- Benzazepine Dicarboxamide Compounds
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This invention relates to novel benzazepine dicarboxamide compounds of the formula wherein R1 to R4 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer, autoimmune diseases, inflammation, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases.
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Paragraph 0441; 0442
(2016/09/26)
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- CATIONIC BIS-UREA COMPOUNDS AS EFFECTIVE ANTIMICROBIAL AGENTS
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A cationic bis-urea compound is disclosed of formula (1): wherein: each m is independently an integer of 0 to 4,each k is independently 0 or 1,each Z′ is a monovalent radical independently selected from the group consisting of hydroxyl (*—OH), carboxyl (*—COOH), cyano (*—CN), nitro (*—NO2), sulfonate (*—SO3?), trifluoromethyl (*—CF3), halides, amine groups, ketone groups, alkyl groups comprising 1 to 6 carbons, alkoxy groups comprising 1 to 6 carbons, thioether groups comprising 1 to 6 carbons, and combinations thereof,each L′ is independently a divalent alkylene group comprising 1 to 6 carbons, wherein a *-[-L′-]k- is a single bond when k is 0,each Y′ is independently a monovalent non-polymeric radical comprising a positive charged amine, andeach X′ is independently a negative charged counterion.
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Paragraph 0178; 0179
(2013/11/05)
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- Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design
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β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.
- Mok, N. Yi,Chadwick, James,Kellett, Katherine A. B.,Casas-Arce, Eva,Hooper, Nigel M.,Johnson, A. Peter,Fishwick, Colin W. G.
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p. 1843 - 1852
(2013/05/08)
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- Red-fluorescent argininamide-type NPY Y1 receptor antagonists as pharmacological tools
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Fluorescently labelled NPY Y1 receptor (Y1R) ligands were synthesized by connecting pyrylium and cyanine dyes with the argininamide-type Y1R antagonist core structure by linkers, covering a wide variety in length and chemical nature, attached to the guanidine group. The most promising fluorescent probes had Y1R affinities (radioligand binding) and antagonistic activities (calcium assay) in the one- to two-digit nanomolar range. These compounds turned out to be stable under assay conditions and to be appropriate for the detection of Y1Rs by confocal microscopy in live cells. To improve the signal-to-noise ratio by shifting the emission into the near infrared, a new benzothiazolium-type fluorescent cyanine dye (UR-DE99) was synthesized and attached to the parent antagonist via a carbamoyl linker yielding UR-MK131, a highly potent fluorescent Y1R probe, which was also successfully applied in flow cytometry.
- Keller, Max,Erdmann, Daniela,Pop, Nathalie,Pluym, Nikola,Teng, Shangjun,Bernhardt, Günther,Buschauer, Armin
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experimental part
p. 2859 - 2878
(2011/06/22)
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- Covalent modification of glassy carbon surface with organic redox probes through diamine linkers using electrochemical and solid-phase synthesis methodologies
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Various mono-Boc-protected diamines have been covalently grafted to glassy carbon electrodes by electrochemical oxidation of the free amine. After deprotection of the Boc group, anthraquinone and nitrobenzene probes were coupled to the linkers using solid-phase coupling reactions. X-Ray photoelectron spectroscopy and cyclic voltammetry were used to monitor the coupling efficiency, effect of linker length on the surface coverage and electron transfer between the attached redox probes and electrode. The anthraquinone surface coverage was found to decrease as the chain length of alkyl diamine linker increased and the electron transfer kinetics were found to be faster for the lower coverages and the longer, more flexible linkers. In the case of nitrobenzene, there was only a slightly change in coverage with increasing linker length. This electrochemical attachment of protected diamine linkers followed by solid-phase coupling provides a very versatile methodology for attaching a wide range of molecular architectures onto glassy carbon surfaces. The Royal Society of Chemistry 2008.
- Ghanem, Mohamed A.,Chretien, Jean-Mathieu,Pinczewska, Aleksandra,Kilburn, Jeremy D.,Bartlett, Philip N.
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experimental part
p. 4917 - 4927
(2010/02/28)
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- EP-2104R: A fibrin-specific gadolinium-based MRI contrast agent for detection of thrombus
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Thrombus (blood clot) is implicated in a number of life threatening diseases, e.g., heart attack, stroke, pulmonary embolism. EP-2104R is an MRI contrast agent designed to detect thrombus by binding to the protein fibrin, present in all thrombi. EP-2104R
- Overoye-Chan, Kirsten,Koerner, Steffi,Looby, Richard J.,Kolodziej, Andrew F.,Zech, Stephan G.,Deng, Qing,Chasse, Jaclyn M.,McMurry, Thomas J.,Caravan, Peter
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p. 6025 - 6039
(2008/09/21)
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- Optically pure and enriched isomers of chelating ligands and contrast agents
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Organic chelating ligands, organic chelating ligand precursors, and metal chelates are disclosed. Methods for synthesizing the same are also described, including methods for preparing optically-enriched or optically-pure compositions of the same.
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Page/Page column 25
(2008/06/13)
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- MATRIX METALLOPROTEINASE INHIBITORS
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Thus the present invention describes novel compounds comprising: 1-10 targeting moieties; a chelator (Ch); and 0-1 linking groups (Ln) between the targeting moiety and chelator; wherein the targeting moiety is a matrix metalloproteinase inhibitor; and whe
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- 5-Substituted isoquinoline derivatives
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A compound represented by the following formula (1) or a salt thereof: wherein R1 represents hydrogen atom, a halogen atom and the like; R2 represents hydrogen atom, a halogen atom, a C1-6 alkyl group and the like; and R3 represents —O—X—C(A1)(A11)—C(A2)(A2l)—N(A3l)(A3)(X represents propylene group etc., A11 and A21 represent hydrogen atom, or a C1-6 alkyl group, A31 represents a C1-6 alkyl group substituted with hydroxyl group, or hydrogen atom, and A1, A2, and A3 represent hydrogen atom, a C1-6 alkyl group and the like) and the like, which has an inhibitory activity on the phosphorylation of myosin regulatory light chain, and is useful for treatment of diseases relating to contraction of various cells and the like.
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- 2-AMINO-PYRIDINE DERIVATIVES AS BETA-2 ADRENORECEPTOR AGONISTS
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The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in
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- beta-sheet mimetics and composition and methods relating thereto
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Compounds having the following structure: including pharmaceutically acceptable salts and stereoisomers thereof, wherein A, A′, B, X, Y, R2, R3, R4 and R5 are as defined herein. Such compounds have utility over
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- Unexpected enhancement of thrombin inhibitor potency with o-aminoalkylbenzylamides in the P1 position
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Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the α-thrombin-hirugen complex provides an explanation for these unanticipated results.
- Rittle, Kenneth E.,Barrow, James C.,Cutrona, Kellie J.,Glass, Kristen L.,Krueger, Julie A.,Kuo, Lawrence C.,Lewis, S. Dale,Lucas, Bobby J.,McMasters, Daniel R.,Morrissette, Matthew M.,Nantermet, Philippe G.,Newton, Christina L.,Sanders, William M.,Yan, Youwei,Vacca, Joseph P.,Selnick, Harold G.
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p. 3477 - 3482
(2007/10/03)
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- Synthesis of N-benzyl- and N-phenyl-2-amino-4,5-dihydrothiazoles and thioureas and evaluation as modulators of the isoforms of nitric oxide synthase
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Inhibition of the isoforms of nitric oxide synthase (NOS) has important applications in therapy of several diseases, including cancer. Using 1400W [N-(3-aminomethylbenzyl)acetamidine], thiocitrulline and N δ-(4,5-dihydrothiazol-2-yl)ornithine as lead compounds, series of N-benzyl- and N-phenyl-2-amino-4,5-dihydrothiazoles and thioureas were designed as inhibitors of NOS. Ring-substituted benzyl and phenyl isothiocyanates were synthesised by condensation of the corresponding amines with thiophosgene and addition of ammonia gave the corresponding thioureas in high yields. The substituted 2-amino-4,5-dihydrothiazoles were approached by two routes. Treatment of simple benzylamines with 2-methylthio-4,5-dihydrothiazole at 180 °C afforded the corresponding 2-benzylamino-4,5-dihydrothiazoles. For less nucleophilic amines and those carrying more thermally labile substituents, the 4,5-dihydrothiazoles were approached by acid-catalysed cyclisation of N-(2-hydroxyethyl)thioureas. This cyclisation was shown to proceed by an SN2-like process. Modest inhibitory activity was shown by most of the thioureas and 4,5-dihydrothiazoles, with N-(3-aminomethylphenyl)thiourea (IC50=13 μM vs rat neuronal NOS and IC50=23 μM vs rat inducible NOS) and 2-(3-aminomethylphenylamino)-4,5-dihydrothiazole (IC50=13 μM vs rat neuronal NOS and IC50=19 μM vs human inducible NOS) being the most potent. Several thioureas and 4,5-dihydrothiazoles were found to stimulate the activity of human inducible NOS in a time-dependent manner.
- Goodyer, Claire L. M.,Chinje, Edwin C.,Jaffar, Mohammed,Stratford, Ian J.,Threadgill, Michael D.
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p. 4189 - 4206
(2007/10/03)
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- Nicotinamide derivatives and a tiotropium salt in combination for the treatment of diseases
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The invention relates to a combination of a nicotinamide derivative and tiotropium or a derivative thereof, compositions containing it and the uses of, such a combination. The combination according to the present invention is useful in numerous diseases,
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Page/Page column 15
(2008/06/13)
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- Matrix metalloproteinase inhibitors
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Thus the present invention describes diagnostic agents comprising a diagnostic metal and a compound, wherein the compound comprises: 1-10 targeting moieties;a chelator; and 0-1 linking groups between the targeting moiety and chelator; wherein the targeting moiety is a matrix metalloproteinase inhibitor; and wherein the chelator is capable of conjugating to the diagnostic metal. The present invention also provides novel compositions of the compounds of the invention, kits, and their uses in diagnosis of diseases associated with MMPs.
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Page column 65
(2010/02/05)
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- Modular synthesis of π-acceptor cyclophanes derived from 1,4,5,8-naphthalenetetracarboxylic diimide and 1,5-dinitronaphthalene
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Three neutral cyclophanes were synthesized, and their association with indole, an aromatic π-donor, was studied. The cyclophanes were designed to contain a rigid, hydrophobic binding cavity with 1,4,5,8-naphthalenetetracarboxylic diimide or 1,5-dinitronaphthalene as the π-acceptor. Two of the cyclophanes also contain a (S)-(valine-leucine-alanine) tripeptide unit to provide chiral hydrogen bonding interactions with guest molecules. Despite the fact that these cyclophanes contain a hydrophobic binding cavity of appropriate dimensions, their association with indole is very weak. In the case of cyclophanes derived from 1,5-dinitronaphthalene, steric interactions force the nitro groups out of the plane of the naphthalene ring, diminishing their effectiveness as π-acceptors. A simple UV-visible titrimetric method, using N,N,N′,N′-tetramethyl-1,4-phenylenediamine (TMPD) as a π-donor, was used to rank the π-acceptor strength of these and other aromatic units. These titrations show that 1,4,5,8-naphthalenetetracarboxylic diimide and 1,5-dinitronaphthalene derivatives are weaker π-acceptors than viologens, which make good π-acceptor cyclophanes. Methyl viologen is in turn a weaker π-acceptor than anthaquinone disulfonate, suggesting that the latter may serve as a useful building block for π-accepting cyclophane hosts.
- Chen,Lean,Alcala,Mallouk
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p. 3027 - 3034
(2007/10/03)
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- Substituted urea and isothiourea derivatives as no synthase inhibitors
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PCT No. PCT/GB94/02138 Sec. 371 Date Mar. 28, 1996 Sec. 102(e) Date Mar. 28, 1996 PCT Filed Oct. 3, 1994 PCT Pub. No. WO95/09619 PCT Pub. Date Apr. 13, 1995The use of an N-substituted urea derivative for the manufacture of a medicament for the treatment o
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the Formula IX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- ANTITHROMBOTIC AGENTS
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This invention relates to thrombin inhibiting compounds having the FormulaIX--Y--NH--(CH 2) r--G I where X, Y, r and G have the values defined in the description, as well as pharmaceutical formulations containing those compounds and methods of their use as thrombin inhibitors, coagulation inhibitors, and thromboembolic disorder agents.
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- SULFURIC ACID ESTERS OF SUGAR ALCOHOLS
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Compounds of the formula STR1 wherein n 1-n 9 are each independently 0 or 1;m 1-m 9 are each independently 0 or 1, but with the proviso that at least one of m 1, m 2 and m. sup.3, at least one of m 4, m 5 and m 6 and, when present, at least one of m 7, m 8 and m 9 is 1; and whereinX. sup.1-X 18 each independently is--O--,--CONR 1,--NR 1 CO--or--NR 1--;R 1 is hydrogen or lower alkyl;W is a benzene or s-triazine; Y. sup.1-Y 9 each independently is an aromatic ring systems;A 1-A 3 each independently is a residue of a sugar alcohol devoid of the 1-hydroxy group or a derivative thereof, a residue of a sugar acid devoid of the 1-carboxy group or a derivative thereof or tris-(hydroxymethyl)-methyl;D is the di-residue of a sugar alcohol devoid of 2 hydroxy groups or a derivative thereof or the di-residue of a sugar dicarboxylic acid devoid of 2 carboxy group or a derivative thereof;Q 1-Q. sup.3 and Z 1-Z3 each independently are the di-residue of a sugar alcohol devoid of 2 hydroxy groups or a derivative thereof or the di-residue of a sugar dicarboxylic acid devoid of 2 carboxy groups or a derivative thereof or didesoxyglycopyranoside or a derivative thereof, wherein at least one hydroxy group of residues A 1-A 3, D, Q 1-Q 3 and Z. sup.1-Z 3 is esterified with sulfuric acid, and pharmaceutically usable salts thereof are useful for the treatment of disorders which are characterized by excessive or destructive proliferation of smooth muscle cells.
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- COMPOSITIONS AND METHODS FOR TREATING MAST-CELL MEDIATED CONDITIONS
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The present invention describes compounds, methods and compositions effective to treat mast cell mediated inflammatory conditions, such as conjunctivitis, asthma and allergic rhinitis. The compounds of the invention comprise novel mono-and di-aminomethylb
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- Solid and Solution Phase Organic Syntheses of Oligomeric Thioureas
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In order to study supramolecular architectures built from unnatural oligomeric and polymeric structures, one must first have an efficient synthetic strategy to produce them. Oligomers built from thiourea groups should form complex secondary and tertiary structures due to the hydrogenbonding capabilities of the thioureas. Herein, both solution and solid phase synthetic procedures that yield oligomeric thioureas are described. They rely on the coupling of an isothiocyanate with an amine to produce the thiourea linkage. The monomers are derived from simple diamines. Higher yields are achieved using the solid phase method due to the ability to easily monitor the extent of reaction, to use a large excess of reagent, and to perform purification after cleavage from the solid support. A variety of oligomers are given as examples. The procedure is quite general, should be easily extended to complex monomers, and will allow the investigation of intramolecular and intermolecular interactions.
- Smith, Joseph,Liras, Jennifer L.,Schneider, Stephen E.,Anslyn, Eric V.
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p. 8811 - 8818
(2007/10/03)
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- Structure-activity relationships of novel vasopressin antagonists containing C-terminal diaminoalkanes and (aminoalkyl)guanidines
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We report the synthesis and biological activity of a series of analogues of the vasopressin antagonists [Pmp1,D-Tyr(Et)2,Val4]arginine-vasopressin (1) and [Pmp1,D-Tyr(Et)2,Val4,desGly9]arginine-vasopressin (2), where part or all of the tripeptide tail has been replaced by a simple alkyldiamine [NH(CH2)(n)NH2] or (aminoalkyl)guanidine [NH(CH2)(n)NHC(=NH)NH2] in order to examine the effects that variation of the length and orientation of the tripeptide tail have on renal vasopressin (V2) receptor antagonist activity. The results show that the entire tripeptide tail (Pro-Arg-Gly-NH2) can be replaced by an alkyldiamine or an (aminoalkyl)guanidine, compounds 15 and 16, respectively, indicating that there is no orientational requirement for the basic functional group coming off the cyclic hexapeptide ring. Also, there seems to be an 'optimal' distance between the basic functional group and the hexapeptide ring since receptor affinity of the antagonists begins to fall off when the basic functional group is too close (compound 13) or extends too far (compounds 8-10) from the hexapeptide ring. These results suggest all that is necessary for retention of antagonist affinity and potency is a basic functional group, amine or guanidine, extended an optimal distance from the hexapeptide ring.
- Callahan,Ashton-Shue,Bryan,Bryan,Heckman,Kinter,McDonald,Moore,Schmidt,Silvestri,Stassen,Sulat,Yim,Huffman
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p. 391 - 396
(2007/10/02)
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- AROMATIC BASIC-TAILED VASOPRESSIN ANTAGONISTS
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Certain new vasopressin-like peptides which have structures characterized by having a bisaminoalkylbenzene present in the vasopressin tail at the 7-or 8-position retain vasopressin antagonist activity. A species of the invention is 1-β-mercapto-β,β-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-8-1', 4'-bis(aminomethyl)benzene-9-des glycinamide!-vasopressin.
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