- SYNTHETIC RETINOIDS FOR USE IN RAR ACTIVATION
-
The present invention relates to compounds of formula I: in which A1-A7 and R1 to R5 are defined herein, for use in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). The invention also relates to pharmaceutical compounds comprising such compounds, and related methods of treatment. In an aspect, the invention relates to a method of screening compounds for therapeutic potential in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). Aspects of the invention relate to novel compounds of formula I in which at least one of A1 to A3 is N or at least one of A4 is CR12 or A5 is CR13 in which R12/R13 is halogen.
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Page/Page column 18-19
(2020/09/27)
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- CARBOXAMIDES AS MODULATORS OF SODIUM CHANNELS
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Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.
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Paragraph 00559
(2020/07/25)
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- HETEROCYCLIC INTEGRIN AGONISTS
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The present invention provides polycyclic oxothioxoimidazolidines, dioxoimidazolines, oxothioxooxazolidines, dioxooxazolidines, and related compounds, which are useful as integrin agonists. Methods for the treatment of integrin-mediated diseases such as cancer are also described.
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Paragraph 0246; 0247
(2018/07/29)
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- A biocatalytic method for the chemoselective aerobic oxidation of aldehydes to carboxylic acids
-
Herein, we present a study on the oxidation of aldehydes to carboxylic acids using three recombinant aldehyde dehydrogenases (ALDHs). The ALDHs were used in purified form with a nicotinamide oxidase (NOx), which recycles the catalytic NAD+ at the expense of dioxygen (air at atmospheric pressure). The reaction was studied also with lyophilised whole cell as well as resting cell biocatalysts for more convenient practical application. The optimised biocatalytic oxidation runs in phosphate buffer at pH 8.5 and at 40 °C. From a set of sixty-one aliphatic, aryl-Aliphatic, benzylic, hetero-Aromatic and bicyclic aldehydes, fifty were converted with elevated yield (up to >99%). The exceptions were a few ortho-substituted benzaldehydes, bicyclic heteroaromatic aldehydes and 2-phenylpropanal. In all cases, the expected carboxylic acid was shown to be the only product (>99% chemoselectivity). Other oxidisable functionalities within the same molecule (e.g. hydroxyl, alkene, and heteroaromatic nitrogen or sulphur atoms) remained untouched. The reaction was scaled for the oxidation of 5-(hydroxymethyl)furfural (2 g), a bio-based starting material, to afford 5-(hydroxymethyl)furoic acid in 61% isolated yield. The new biocatalytic method avoids the use of toxic or unsafe oxidants, strong acids or bases, or undesired solvents. It shows applicability across a wide range of substrates, and retains perfect chemoselectivity. Alternative oxidisable groups were not converted, and other classical side-reactions (e.g. halogenation of unsaturated functionalities, Dakin-Type oxidation) did not occur. In comparison to other established enzymatic methods such as the use of oxidases (where the concomitant oxidation of alcohols and aldehydes is common), ALDHs offer greatly improved selectivity.
- Knaus, Tanja,Tseliou, Vasilis,Humphreys, Luke D.,Scrutton, Nigel S.,Mutti, Francesco G.
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p. 3931 - 3943
(2018/09/11)
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- Structure–Activity Relationship of Propargylamine-Based HDAC Inhibitors
-
As histone deacetylases (HDACs) play an important role in the treatment of cancer, their selective inhibition has been the subject of various studies. These continuous investigations have given rise to a large collection of pan- and selective HDAC inhibitors, containing diverse US Food and Drug Administration (FDA)-approved representatives. In previous studies, a class of alkyne-based HDAC inhibitors was presented. We modified this scaffold in two previously neglected regions and compared their cytotoxicity and affinity toward HDAC1, HDAC6, and HDAC8. We were able to show that R-configured propargylamines contribute to increased selectivity for HDAC6. Docking studies on available HDAC crystal structures were carried out to rationalize the observed selectivity of the compounds. Substitution of the aromatic portion by a thiophene derivative results in high affinity and low cytotoxicity, indicating an improved drug tolerance.
- Wünsch, Matthias,Senger, Johanna,Schultheisz, Philipp,Schwarzbich, Sabrina,Schmidtkunz, Karin,Michalek, Carmela,Kla?, Michaela,Goskowitz, Stefanie,Borchert, Philipp,Praetorius, Lucas,Sippl, Wolfgang,Jung, Manfred,Sewald, Norbert
-
supporting information
p. 2044 - 2053
(2017/12/07)
-
- Fusaric acid and analogues as Gram-negative bacterial quorum sensing inhibitors
-
Taking advantage of microwave-assisted synthesis, efficient and expedite procedures for preparation of a library of fusaric acid and 39 analogues are reported. The fusaric acid analogues were tested in cell-based screening assays for inhibition of the las and rhl quorum sensing system in Pseudomonas aeruginosa and the lux quorum sensing system in Vibrio fischeri. Eight of the 40 compounds in the library including fusaric acid inhibited lux quorum sensing and one compound inhibited activity of the las quorum sensing system. To our delight, none of the compounds showed growth inhibitory effects in the tested concentration ranges.
- Tung, Truong Thanh,Jakobsen, Tim Holm,Dao, Trong Tuan,Fuglsang, Anja Thoe,Givskov, Michael,Christensen, S?ren Br?gger,Nielsen, John
-
p. 1011 - 1020
(2016/12/30)
-
- Design, synthesis and evaluation of antiproliferative activity of melanoma-targeted histone deacetylase inhibitors
-
The clinical validation of histone deacetylase inhibition as a cancer therapeutic modality has stimulated interest in the development of new generation of potent and tumor selective histone deacetylase inhibitors (HDACi). With the goal of selective delivery of the HDACi to melanoma cells, we incorporated the benzamide, a high affinity melanin-binding template, into the design of HDACi to generate a new series of compounds 10a-b and 11a-b which display high potency towards HDAC1 and HDAC6. However, these compounds have attenuated antiproliferative activities relative to the untargeted HDACi. An alternative strategy furnished compound 14, a prodrug bearing the benzamide template linked via a labile bond to a hydroxamate-based HDACi. This pro-drug compound showed promising antiproliferative activity and warrant further study.
- Raji, Idris,Ahluwalia, Kabir,Oyelere, Adegboyega K.
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supporting information
p. 744 - 749
(2017/02/18)
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- PYRAZOLYL-SUBSTITUTED PYRIDONE COMPOUNDS AS SERINE PROTEASE INHIBITORS
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There are provided inter alia pyrazolyl-substituted pyridone compounds, which exhibit biological activity, e.g., inhibitory action, against serine proteases, including thrombin and various kallikreins. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing certain diseases or disorders, which disease or disorder is amenable to treatment or prevention by the inhibition of serine proteases, including thrombin and various kallikreins.
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Paragraph 00379-00380
(2016/04/09)
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- A thiophene and pyrimidine derivatives, its preparation process and its use in medicine
-
The invention discloses thiophene miazines derivates as well as a preparation method and a medical application thereof. The thiophene miazines derivates are compounds with a general formula I, a general formula II or a general formula III, wherein in the general formulae, Ar is any one of phenyl, halogen-substituted phenyl, C1-6 alkyl-substituted phenyl, biphenylyl, halogen-substituted biphenylyl, naphthyl, pyridyl, thienyl, halogen-substituted thienyl, C1-3 alkyl-substituted thienyl, furyl, halogen-substituted furyl and C1-3 alkyl-substituted furyl, A, D and E are respectively carbon atoms or nitrogen atoms but are not carbon atoms at the same time, and R is R1-NH-. The thiophene miazines derivates provided by the invention can be used for obviously restraining the activity of an EGFR (Epidermal Growth Factor Receptor) and the activity of A431 cells, are expected to be developed as a tyrosine kinase inhibitor, and are extensive in application prospect and medicinal value.
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Paragraph 0135-0137
(2016/12/01)
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- CYCLOPROPYL FUSED THIAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE
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The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula (I): wherein variables A4, A5, A6, A8, and each of Ra, Rb, R1, R2, R3 and R7 of Formula (I), independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and 15 deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimers Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas (II) and (III), and sub-formula embodiments thereof, intermediates and methods for preparing compounds of the invention.
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Page/Page column 330
(2016/04/20)
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- N-ARYLMETHYL SULFONAMIDE NEGATIVE MODULATORS OF NR2A
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Compounds that selectively negatively modulate NMDA receptors containing an NR2A subunit, pharmaceutical compositions comprising the compounds, and methods of treating a disease using the compounds are disclosed.
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Paragraph 0129
(2015/04/15)
-
- Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
-
The invention provides novel compounds having the general formula: wherein R1, R2, R3, R4, R5, R6, X, Y, W and n are as described herein, compositions including the compounds and methods of using the compounds.
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-
Paragraph 0937; 0938; 0939
(2015/11/02)
-
- Assignment of the absolute configuration and total synthesis of (+)-caripyrin
-
The antifungal secondary metabolite (+)-caripyrin was studied by vibrational circular dichroism spectroscopy. Analysis of the recorded data, with the Boltzmann weighted-average of the spectra calculated at the B3LYP/6-311G(d,p) level of theory for all relevant conformers, unequivocally proved the (R,R)-configuration for the dextrorotatory natural product. Based on this finding, a short enantioselective synthesis of (+)-caripyrin was developed.
- Andernach, Lars,Opatz, Till
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p. 4780 - 4784
(2014/08/05)
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- PERFLUORINATED CYCLOPROPYL FUSED 1,3-OXAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE
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PERFLUORINATED CYCLOPROPYL FUSED 1,3-OXAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE ABSTRACT OF THE DISCLOSURE The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: {INSERT STRUCTURE HERE} I wherein variables A4, A5, A6, A8, each of Ra, Rb, R1, R2, R3 and R7 of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas II and III, and sub-formula embodiments thereof, intermediates and methods for preparing compounds of the invention.
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Page/Page column 187; 188
(2014/09/29)
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- Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor
-
Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure-activity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chemical analoging of 1 improved the 1,2,4-triazole based core and led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5- (methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3, 4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, "rule of 5" compliant and a metabolically stable TNKS1/2 inhibitor. G007-LK (66) displayed high selectivity toward tankyrases 1 and 2 with biochemical IC50 values of 46 nM and 25 nM, respectively, and a cellular IC50 value of 50 nM combined with an excellent pharmacokinetic profile in mice. The PARP domain of TNKS2 was cocrystallized with 66, and the X-ray structure was determined at 2.8 ? resolution in the space group P3221. The structure revealed that 66 binds to unique structural features in the extended adenosine binding pocket which forms the structural basis for the compound's high target selectivity and specificity. Our study provides a significantly optimized compound for targeting TNKS1/2 in vitro and in vivo.
- Voronkov, Andrew,Holsworth, Daniel D.,Waaler, Jo,Wilson, Steven R.,Ekblad, Bie,Perdreau-Dahl, Harmonie,Dinh, Huyen,Drewes, Gerard,Hopf, Carsten,Morth, Jens P.,Krauss, Stefan
-
p. 3012 - 3023
(2013/06/04)
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- TRIAZOLE DERIVATIVES AS WNT SIGNALING PATHWAY INHIBITORS
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The present invention relates to compounds of formula (I), to processes for their preparation, to pharmaceutical formulations containing such compounds and to their use in therapy: Such compounds find particular use in the treatment and/or prevention of conditions or diseases which are affected by over-activation of signaling in the Wnt pathway and increased presence of nuclear β-catenin. For example, these may be used in preventing and/or retarding proliferation of tumor cells and metastasis, for example carcinomas such as colon carcinomas.
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-
Page/Page column 64-65
(2012/06/30)
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- ETHYNYLBENZENE DERIVATIVES
-
Disclosed are compounds of formulae (I), (II), and (II)I: and pharmaceutically acceptable salts thereof, wherein the variables, R, R1, R2, R3, R101, L, D, Q, Y, X, and Z are defined herein. These compounds are useful for treating Gram-negative bacteria infections.
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Page/Page column 123-124
(2012/03/26)
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- Facile synthesis and platinum complexes of 4′,5,5′′- trisubstituted-2,2′:6′,2′′-terpyridines
-
The synthesis of trisubstituted 4′,5,5′′ terpyridines is described. The strategy begins with synthesis of 2-acetyl-5-bromopyridine (3) from 2,5-dibromopyridine, substitution of the bromine in 3 using a variety of metal-catalyzed reactions and then formation of the terpyridine using the Krohnke reaction. The complexes have been prepared by reaction of [Pt(PhCN) 2Cl2] with the appropriate silver salt followed by addition of the terpyridyl ligand. The crystal structure of two complexes have been determined via X-ray diffraction and the MLCT (metal-to-ligand charge-transfer) emissions determined by UV/Vis spectroscopy. The Royal Society of Chemistry 2011.
- Huo, Jianqiang,Arulsamy, Navamoney,Hoberg, John O.
-
scheme or table
p. 7534 - 7540
(2011/10/12)
-
- NEW TETRACYCLIC COMPOUNDS
-
This disclosure relates to new tetracyclic compounds that may be used to modulate a histamine receptor in an individual. The compounds in one embodiment are tetracyclic [4,3- b]indoles. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.
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Page/Page column 282
(2009/05/30)
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- BENZOTHIAZOLES AND AZA-ANALOGUES THEREOF USE AS ANTIBACTERIAL AGENTS
-
The present invention provides Gyrase B and/or Topoisomerase IV par E inhibitors, which can be used as antibacterial agents. Compounds disclosed herein can be used for treating or preventing conditions caused by or contributed by gram positive, gram negative and anaerobic bacteria, more particularly against, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Pseudomonas spp., Acenetobacter spp., Moraxalla spp., Chlamydia spp., Mycoplasma spp., Legionella spp., Ktycobacterium spp., Helicobacter, Clostridium spp., Bacteroides spp., Coryne bacterium, Bacillus spp., Enterobactericeae,' (E.coli, Klebsiella spp., Proteus spp.,etc. ) or any combination thereof Also provided, are processes for preparing compounds disclosed herein, pharmaceutical compositions containing compounds disclosed herein, and methods of treating bacterial infections. (Formula)
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Page/Page column 38
(2010/01/30)
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- Design, synthesis, and biological evaluation of 8-biarylquinolines: A novel class of PDE4 inhibitors
-
The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC50 50 0.5 μM) the LPS-induced release of the cytokine TNF-α. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.
- Gallant, Michel,Chauret, Nathalie,Claveau, David,Day, Stephen,Deschenes, Denis,Dube, Daniel,Huang, Zheng,Lacombe, Patrick,Laliberte, France,Levesque, Jean-Francois,Liu, Susana,Macdonald, Dwight,Mancini, Joseph,Masson, Paul,Mastracchio, Anthony,Nicholson, Donald,Nicoll-Griffith, Deborah A.,Perrier, Helene,Salem, Myriam,Styhler, Angela,Young, Robert N.,Girard, Yves
-
p. 1407 - 1412
(2008/12/22)
-
- SUBSTITUTED PYRIDYL AMIDE COMPOUNDS AS MODULATORS OF THE HISTAMINE H3 RECEPTOR
-
Certain substituted pyridyl amide compounds are histamine H3 receptor modulators useful in the treatment of histamine H3 receptor-mediated diseases.
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Page/Page column 23
(2008/06/13)
-
- Novel gamma secretase inhibitors
-
This invention discloses novel gamma secretase inhibitors of the formula: wherein: R1 is a substituted aryl or substituted heteroaryl group; R2 is an R1 group, alkyl, —XC(O)Y, alkylene-XC(O)Y, cycloalkylene-X—C(O)—Y, —CH—X—C(O)—NR3—Y or —CH—X—C(O)—Y, wherein X and Y are as defined herein; each R3 and each R3A are independently H, or alkyl; R11 is aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, or alkoxyalkyl. Also disclosed is a method of treating Alzheimer's Disease using one or more compounds of the invention.
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-
-
- Ligand creation via linking - A rapid and convenient method for construction of novel supported PyOX-ligands
-
A novel supported amino alcohol linker was synthesized and utilized for attachment of picolinic acid derivatives onto different supports. When the resin bound molecule was further activated, the PyOX-moiety could be constructed reliably in enantiopure form. Furthermore, an efficient Pd-catalyzed modification of a picolinic acid derivative is presented.
- Oila, Markku J.,Tois, Jan E.,Koskinen, Ari M.P.
-
p. 10748 - 10756
(2007/10/03)
-
- Novel gamma secretase inhibitors
-
This invention discloses novel gamma secretase inhibitors of the formula: wherein: R1 is a substituted aryl or substituted heteroaryl group; R2 is an R1 group, alkyl, —XC(O)Y, alkylene-XC(O)Y, cycloalkylene-X-C(O)—Y, —CH—X—C(O)—NR3—Y or —CH—X—C(O)—Y, wherein X and Y are as defined herein; each R3 and each R3A are independently H, or alkyl; R11 is aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, or alkoxyalkyl. Also disclosed is a method of treating Alzheimer's Disease using one or more compounds of the invention.
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-
-
- Viral polymerase inhibitors
-
An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I: wherein R1 is selected from: H, haloalkyl, (C1-6)alkyl, (C2-6)alkenyl, (C3-7)cycloalkyl, (C2-6)alkynyl, (C5-7)cycloalkenyl, 6 or 10-membered aryl, Het all optionally substituted; R2 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C6-10)bicycloalkyl, 6- or 10-membered aryl, or Het all optionally substituted; B is N or CR5, wherein R5 is H, halogen, haloalkyl, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; X is N or CR5; D is N or CR5; each of Y1 and Y2 is independently O or S; Z is O, N, or NRz wherein Rz is H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; R3 and R4 are each independently H, (C1-6)alkyl, first (C3-7)cycloalkyl or 6- or 10-membered aryl, Het (C1-6)alkyl-6- or 10-membered aryl, (C1-6)alkyl-Het; or each R3 and R4 are independently covalently bonded together to form second (C3-7)cycloalkyl, or heterocycle, all optionally substituted; or when Z is N, either R3 or R4 are independently covalently bonded thereto to form a nitrogen-containing heterocycle; R7 is H, (C1-6 alkyl), (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; or R7 is covalently bonded to either of R3 or R4 to form a heterocycle; A is (C1-6) alkyl-CONHR8 wherein R8 is-6- or 10-membered aryl, or Het; or A is a 6- or 10-membered aryl, or Het said aryl or Het being optionally substituted; or a salt or a derivative thereof; such compounds being potent inhibitors of HCV NS5B polymerase.
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-
-
- Regiospecific carboalkoxylation of 2,5-dibromopyridine
-
Carboalkoxylation of 2,5-dibromopyridine with carbon monoxide and an alcohol in the presence of palladium acetate and 1,1'-bis(diphenylphosphino)ferrocene (dppf) occurs regiospecifically to afford esters of 5-bromo-pyridine-2-carboxylic acid in good yield.
- Chambers,Marfat
-
p. 515 - 520
(2007/10/03)
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