent and selective AChE inhibitor for further anti-AD drug development.
- Cao, Zhongcheng,Deng, Yong,Li, Yan,Luo, Li,Qiang, Xiaoming,Song, Qing,Tan, Zhenghuai
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- Synthesis of 2-Azabicyclo[m.n.0]–Alkanes and Their Application towards the Synthesis of Strychnos and Stemona Classes of Alkaloids
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2-Azabicyclo[m.n.0]alkane ring systems, the conceptual precursors towards the synthesis of Strychnos and Stemona classes of alkaloids, were synthesized from tert-butyl 2-(phenylsulfonyl)-7-aza-bicyclo[2.2.1]hept-2-ene-7-carboxylate by alkyl Grignard reaction and intramolecular cyclisation of the in situ generated ring opening product 2. The synthesized cis-hexahydroindole 3 and cis-octahydro-benzo[b]azepine 5 scaffolds were utilized to construct the advanced intermediates 25 and 35, respectively, towards the synthesis of the corresponding Strychnos and Stemona classes of alkaloids.
- Majumder, Binoy,Pandey, Ganesh
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supporting information
p. 3883 - 3888
(2020/06/02)
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- Continuous-Flow Amide and Ester Reductions Using Neat Borane Dimethylsulfide Complex
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Reductions of amides and esters are of critical importance in synthetic chemistry, and there are numerous protocols for executing these transformations employing traditional batch conditions. Notably, strategies based on flow chemistry, especially for amide reductions, are much less explored. Herein, a simple process was developed in which neat borane dimethylsulfide complex (BH3?DMS) was used to reduce various esters and amides under continuous-flow conditions. Taking advantage of the solvent-free nature of the commercially available borane reagent, high substrate concentrations were realized, allowing outstanding productivity and a significant reduction in E-factors. In addition, with carefully optimized short residence times, the corresponding alcohols and amines were obtained in high selectivity and high yields. The synthetic utility of the inexpensive and easily implemented flow protocol was further corroborated by multigram-scale syntheses of pharmaceutically relevant products. Owing to its beneficial features, including low solvent and reducing agent consumption, high selectivity, simplicity, and inherent scalability, the present process demonstrates fewer environmental concerns than most typical batch reductions using metal hydrides as reducing agents.
- ?tv?s, Sándor B.,Kappe, C. Oliver
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p. 1800 - 1807
(2020/02/27)
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- METHODS AND COMPOUNDS FOR TARGETED AUTOPHAGY
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Provided herein, inter alia, are methods and compounds for targeted autophagy.
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Paragraph 0030; 1190; 1191
(2019/10/12)
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- [...] curved nitroxide derivative and its preparation method and application (by machine translation)
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The invention discloses a sand-kouba curved nitroxide derivatives, have the formula I shown in the chemical structure of: Also discloses the sand kouba curved nitrooxyderivatives pharmaceutically acceptable salts or its pharmaceutically acceptable solvates. Also discloses a pharmaceutical composition, comprising a pharmaceutically-acceptable carrier, a pharmaceutically effective amount of the nitroxide derivatives [...] curved and/or its salt or stereoisomers. Also disclosed sand kouba curved nitrooxyderivatives of the preparation method, and [...] curved nitroxide derivatives or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for treating cardiovascular diseases in the application. (by machine translation)
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Paragraph 0067; 0068
(2019/01/06)
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- Total Synthesis of Emmyguyacins A and B, Potential Fusion Inhibitors of Influenza Virus
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Fungal glycolipids emmyguyacins A and B inhibit the pH-dependent conformational change of hemaglutinin A during replication of the Influenza virus. Herein, we report the first total synthesis and structure confirmation of emmyguyacins A and B. Our efficient route, which involves regioselective functionalization of trehalose, allows rapid access to adequate amounts of chemically pure emmyguyacin analogues including the desoxylate derivatives for SAR studies.
- Jana, Santanu,Sarpe, Vikram A.,Kulkarni, Suvarn S.
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supporting information
p. 6938 - 6942
(2018/10/25)
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- NITRIC OXIDE RELEASING PROSTAGLANDIN DERIVATIVES FOR TREATING NORMAL TENSION GLAUCOMA
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This invention provides a method of lowering intraocular pressure in a patient having normal tension glaucoma, comprising contacting an eye of a subject having normal tension glaucoma with a pharmaceutical composition comprising an effective amount of Nitric Oxide releasing prostaglandin derivatives of formula (I).
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Page/Page column 13
(2018/05/27)
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- Dihydroarteannuin-memantine diad compounds, and synthesis method and application thereof
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The invention discloses dihydroarteannuin-memantine diad compounds, and a synthesis method and application thereof. The structure of the compounds is disclosed as Formula I. The synthesis method comprises the following steps: reducing arteannuin to obtain dihydroarteannuin, carrying out acetalation reaction on the dihydroarteannuin and 2-bromoethanol under the catalytic action of Lewis acid, and carrying out reaction on the acetalation reaction product and memantine hydrochloride to obtain the dihydroarteannuin-memantine diad compounds. The compounds are reported for the first time, have an therapeutic effect on neurodegenerative diseases, and can be used for preparing drugs for treating neurodegenerative diseases. Compared with other prior arts, the compounds disclosed by the invention have the advantages of simple preparation technique and better curative effect than memantine.
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Paragraph 0057; 0058
(2016/10/10)
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- Preparation of useful building blocks, α-iodo- and bromoalkanols from cyclic ethers using the Dowex H+/NaX (X = I, Br) approach
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Our recently reported novel green chemistry tool was effectively used for opening cyclic ethers to produce α-iodo- and bromoalkanols. The synthesis of 4-iodobutanoic acid from γ-butyrolactone has also been described. The method is based on the use of a dried Dowex H+/NaX (X = Br, I)-system, which is effective at producing α-iodoalkanols and some α-bromoalkanols from commercially available cyclic ethers. Additionally, opening of three different crown ethers to form α-iodo(polyethylene)glycols with various chain lengths is demonstrated. Haloalkanols are important building blocks in synthetic chemistry e.g. for medicinal chemistry purposes.
- Turhanen, Petri A.,Veps?l?inen, Jouko J.
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p. 15937 - 15940
(2016/02/19)
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- Unusual Adsorption at the Air-Water Interface of a Zwitterionic Carboxybetaine with a Large Charge Separation
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The structures of layers of three different dodecylcarboxybetaine surfactants adsorbed at the air-water interface have been determined by neutron reflection. The zwitterionic compounds differed in the length of the spacer separating the quaternary ammonium and carboxylate groups, which was (CH2)1, (CH2)4, or (CH2)8. The limiting area per molecule was found to be 45, 52, or 84 ?2, respectively, and compared reasonably with results from surface tension showing that the Gibbs prefactor is 1 in each case. Isotopic labeling was used to distinguish between the position of the alkyl and spacer groups in the layer. The spacer was found to be well-immersed in water for the (CH2)1 and (CH2)4 spacers but significantly above water for the (CH2)8 spacer. The distribution of the (CH2)8 spacer along the surface normal was found to be similar to that of the dodecyl group; i.e., it projects out of the water, contrary to an earlier hypothesis that it forms a loop. Comparison of the overlap of water with dodecyl and spacer groups also indicates that the (CH2)8 spacer is well out of the water. This in turn suggests that the anionic carboxylic acid group, which is dissociated in solution, is not ionized in the adsorbed layer. A further observation is that the dodecylcarboxybetaine with the (CH2)8 spacer reaches surface saturation at one-tenth of the critical micelle concentration. This is highly unusual and is attributed to the long spacer destabilizing the micelle relative to the surface layer.
- Ma, Kun,Li, Pei Xun,Dong, Chu Chuan,Thomas, Robert K.,Penfold, Jeffrey
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p. 3340 - 3347
(2016/05/10)
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- Visible-Light-Promoted Oxidative [4 + 2] Cycloadditions of Aryl Silyl Enol Ethers
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Visible-light-promoted oxidative [4 + 2] cycloadditions of μ,3-unsaturated silyl enol ethers have been developed to efficiently and diastereoselectively construct polycyclic skeletons under mild conditions. The diastereoselectivities were dependent on the stereoconfiguration of silyl enol ether, substitutions on the link, as well as electric properties of substitutions on aryl rings. The intermediates could be trapped by TEMPO, oxygen or methanol. Mechanistic studies indicated the reaction was initiated by one-electron oxidation of the silyl enol ether.
- Yang, Bo,Lu, Zhan
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p. 7288 - 7300
(2016/08/30)
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- Racemic total synthesis of dactyloidin and demethyldactyloidin through the dl-proline-catalyzed Knoevenagel condensation/[4 + 2] cycloaddition cascade
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An efficient approach towards the first racemic total synthesis of dactyloidin (2) and demethyldactyloidin (3) is described. Their oxygen-bridged tricyclic ketal systems were rapidly constructed by using a remarkable biomimetic Knoevenagel condensation/[4 + 2] cycloaddition cascade as the critical strategy and the 1,5-dicarbonyl segment was assembled by Grignard addition.
- Tan, Haibo,Liu, Hongxin,Chen, Xinzheng,Chen, Huiyu,Qiu, Shengxiang
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supporting information
p. 9977 - 9983
(2015/10/12)
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- METALLOENZYME INHIBITOR COMPOUNDS
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The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
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Page/Page column 105-106
(2014/08/07)
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- Development of a benzophenone and alkyne functionalised trehalose probe to study trehalose dimycolate binding proteins
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Trehalose dimycolates (TDMs) are the most abundant glycolipids found in the cell wall of Mycobacterium tuberculosis (M. tb). TDMs play an important role in the pathogenesis of M. tb yet the only known receptor for TDM is the macrophage inducible C-type lectin (mincle). To understand more about the interaction of TDMs with immune cells, affinity based proteome profiling (AfBPP) can be used to determine receptors that bind TDMs. To this end, we present the synthesis of the first AfBPP-TDM probe and report on its ability to activate macrophages. By doing so, we establish that the AfBPP-TDM probe appears to be a suitable substrate for future proteomic profiling experiments.
- Khan, Ashna A.,Kamena, Faustin,Timmer, Mattie S.M.,Stocker, Bridget L.
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supporting information
p. 881 - 885
(2013/02/26)
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- Spiroaminal model systems of the marineosins with final step pyrrole incorporation
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In this Letter, we describe a short, six step enantioselective route to spiroaminal lactam model systems reminiscent of marineosins A and B that has been developed starting from either (R)- or (S)-hydroxysuccinic acid, respectively, in ~9% overall yield. This route enables late stage incorporation of the pyrrole ring at C5 via nucleophilic displacement of an iminium triflate salt.
- Panarese, Joseph D.,Konkol, Leah C.,Berry, Cynthia B.,Bates, Brittney S.,Aldrich, Leslie N.,Lindsley, Craig W.
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p. 2231 - 2234
(2013/05/09)
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- NITROXY DERIVATIVES OF SOFT STEROIDS
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A compound of formula (I) or a pharmaceutically acceptable salt thereof, and an ophthalmic composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention is also directed to the use of the ophthalmic compositions for treating inflammatory conditions of the palpebral or bulbar conjunctiva, cornea and anterior segment of the globe, and to ameliorate inflammation associated with corneal injury.
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Page/Page column 17
(2013/09/26)
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- Construction of enantioenriched cyclic compounds by asymmetric allylic alkylation and ring-closing metathesis
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A new approach to highly enantioenriched cyclic compounds (up to 98a€‰% ee) has been developed by using ω-ethylenic allylic substrates in a one-pot asymmetric allylic alkylation and ring-closing metathesis sequence. The starting compounds are synthetic equivalents of cyclic allylic substrates. The method is exemplified with both Cu and Ir catalysts, and chiral phosphoramidite ligands. A new approach to highly enantioenriched cyclic compounds (up to 98a€‰% ee) has been developed by using ω-ethylenic allylic substrates in a one-pot asymmetric allylic alkylation and ring-closing metathesis sequence. The starting compounds are synthetic equivalents of cyclic allylic substrates. The method is exemplified with both Cu and Ir catalysts, and chiral phosphoramidite ligands. Copyright
- Giacomina, Francesca,Alexakis, Alexandre
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supporting information
p. 6710 - 6721
(2013/11/06)
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- PHOTORESIST COMPOSITION, RESIST-PATTERN FORMING METHOD, POLYMER, AND COMPOUND
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A photoresist composition includes a polymer that includes a structural unit shown by the following formula (1), and a photoacid generator. R1 in the formula (1) represents a hydrogen atom, a fluorine atom, a methyl group, or a trifluoromethyl group, Z represents a group that forms a divalent alicyclic group having 3 to 20 carbon atoms together with a carbon atom bonded to X, X represents an alkanediyl group having 1 to 6 carbon atoms, Y represents a hydrogen atom or —CR2R3(OR4), and R2 to R4 independently represent a hydrogen atom or a monovalent hydrocarbon group, provided that R3 and R4 optionally bond to each other to form a cyclic ether structure together with a carbon atom bonded to R3 and an oxygen atom bonded to R4.
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- An expedient route for the reduction of carboxylic acids to alcohols employing 1-propanephosphonic acid cyclic anhydride as acid activator
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A simple and efficient method for the synthesis of alcohols from the corresponding carboxylic acids is described. Activation of carboxylic acid with 1-propane phosphonic acid cyclic anhydride (T3P) and subsequent reduction of the intermediate phosphonic anhydride with NaBH4 yield the alcohol in excellent yields with good purity in less duration. Reduction of several alkyl/aryl carboxylic acids and Nα-protected amino acids/peptide acids as well as Nβ-protected amino acids was successfully carried out to obtain corresponding alcohols in good yields and the products characterized. The procedure is mild, safe, simple and the isolation of the products is easy.
- Nagendra,Madhu,Vishwanatha,Sureshbabu, Vommina V.
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experimental part
p. 5059 - 5063
(2012/09/22)
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- 17(R),18(S)-Epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: Structure-activity relationships and stable analogues
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17(R),18(S)-Epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca 2+-overload with EC50 ≈ 1-2 nM. Structure-activity studies revealed that a cis-Δ11,12- or Δ14,15- olefin and a 17(R),18(S)-epoxide are minimal structural elements for antiarrhythmic activity whereas antagonist activity was often associated with the combination of a Δ14,15-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogues are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.
- Falck, John R.,Wallukat, Gerd,Puli, Narender,Goli, Mohan,Arnold, Cosima,Konkel, Anne,Rothe, Michael,Fischer, Robert,Müller, Dominik N.,Schunck, Wolf-Hagen
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supporting information; experimental part
p. 4109 - 4118
(2011/08/05)
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- Synthesis of deuterated 5(Z),11(Z)-eicosadienoic acid as a biomarker for trophic transfer
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The poly-methylene interrupted fatty acid 5(Z),11(Z)-eicosadienoic acid and its tetradeuterated analogue were prepared via a convergent synthetic sequence.
- Albu, Siliva,Sverko, Ed,Arts, Michael T.,Capretta, Alfredo
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scheme or table
p. 787 - 788
(2011/03/21)
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- PHOSPHONATED RIFAMYCINS AND USES THEREOF FOR THE PREVENTION AND TREATMENT OF BONE AND JOINT INFECTIONS
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The present invention relates to phosphonated Rifamycins, and methods of making and using such compounds. These compounds are useful as antibiotics for prophylaxis and/or the treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.
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(2011/11/06)
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- Steroids modified at C15. Synthesis and spectra-structure correlations
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A synthesis of 15-benzoyloxybutyl-20-hydroxymethylpregn-16-enes, the intermediates in the synthesis of brassino-and ecdysteroids modified in the D ring was performed starting with 2α,3α-isopropylidenedioxy-6,6- ethylenedyoxy-5α-androst-15-ene-17-one and its 2β,3β-isomer through a sequence of reactions involving Michael addition, Wittig reaction and ene reaction. Structures of the compounds were proved by the methods of two-dimensional NMR spectroscopy. Pleiades Publishing, Ltd., 2011.
- Baranovskii,Khripach
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body text
p. 2142 - 2150
(2012/03/11)
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- Superelectrophilic sp3 C-H carbonylation of n-octyl acetate as a way to new bifunctional neo-octanes
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Carbonylation of n-octyl acetate in the presence of CBr4· 2AlBr3 followed by treatment with nucleophiles such as alcohols, amines or (het)arenes affords 7-acetoxy-2,2-dimethylheptanoyl-containing products.
- Akhrem, Irena S.,Avetisyan, Dzhul'Etta V.,Afanas'Eva, Lyudmila V.,Orlinkov, Alexander V.,Kagramanov, Nikolai D.,Petrovskii, Pavel V.
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experimental part
p. 323 - 325
(2012/02/04)
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- Reduction of carboxylic acids using esters of benzotriazole as high-reactivity intermediates
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Herein, we describe a simple and practical protocol for the reduction of carboxylic acids via the in situ formation of hydroxybenzotriazole esters followed by reaction with sodium borohydride to give the corresponding alcohols. The reaction proceeds with excellent yields in the presence of water. Georg Thieme Verlag Stuttgart - New York.
- Morales-Serna, Jose Antonio,Garcia-Rios, Erendira,Bernal, Jorge,Paleo, Ehecatl,Gavino, Ruben,Cardenas, Jorge
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scheme or table
p. 1375 - 1382
(2011/06/19)
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- Novel eicosanoid derivatives
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The present invention provides compounds (n-3 PUFA derivatives) of formula (I): that modulate conditions associated with cardiac damage, especially cardiac arrhythmias.
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Page/Page column 16
(2010/08/07)
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- On the mechanism of ylide-mediated cyclopropanations: Evidence for a proton-transfer step and its effect on stereoselectivity
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In this paper, we describe studies on the cyclopropanation of Michael acceptors with chiral sulfur ylides. It had previously been found that semi-stabilized sulfonium ylides (e.g., Ph-stabilized) reacted with cyclic and acyclic enones and substituted acrylates with high ee and that stabilized sulfonium ylides (e.g., ester-stabilized) reacted with cyclic enones again with high ee. The current study has focused on the reactions of stabilized sulfonium ylides with acyclic enones which unexpectedly gave low ee. Furthermore, a clear correlation of ee with ylide stability was observed in reactions with methyl vinyl ketone (MVK): ketone-stabilized ylide gave 25% ee, ester-stabilized ylide gave 46% ee, and amide-stabilized ylide gave 89% ee. It is believed that following betaine formation an unusual proton transfer step intervenes which compromises the enantioselectivity of the process. Thus, following addition of a stabilized ylide to the Michael acceptor, rapid and reversible intramolecular proton transfer within the betaine intermediate, prior to ring closure, results in an erosion of ee. Proton transfer occurred to the greatest extent with the most stabilized ylide (ketone). When the same reactions were carried out with deuterium-labeled sulfonium ylides, higher ees were observed in all cases since proton/deuteron transfer was slowed down. The competing proton transfer or direct ring-closure pathways that are open to the betaine intermediate apply not only to all sulfur ylides but potentially to all ylides. By applying this model to S-, N-, and P-ylides we have been able to rationalize the outcome of different ylide reactions bearing a variety of substituents in terms of chemo- and enantioselectivity.
- Riches, Samantha L.,Saha, Chandreyee,Filgueira, Noelia Fontan,Grange, Emma,McGarrigle, Eoghan M.,Aggarwal, Varinder K.
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supporting information; experimental part
p. 7626 - 7630
(2010/07/09)
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- PHOSPHONATED RIFAMYCINS AND USES THEREOF FOR THE PREVENTION AND TREATMENT OF BONE AND JOINT INFECTIONS
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The present invention relates to phosphonated Rifamycins, and methods of making and using such compounds. These compounds are useful as antibiotics for prophylaxis and/or the treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.
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Page/Page column 93
(2010/04/03)
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- PHOSPHONATED GLYCOPEPTIDE AND LIPOGLYCOPEPTIDE ANTIBIOTICS AND USES THEREOF FOR THE PREVENTION AND TREATMENT OF BONE AND JOINT INFECTIONS
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The present invention is directed to antimicrobial compounds which have an affinity for binding bones. More particularly, the invention is directed to phosphonated derivatives of glycopeptide or lipoglycopeptide antibiotics. These compounds are useful as antibiotics for the prevention or treatment of bone and joint infections, especially for the prevention and treatment of osteomyelitis.
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- Cysteine Protease Inhibitors
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Compounds of the formula II: wherein R2 is the side chain of leucine, isoleucine, cyclohexylglycine, O-methyl threonine, 4-fluoroleucine or 3-methoxyvaline; R3 is H, methyl or F; Rq is trifluoromethyl and Rq′ is H or Rq and Rq′ define keto; Q is a p-(C1-C6alkylsulphonyl)phenyl- or an optionally substituted 4-(C1-C6alkyl)piperazin-1-yl-thiazol-4-yl- moiety have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsin K, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.
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Page/Page column 15
(2009/02/11)
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- NITRATE ESTERS OF CARBONIC ANHYDRASE INHIBITORS
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Nitroderivatives of carbonic anhydrase inhibitors having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, cancer, epilepsy, high-altitude disorders and neuromuscular diseases.
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Page/Page column 63-64
(2008/12/06)
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- Phosphonated Fluoroquinolones, Antibacterial Analogs Thereof, and Methods for the Prevention and Treatment of Bone and Joint Infections
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The present invention relates to phosphonated fluoroquinolones, antibacterial analogs thereof, and methods of using such compounds. These compounds are useful as antibiotics for prevention and/or the treatment of bone and joint infections, especially for the prevention and/or treatment of osteomyelitis.
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Page/Page column 61
(2008/12/09)
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- PROTEASE INHIBITORS
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Compounds of the formula (II): wherein R2 is the side chain of leucine, isoleucine, cyclohexylglycine, O-methyl threonine, 4-fluoroleucine or 3-methoxyvaline; R3 is H, methyl or fluoro; R4 is C1-C6alkyl; E is a bond or thiazolyl, optionally substituted with methyl or fluoro; n is 0 or 1; or a pharmaceutically acceptable salt, N-oxide or hydrate thereof; have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsinK, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.
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Page/Page column 41-42
(2008/12/07)
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- PROSTAGLANDIN DERIVATIVES
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Nitroderivatives of prostaglandin amides having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.
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Page/Page column 59
(2008/06/13)
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- FLUOROPROSTAGLANDINS NITRODERIVATIVES
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Nitroderivatives of fluoroprostaglandins having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.
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Page/Page column 34
(2008/06/13)
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- Development of a commercial process to produce oxandrolone
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A manufacturing scale process for the preparation of the anabolic steroid Oxandrolone was developed. Key elements included the following: the bromination of methylandrostanolone with perbromide to give the 2-bromoketone in ca. 80% yield with minimal dehydration, subsequent elimination of the bromide with Li2CO3/LiBr to give the 2-enone in ca. 70% yield with minimal formation of methyltestosterone, and an ozonolysis procedure to give the penultimate intermediate in ca. 90% yield. The overall yield from methylandrostanolone to Oxandrolone using the described process was 45% as compared to the original Searle yield of 8%.
- Cabaj, John E.,Kairys, David,Benson, Thomas R.
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p. 378 - 388
(2012/12/31)
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- 2,3,4,5-TETRAHYDRO-1H-1,5-BENZODIAZEPINE DERIVATIVE AND MEDICINAL COMPOSITION
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The present invention has its object to provide a 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine derivative represented with the Formula (1) , or the pharmaceutically acceptable salt, which is effective as a therapeutic and prophylactic agent for diabetes, diabetic nephropathy, or glomerulosclerosis.
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- PROSTAGLANDIN NITROOXYDERIVATIVES
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Prostaglandin nitrooxyderivatives having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.
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Page/Page column 35-36
(2008/06/13)
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- Novel 17beta-hydroxysteroid dehydrogenase type I inhibitors
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3,15-substituted estrone compounds which act as inhibitors of 17β-hydroxysteroid dehydrogenase type I (17β-HSD1), salts thereof, pharmaceutical preparations containing such compounds, processes for preparing such compounds, and therapeutic uses of such compounds, particularly in the treatment or inhibition of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of 17β-hydroxysteroid dehydrogenase type I enzymes and/or requiring the lowering of the endogenous 17β-estradiol concentration, as well as the general use of selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors which possess in addition no or only pure antagonistic binding affinities to the estrogen receptor for the treatment or inhibition of benign gynecological disorders, particularly endometriosis.
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Page/Page column 34-35
(2010/02/13)
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- CYSTEINE PROTEASE INHIBITORS
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A compound of the formula (II) wherein one of R1 and R2 is halo and the other is H or halo; R3 is C1-C4 straight or branched chain, optionally fluorinated, alkyl; R4 is H; or R3 together with R4 and the adjoining backbone carbon defines: a spiro-C5-C7 cycloalkyl, optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C4 alkyl or C1-C4 haloalkyl; or optionally bridged with a methylene group; or a C4-C6 saturated heterocycle having a hetero atom selected from O, NRa, S, S(=O)2 ; where Ra is H, C1-C4 alkyl or CH3C(=O); R5 is independently selected from H or methyl; E is -C(=O)-, -S(=O)m-, -NR5S(=O)m-, -NR5C(=O)-, -OC(=O)-, R6 is a stable, optionally substituted, monocyclic or bicyclic, carbocycle or hetorocycle; m is independently 0,1 or 2; are inhibitors of cathepsin K and useful in the treatment or prophylaxis of osteoporosis.
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Page/Page column 89-91
(2010/02/12)
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- Biosynthesis of iso-fatty acids in myxobacteria
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The fatty acid (FA) profiles of the myxobacteria Stigmatella aurantiaca and Myxococcus xanthus were investigated by acidic methanolysis of total cell extracts and GC or GC-MS analysis. The main components were 13- methyltetradecanoic acid (iso-15:0) and (Z)-hexadec-11-enoic acid (16:1, ω-5 cis). The biosynthesis of iso-FAs was investigated in several feeding experiments. Feeding of isovaleric acid (IVA) to a mutant impaired in the degradation of leucine to isovaleryl-CoA (IV-CoA) (bkd mutant) of M. xanthus only increased the amount of iso-odd FAs, whereas feeding of isobutyric acid (IBA) gave increased amounts only of iso-even FAs. In contrast, a bkd mutant of S. aurantiaca gave increased amounts of iso-odd and iso-even fatty acids in both experiments. We assumed that in S. aurantiaca α-oxidation takes place. [D7]-15-Methylhexadecanoic acid (8) was synthesised and fed to S. aurantiaca as well as [D10]leucine and [D8]valine to elucidate this pathway in more detail. The iso-fatty acid 8 was degraded by α- and β-oxidation steps. [D10]Leucine was strongly incorporated into iso-odd and iso-even fatty acids, whereas the incorporation rates for [D8]valine into both types of fatty acids were low. Thus α-oxidation plays an important role in the biosynthesis of iso-fatty acids in S. aurantiaca. The incorporation rates observed after feeding of [D 10]leucine and [D8]valine are the highest for iso-17:0 compared to the other acids. This indicates the central role of iso-17:0 in the biosynthesis of iso-FAs. The shorter homologues seem to be formed mainly by α-oxidation and β-oxidation of this acid. After feeding of 8 traces of unsaturated counterparts of this labelled FA occurred in the extracts indicating that desaturases are active in the biosynthesis of unsaturated fatty acids in S. aurantiaca. The Royal Society of Chemistry 2005.
- Dickschat, Jeroen S.,Bode, Helge B.,Kroppenstedt, Reiner M.,Mueller, Rolf,Schulz, Stefan
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p. 2824 - 2831
(2007/10/03)
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- PRODRUGS OF EXCITATORY AMINO ACIDS
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This invention relates to a synthetic excitatory amino acid prodrug and processes for its preparation. The invention further relates to methods of using, and pharmaceutical compositions comprising, the compounds for the treatment of neurological disorders and psychiatric disorders.
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Preparation 1
(2010/11/30)
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- KETONES AND REDUCED KETONES AS THERAPEUTIC AGENTS FOR THE TREATMENT OF BONE CONDITIONS
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The present invention pertains to certain ketones and reduced ketones and derivatives thereof which, inter alia, inhibit osteoclast survival, formation, and/or activity; and/or inhibit bone resorption, and more particularly to compounds of the formulae: (1) (2) wherein: Ar1 is independently a biphenyl, phenanthryl, fluorenyl, or carbazolyl, and is optionally substituted; Ralk is independently a C2-10alkylene group, and is optionally substituted; -ORO, if present, is independently -OH or -ORK; -ORK, if present, is independently selected from: -O-RK1; -O-C(=O)RK2; -O-C(=O)ORK3; -O-S(=O)2ORK4; Q is independently -OH or -OROT; wherein: -OROT, if present, is independently selected from: -O-RE1; -O-C(=O)-RE2; -O-C(=O)-O-RE3; -O-C(=O)-O-SO3RE4; -O-C(=O)-O-(CH2)n-COORE5; -O-C(=O)-(CH2)n-NRN1RN2; -O-C(=O)-(CH2)n-NH-C(=O)RE6; -O-C(=O)-(CH2)n-C(=O)-NRN3RN4; -O-P(=O)(ORE7)(ORE8); -O-RPA; RPA, if present, is an organic group which incorporates a phosphonic acid group; with the proviso that if -OROT is -O-RE1, then RE1 is not a phenyl group substituted with a sulfonyl group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, or prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit osteoclast survival, formation, and/or activity, and to inhibit conditions mediated by osteoclasts and/or characterised by bone resorption, in the treatment of bone disorders such as osteoporosis, rheumatoid arthritis, cancer associated bone disease, Paget's disease, aseptic loosening of prosthetic implants, and the like; and/or in the treatment of conditions associated with inflammation or activation of the immune system.
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Page 74; 100
(2008/06/13)
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- Functional group transformations of diols, cyclic ethers, and lactones using aqueous hydrobromic acid and phase transfer catalyst under microwave irradiation
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Synthesis of bromoalkanols has been achieved from diols, ethers, and lactones using aq HBr (48%) and tetrabutylammonium iodide/bromide as phase transfer catalyst under microwave irradiation. This environmentally benign route provides enhanced yields of products and does away with the use of benzene as compared to existing conventional methods.
- Kad, Goverdhan L.,Kaur, Irvinder,Bhandari, Monica,Singh, Jasvinder,Kaur, Jasamrit
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p. 339 - 340
(2013/09/06)
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- An extremely simple, convenient and mild one-pot reduction of carboxylic acids to alcohols using 3,4,5-trifluorophenylboronic acid and sodium borohydride
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Acyloxyboron intermediates formed in situ from carboxylic acids and 3,4,5-trifluorophenylboronic acids react with sodium borohydride in THF to give alcohols in good to high yields.
- Tale,Patil,Dapurkar
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p. 3427 - 3428
(2007/10/03)
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- Towards an unprotected self-activating glycosyl donor system: Bromobutyl glycosides
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Bromobutyl mannopyranosides have been successfully used as both protected and unprotected glycosyl donors both with and without the use of an external activator.
- Davis, Benjamin G.,Wood, Steven D.,Maughan, Michael A.T.
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p. 555 - 558
(2007/10/03)
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- An efficient and extremely mild method for protecting alcohols as 2-tetrahydrofuranyl ethers
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Reaction of primary or secondary alcohols with BrCCl3 and tetrahydrofuran, usually in the presence of 2,4,6-collidine, leads to the formation of 2-tetrahydrofuranyl ethers in good to excellent yield (56-92%). The reaction mechanism is believed to involve a free-radical chain reaction. (C) 2000 Elsevier Science Ltd.
- Barks,Gilbert,Parsons,Upeandran
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p. 6249 - 6252
(2007/10/03)
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- Rate constants for 5-exo secondary alkyl radical cyclizations onto hydrazones and oxime ethers via intramolecular competition experiments
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The kinetics for the 5-exo cyclizations of secondary radicals onto various imine acceptors (aryl-, alkyl-, and benzoylhydrazones, oxime ethers, etc.) have been determined. The rate constants have been established by competitive 'internal radical clock' type cyclizations on the basis of the known rate constants for alkene and N,N-diphenylhydrazone systems. In refluxing benzene (80 °C) the rate constants for these 5-exo cyclizations fall within the range of 16 x 107 to 4 x 107 s-1 depending on the electron-withdrawing capacity of the imine acceptor (C=NR). The fastest rate constants were observed for the N-benzyoylhydrazone acceptor (cis, 1.2 x 108 s-1), a value that is very similar to rate constant determined previously for N,N-diphenylhydrazones (cis, 1.1 x 108 s-1). These rate constants are approximately 200 times faster than those for the corresponding 5-exo cyclization onto alkenes.
- Tauh, Poonam,Fallis, Alex G.
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p. 6960 - 6968
(2007/10/03)
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