- Virtual Screening Approach to Identifying a Novel and Tractable Series of Pseudomonas aeruginosa Elastase Inhibitors
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Novel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is Pseudomonas aeruginosa, which persists within the lungs of CF sufferers despite intensive antibiotic treatment. P. aeruginosa elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of P. aeruginosa infections in CF patients. The crucial role of LasB in pseudomonal virulence makes it a good target for the development of an adjuvant drug for CF treatment. Herein we discuss the discovery of a new series of LasB inhibitors by virtual screening and computer assisted drug design (CADD) and their optimization leading to compounds 29 and 39 (Ki = 0.16 μM and 0.12 μM, respectively).
- Leiris, Simon,Davies, David T.,Sprynski, Nicolas,Castandet, Jér?me,Beyria, Lilha,Bodnarchuk, Michael S.,Sutton, Jonathan M.,Mullins, Toby M. G.,Jones, Mark W.,Forrest, Andrew K.,Pallin, T. David,Karunakar, Paduri,Martha, Sathish Kumar,Parusharamulu, Battu,Ramula, Ramesh,Kotha, Venkatesh,Pottabathini, Narender,Pothukanuri, Srinivasu,Lemonnier, Marc,Everett, Martin
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supporting information
p. 217 - 227
(2021/02/01)
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- COMBINATION THERAPY
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The invention provides a combinations and pharmaceutical compositions comprising (i) a compound which is an indane according to Formula (I) or a pharmaceutically acceptable salt thereof; and (ii) one or more CFTR modulator; wherein R1, R2
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Page/Page column 83-85; 135; 137
(2021/10/02)
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- N-Atom Deletion in Nitrogen Heterocycles
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Excising the nitrogen in secondary amines, and coupling the two residual fragments is a skeletal editing strategy that can be used to construct molecules with new skeletons, but which has been largely unexplored. Here we report a versatile method of N-atom excision from N-heterocycles. The process uses readily available N-heterocycles as substrates, and proceeds by N-sulfonylazidonation followed by the rearrangement of sulfamoyl azide intermediates, providing various cyclic products. Examples are provided of deletion of nitrogen from natural products, synthesis of chiral O-heterocycles from commercially available chiral β-amino alcohols, formal inert C?H functionalization through a sequence of N-directed C?H functionalization and N-atom deletion reactions in which the N-atom can serve as a traceless directing group.
- Qin, Haitao,Cai, Wangshui,Wang, Shuang,Guo, Ting,Li, Guigen,Lu, Hongjian
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p. 20678 - 20683
(2021/08/25)
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- INDANE DERIVATIVES FOR USE IN THE TREATMENT OF BACTERIAL INFECTION
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The invention relates to a compound which is an indane according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, n and p are as defined herein
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Paragraph 0093; 0104-0105
(2020/04/09)
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- INDANE DERIVATIVES FOR USE IN THE TREATMENT OF BACTERIAL INFECTION
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The invention relates to a compound which is an indane according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, L, M, ?, n, p, and q are as defined herein. The compounds are useful in the treatment of antibacterial infection either as stand alone antibiotics, or in combination with further antibiotics.
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Paragraph 0122-0123; 0128-0129
(2020/04/09)
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- A general platinum-catalyzed alkoxycarbonylation of olefins
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Hydroxy- and alkoxycarbonylation reactions constitute important industrial processes in homogeneous catalysis. Nowadays, palladium complexes constitute state-of-the-art catalysts for these transformations. Herein, we report the first efficient platinum-catalysed alkoxycarbonylations of olefins including sterically hindered and functionalized ones. This atom-efficient catalytic transformation provides straightforward access to a variety of valuable esters in good to excellent yields and often with high selectivities. In kinetic experiments the activities of Pd- and Pt-based catalysts were compared. Even at low catalyst loading, Pt shows high catalytic activity.
- Beller, Matthias,Dühren, Ricarda,Franke, Robert,Ge, Yao,Huang, Weiheng,Jackstell, Ralf,Liu, Jiawang,Neumann, Helfried,Schneider, Carolin,Yang, Ji
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supporting information
p. 5235 - 5238
(2020/07/30)
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- Cobalt(II)-Catalyzed Alkoxycarbonylation of Aliphatic Amines via C-N Bond Activation
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The first cobalt-catalyzed deaminative alkoxycarbonylation reaction was described for the conversion of readily available primary alkyl amines to synthetically versatile esters with moderate to high yields. This transformation shows good functional group compatibility and can serve as a powerful tool for the modification of alkyl amine-containing complex natural products and drug molecules.
- Li, Chong-Liang,Jiang, Xuan,Lu, Liang-Qiu,Xiao, Wen-Jing,Wu, Xiao-Feng
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p. 6919 - 6923
(2019/09/07)
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- Alkoxycarbonylation of olefins with carbon dioxide by a reusable heterobimetallic ruthenium-cobalt catalytic system
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The heterobimetallic ruthenium-cobalt catalytic system exhibited good catalytic performance and reusability in the reductive alkoxycarbonylation of olefins with carbon dioxide. Compared to the previous system only consisting of ruthenium catalyst, the binary catalyst system effectively reduced the usage of noble metal and ionic liquid additives. The respective contribution of ruthenium and cobalt catalysts in this multiple-step catalytic process was investigated by a series of condition-controlled experiments. The evolution of the ruthenium catalyst and the occurrence of alkene hydrogenation during the reaction was explained by theortical calculations.
- Zhang, Xuehua,Shen, Chaoren,Xia, Chungu,Tian, Xinxin,He, Lin
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supporting information
p. 5533 - 5539
(2019/01/03)
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- Development of efficient palladium catalysts for alkoxycarbonylation of alkenes
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Herein, we report a general and efficient Pd-catalysed alkoxycarbonylation of sterically hindered and demanding olefins including a variety of tri-, tetra-substituted and 1,1-disubstituted alkenes. In the presence of 1,3-bis(tert-butyl(pyridin-2-yl)phosphanyl)propane L3 or 1,4-bis(tert-butyl(pyridin-2-yl)phosphanyl)butane L4 the desired esters are obtained in good yields and selectivities. Similar transformation is obtained using tertiary ether as showcased in the carbonylation of MTBE to the corresponding linear ester in high yield and selectivity.
- Liu, Jiawang,Dong, Kaiwu,Franke, Robert,Neumann, Helfried,Jackstell, Ralf,Beller, Matthias
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supporting information
p. 12238 - 12241
(2018/11/21)
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- Palladium-catalyzed selective generation of CO from formic acid for carbonylation of alkenes
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A general and selective palladium-catalyzed alkoxycarbonylation of all kinds of alkenes with formic acid (HCOOH, FA) is described. Terminal, di-, tri-, and tetra-substituted including functionalized olefins are converted into linear esters with high yields and regioselectivity. Key-to-success is the use of specific palladium catalysts containing ligands with built-in base, e.g., L5. Comparison experiments demonstrate that the active catalyst system not only facilitates isomerization and carbonylation of alkenes but also promotes the selective decomposition of HCOOH to CO under mild conditions.
- Sang, Rui,Kucmierczyk, Peter,Dong, Kaiwu,Franke, Robert,Neumann, Helfried,Jackstell, Ralf,Beller, Matthias
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supporting information
p. 5217 - 5223
(2018/04/24)
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- INHIBITORS OF THE MENIN-MLL INTERACTION
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The present invention is directed to inhibitors of the interaction of menin with MLL and MLL fusion proteins, pharmaceutical compositions containing the same, and their use in the treatment of cancer and other diseases mediated by the menin-MLL interaction.
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-
Page/Page column 206
(2018/01/17)
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- Iridium-Catalyzed Enantioselective Allylic Substitution of Aliphatic Esters with Silyl Ketene Acetals as the Ester Enolates
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Enantioselective allylic substitution with enolates derived from aliphatic esters under mild conditions remains challenging. Herein we report iridium-catalyzed enantioselective allylation reactions of silyl ketene acetals, the silicon enolates of esters, to form products containing a quaternary carbon atom at the nucleophile moiety and a tertiary carbon atom at the electrophile moiety. Under relatively neutral conditions, the allylated aliphatic esters were obtained with excellent regioselectivity and enantioselectivity. These products were readily converted into primary alcohols, carboxylic acids, amides, isocyanates, and carbamates, as well as tetrahydrofuran and γ-butyrolactone derivatives, without erosion of enantiomeric purity.
- Jiang, Xingyu,Hartwig, John F.
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supporting information
p. 8887 - 8891
(2017/07/17)
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- Palladium-Catalyzed Carbonylation of sec- and tert-Alcohols
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A general palladium-catalyzed synthesis of linear esters directly from sec- and tert-alcohols is described. Compared to the classic Koch–Haaf reaction, which leads to branched products, this new transformation gives the corresponding linear esters in high yields and selectivity. Key for this protocol is the use of an advanced palladium catalyst system with L2 (pytbpx) as the ligand. A variety of aliphatic and benzylic alcohols can be directly used and the catalyst efficiency for the benchmark reaction is outstanding (turnover number up to 89 000).
- Dong, Kaiwu,Sang, Rui,Liu, Jie,Razzaq, Rauf,Franke, Robert,Jackstell, Ralf,Beller, Matthias
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supporting information
p. 6203 - 6207
(2017/05/22)
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- Azetidines and spiro azetidines as novel P2 units in hepatitis C virus NS3 protease inhibitors
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Herein, we report the synthesis and structure-activity relationship studies of new analogs of boceprevir 1 and telaprevir 2. Introduction of azetidine and spiroazetidines as a P2 substituent that replaced the pyrrolidine moiety of 1 and 2 led to the disco
- Bondada, Lavanya,Rondla, Ramu,Pradere, Ugo,Liu, Peng,Li, Chengwei,Bobeck, Drew,McBrayer, Tamara,Tharnish, Philip,Courcambeck, Jerome,Halfon, Philippe,Whitaker, Tony,Amblard, Franck,Coats, Steven J.,Schinazi, Raymond F.
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p. 6325 - 6330
(2013/11/19)
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- NOVEL OXADIAZOLYL-DIAZABICYCLONONANE DERIVATIVES AND THEIR MEDICAL USE
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This invention relates to novel oxadiazolyl-diazabicyclononane derivatives and their use in the manufacture of pharmaceutical compositions. The compounds of the invention are found to be cholinergic ligands at the nicotinic acetylcholine receptors and modulators of the monoamine receptors and transporters. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
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Page/Page column 17
(2010/04/30)
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- Indane modulators of glucocorticoid receptor, AP-1, and/or NF/kB activity and use thereof
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Novel non-steroidal compounds are provided that are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity including obesity, diabetes, inflammatory and immune diseases having the structure of formula (I): or enantiomers, diastereomers, or a pharmaceutically-acceptable salt, or hydrate, thereof, where X is -A1QA2-; Q is a bond, —C(═O)—, —OC(O)—, —C(═O)NR5—, —SOp—, —SOpNR5—, —C(O)O—, —NR5C(O)—, —OC(O)NR5—, —NR5C(O)O—, —S(O)pNR5C(O)—, —C(O)NR5S(O)p— —NR5S(O)p—, or —NR5C(═O)NR6—. Y is selected from hydrogen, C1-4alkyl, OR16, substituted C1-6alkyl, cycloalkyl, aryl, heterocyclo and heteroaryl. A1 and A2 are independently selected from a bond, C1-3alkylene, or C1-3alkenylene, and R1-R11 are defined herein. Also provided are pharmaceutical compositions, combinations, and methods of treating obesity, diabetes and inflammatory- or immune-associated diseases comprising said compounds.
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Page/Page column 25
(2008/06/13)
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- Compounds that modulate PPAR activity and methods of preparation
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This invention discloses compounds that alter PPAR activity. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, and methods of using them as therapeutic agents for treating or preventing hyperlipidemia and hypercholesteremia in a mammal. The present invention also discloses method for making the disclosed compounds.
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- Indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase
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The present invention relates to certain novel indane-2-mercaptoacetylamide disulfide derivatives of the formula STR1 useful as inhibitors of enkephalinase.
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- 2-substituted indane-2-mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase
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The present invention relates to novel 2-substitited indane-2-mercaptoacetylamide tricyclic derivatives which are useful as inhibitors of Enkephalise.
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- 2-SUBSTITUTED INDANE-2-CARBOXYALKYL DERIVATIVES USEFUL AS INHIBITORS OF ENKEPHALINASE AND ACE
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The present invention relates to novel 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE.
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- 2-MERCAPTOMETHYLENE-TETRAHYDRONAPHTHALENE AND INDANE-2-CARBOXAMIDE DERIVATIVES AS ENKAPHALINASE INHIBITORS
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The present invention relates to novel 2-mercaptomethylene-tetrahydronaphthalene derivatives which are useful as enkephalinase inhibitors.
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- Synthesis and biological activity of novel carbacyclins having bicyclic substituents on the ω-chain
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A number of carbacyclins having bicyclic substituents on the ω-chain have been synthesized and tested for antiplatelet aggregation activity in vitro (against collagen-induced aggregation of rat platelet), for reduction of systemic blood pressure in vivo (ability to reduce the blood pressure in anesthetized rat by iv injection), and for cytoprotective activity (protection against ethanol-induced rat gastric lesion). The most effective compound for each activity was [3aS-[2E,3aα,4α(3R),5β,6aα]]-5-[hexahydro-5-hydroxy-4-[3-hydroxy-3-(2- indanyl)-1-propynyl]-2(1H)-pentalenylidene]pentanoic acid (compound 11a), while some 1,4-benzodioxan analogues had selectivity for organ-protective activity, and indan analogues showed selectivity in their antiaggregation activity.
- Tomiyama,Wakabayashi,Yokota
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p. 1988 - 1996
(2007/10/02)
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- Aromatic Spiranes, XVII: Syntheses of Anellated and Substituted 2,2'-Spirobiindane-1-ones and 4,5'-Disubstituted 2,2'-Spirobiindanes
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The spiroketones 9, 16, and 28 were prepared by cyclisation of the carboxylic acids 7c, 13b, and 25c and their acid chlorides, resp. (7d, 13c, and 25d) with polyphosphoric acid (PPA) or SnCl4.The precursors of the latter compounds were synthesized by alky
- Neudeck, Horst K.
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p. 623 - 642
(2007/10/02)
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- Indaneacetic acid derivatives
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This invention provides new compounds of formula I, STR1 wherein R1 is lower alkyl, R2 is hydrogen or lower alkyl, R3 is hydrogen or lower alkyl, R4 is hydrogen or lower alkyl, R5 is hydrogen, chlorine or lower alkyl, and each of R6 and R7 is hydrogen, or, when R5 is hydrogen, R6 may also be chlorine or lower alkyl, and R7 chlorine or lower alkyl, Useful as anti-phlogistic and anti-arthritic agents.
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- 15-Substituted-ω-pentanorprostaglandins
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The 15-substituted-ω-pentanorprostaglandins and various intermediates employed in their preparation. The novel prostaglandins of this invention have been found to have activity profiles comparable to the parent prostaglandins, but exhibit a greater tissue
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