- Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R
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Even today, the role of the histamine H2 receptor (H2R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pKi = 8.07) were reported as H2R agonists. However, their applicability to the study of the H2R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H2R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [35S]GTPγS and β-arrestin2 recruitment assays) with human (h) H2R affinities in the one-digit nanomolar range (pKi (139, UR-KAT523): 8.35; pKi (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH2R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD2longR and agonists with high affinity at the hD3R (e.g. pKi (139, UR-KAT523): 7.80; pKi (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H2R and D3R agonists for the application in recombinant systems in which either the H2R or the D3R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H2R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H2R in the CNS.
- Biselli, Sabrina,Bresinsky, Merlin,Buschauer, Armin,Forster, Lisa,Honisch, Claudia,Pockes, Steffen,Tropmann, Katharina,Bernhardt, Günther
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supporting information
(2021/02/12)
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- Scope and limitations of reductive amination catalyzed by half-sandwich iridium complexes under mild reaction conditions
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The conversion of aldehydes and ketones to 1° amines could be promoted by half-sandwich iridium complexes using ammonium formate as both the nitrogen and hydride source. To optimize this method for green chemical synthesis, we tested various carbonyl substrates in common polar solvents at physiological temperature (37 °C) and ambient pressure. We found that in methanol, excellent selectivity for the amine over alcohol/amide products could be achieved for a broad assortment of carbonyl-containing compounds. In aqueous media, selective reduction of carbonyls to 1° amines was achieved in the absence of acids. Unfortunately, at Ir catalyst concentrations of 1 mM in water, reductive amination efficiency dropped significantly, which suggest that this catalytic methodology might be not suitable for aqueous applications where very low catalyst concentration is required (e.g., inside living cells).
- Nguyen, Dat P.,Sladek, Rudolph N.,Do, Loi H.
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supporting information
(2020/07/15)
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- Reductive amination of ketonic compounds catalyzed by Cp*Ir(III) complexes bearing a picolinamidato ligand
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Cp*Ir complexes bearing a 2-picolinamide moiety serve as effective catalysts for the direct reductive amination of ketonic compounds to give primary amines under transfer hydrogenation conditions using ammonium formate as both the nitrogen and hydrogen source. The clean and operationally simple transformation proceeds with a substrate to catalyst molar ratio (S/C) of up to 20,000 at relatively low temperature and exhibits excellent chemoselectivity toward primary amines.
- Tanaka, Kouichi,Miki, Takashi,Murata, Kunihiko,Yamaguchi, Ayumi,Kayaki, Yoshihito,Kuwata, Shigeki,Ikariya, Takao,Watanabe, Masahito
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p. 10962 - 10977
(2019/09/03)
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- Bioinspired organocatalytic aerobic C-H oxidation of amines with an ortho -quinone catalyst
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A simple bioinspired ortho-quinone catalyst for the aerobic oxidative dehydrogenation of amines to imines is reported. Without any metal cocatalysts, the identified optimal ortho-quinone catalyst enables the oxidations of α-branched primary amines and cyclic secondary amines. Mechanistic studies have disclosed the origins of different performances of ortho-quinone vs para-quinone in biomimetic amine oxidations.
- Qin, Yan,Zhang, Long,Lv, Jian,Luo, Sanzhong,Cheng, Jin-Pei
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supporting information
p. 1469 - 1472
(2015/03/30)
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- FENDILINE DERIVATIVES AND METHODS OF USE THEREOF
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Disclosed herein are novel derivatives of fendiline, including compounds of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising these derivative compounds. Methods and intermediates useful for making the derivatives, and methods of using the derivatives, for example, for the inhibition of K-Ras plasma membrane localization, and compositions thereof, including for the treatment of cancer, are also provided.
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Page/Page column 74
(2014/03/25)
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- OXAZOLONE AND PYRROLIDINONE-SUBSTITUTED ARYLAMIDES AS P2X3 AND P2X2/3 ANTAGONISTS
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Compounds of the formula 1: or a pharmaceutically acceptable salt thereof, wherein, X, Y, R1, R2, R3, R4, R5, R6 and R7 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X3 and/or a P2X2/3 receptor antagonists and methods of making the compounds.
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Page/Page column 24
(2010/12/31)
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- INDOLE, INDAZOLE AND BENZIMIDAZOLE ARYLAMIDES AS P2X3 AND P2X2/3 ANTAGONISTS
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Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, X, Y, Z, R1, R2, R3, R4 and R5 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X3 and/or a P2X2/3 receptor antagonists and methods of making the compounds.
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Page/Page column 20
(2010/12/31)
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- Asymmetric synthesis of chiral primary amines by transfer hydrogenation of N -(tert -Butanesulfinyl)ketimines
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(Figure presented) The diastereoselective reduction of (R)-N-(tert- butanesulfinyl)ketimines by a ruthenium-catalyzed asymmetric transfer hydrogenation process in isopropyl alcohol, followed by desulfinylation of the nitrogen atom, is an excellent method to prepare highly enantiomerically enriched α-branched primary amines (up to >99% ee) in short reaction times (1-4 h). (1S,2R)-1-Amino-2-indanol has been shown to be a very efficient ligand to perform this transformation. Ketimines bearing either an aryl or a heteroaryl group and an alkyl group as substituents of the iminic carbon atom are very good substrates for this process. The reduction of a dialkyl ketimine could also be achieved, affording the expected amine with moderate optical purity (69% ee). Some amines which are precursors of very interesting biologically and pharmacologically active compounds have been prepared in excellent yields and enantiomeric excesses.
- Guijarro, David,Pablo, Oscar,Yus, Miguel
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supporting information; experimental part
p. 5265 - 5270
(2010/10/21)
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- Voltammetric, potentiometric and spectrophotometric studies of some hydrazones and their metal complexes in ethanolic-aqueous buffered solutions
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The electrochemical behavior of some hydrazones derived from 6-chloro-2-hydrazinopyridine in the Britton-Robinson universal buffer of pH 2-11 containing 35% ethanol was investigated at the mercury electrode using dc-polarography, controlled-potential coulometry, and cyclic voltammetry techniques. The examined hydrazones were reduced in solutions of pH 2 single bond. The mechanistic pathway of the electrode reaction of the studied compounds was elucidated and discussed. The pK a values of the examined hydrazones and the stoichiometry of their complexes in solution with some transition metal ions were determined spectrophotometrically. The dissociation constants and the thermodynamic parameters of the investigated hydrazones, and the stability constants of their metal complexes in solution were determined potentiometrically. Springer-Verlag 2006.
- Ghoneim, Mohammed M.,El-Hallag, Ibrahim S.,El-Baradie, Kamal Y.,El-Desoky, Hanaa S.,El-Attar, Mona A.
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p. 285 - 299
(2007/10/03)
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- AZOLE-BASED KINASE INHIBITORS
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A compound of general formula (I) or pharmaceutically acceptable prodrugs, salts, hydrates, solvates, crystal forms or diastereomers thereof is described. A method of treating kinase-associated disease states using the compound of formula (I) is also desc
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Page/Page column 37-38
(2008/06/13)
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- THIADIAZOLEDIOXIDES AND THIADIAZOLEOXIDES AS CXC- AND CC-CHEMOKINE RECEPTOR LIGANDS
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Disclosed are novel compounds of the formula (IA) and the pharmaceutically acceptable salts and solvates thereof. Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and cardiac reperfusion injury, acute pain, acute and chronic inflammatory pain, and neuropathic pain using a compound of formula (IA).
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- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
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There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
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- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
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There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
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- Substituted 2,4-diamino-1,3,5-triazine and their use as herbicides
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The invention relates to novel substituted 2,4-diamino-1,3,5-triazines of the formula (I) in which R1represents, for exampe, H or C1-C6-alkyl, R2represents, for example, H, C1-C6-alkyl or —CO—R6, R3represents, for example, H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl or C3-C6-cycloalkyl, R4represents, for example, H, C1-C6-alkyl or C3-C6-cycloalkyl, R5represents one of the groupings below, where R6represents, for example, C1-C6-alkyl, C1-C6-alkoxy or C2-C6-alkenyl, R7to R12represents, for example, H or certain organic radicals and Q represents O or S, to processes and novel intermediates for their preparation and to their use as herbicides.
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Page column 62
(2010/01/30)
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