- ADAMANTANYL-SUBSTITUTED BENZAMIDE COMPOUNDS AND THEIR USE AS P2X7 RECEPTOR ANTAGONISTS
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The present invention relates to adamantanyl-substituted benzamide compounds and their use as antagonists of the P2X7 purinoreceptor. The invention further relates to methods for the treatment of disease and conditions associated with the P2X7 purinoreceptor.
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Page/Page column 20; 25
(2020/03/15)
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- Copper and L-(?)-quebrachitol catalyzed hydroxylation and amination of aryl halides under air
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L-(?)-Quebrachitol, a natural product obtained from waste water of the rubber industry, was utilized as an efficient ligand for the copper-catalyzed hydroxylation and amination of aryl halides to selectively give phenols and aryl amines in water or 95percent ethanol. In addition, the hydroxylation of 2-chloro-4-hydroxybenzoic acid was validated on a 100-g scale under air.
- Bao, Xuefei,Chen, Guoliang,Dong, Jinhua,Du, Fangyu,Li, Hui,Liang, Xinjie,Wu, Ying,Zhang, Yongsheng
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supporting information
(2020/08/03)
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- Application of quebrachitol in hydrolysis reaction of copper-catalyzed aryl halide
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The invention belongs to the technical field of drug synthesis, and provides application of quebrachitol in a hydrolysis reaction of a copper-catalyzed aryl halide. According to the hydrolysis reaction, copper serves as a catalyst, quebrachitol serves as a ligand, and the hydrolysis reaction is carried out on the aryl halide. The invention further provides a catalytic system of the hydrolysis reaction of the aryl halide. The reaction system comprises the copper catalyst, the quebrachitol, alkali and water, and the system is environmentally friendly and is suitable for industrial application.
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Paragraph 0048-0050
(2019/07/16)
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- The role of polycyclic frameworks in modulating P2X7 receptor function
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Herein we describe our recent attempts to target the P2X7 receptor for potential treatment of neurological disorders. This work focusses on different polycycles including carborane, adamantane or cubane, joined by either a cyanoguanidine or an amide linker to phenyl or isoquinoline moieties. We have demonstrated the superiority of the adamantyl moiety over other polycycles in terms of synthetic accessibility and biological (cellular) activity. We have also shown that an amide or cyanoguanidine linker can greatly alter the biological activity of compounds. This SAR study provides important insights into the types of functionality required to target the P2X7 receptor.
- Callis, Timothy B.,Reekie, Tristan A.,O'Brien-Brown, James,Wong, Erick C.N.,Werry, Eryn L.,Elias, Nabiha,Jorgensen, William T.,Tsanaktsidis, John,Rendina, Louis M.,Kassiou, Michael
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p. 1207 - 1219
(2017/11/24)
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- Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule
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Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5-and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new indirubin 3′-and 5′-derivatives in the search of water-soluble indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3′-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5′-position appear unfavorable. Screening molecular targets of water-soluble 3′-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5′-position provides limited space for chemical modifications and identify 6ha as a potent water-soluble indirubin-based IGF-1R inhibitor.
- Cheng, Xinlai,Merz, Karl-Heinz,Vatter, Sandra,Zeller, Jochen,Muehlbeyer, Stephan,Thommet, Andrea,Christ, Jochen,W?lfl, Stefan,Eisenbrand, Gerhard
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p. 4949 - 4962
(2017/06/28)
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- Structure-based design of a potent, selective, and brain penetrating PDE2 inhibitor with demonstrated target engagement
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Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up
- Buijnsters, Peter,De Angelis, Meri,Langlois, Xavier,Rombouts, Frederik J. R.,Sanderson, Wendy,Tresadern, Gary,Ritchie, Alison,Trabanco, Andrs A.,Vanhoof, Greet,Roosbroeck, Yves Van,Andrs, Jos-Ignacio
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supporting information
p. 1049 - 1053
(2014/12/10)
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- NOVEL PYRAZOLONE-DERIVATIVES AND THEIR USE AS PD4 INHIBITORS
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The compounds of formula (1) wherein R1 represents a phenyl derivative of formulae (a), (b) or (c) R10 is 1-3C-alkyl and R11 is 1-3C-alkyl, or R10 and R11 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring, A is C(O) or S(O)2, and R12 is phenyl, naphthalenyl, pyridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, 1,6-naphthyridinyl, 1,8-naphthyridinyl, indolyl, phenyl substituted by R13, R14, R15 and R16, pyridinyl substituted by R17 and R18, naphthalenyl substituted by R19 and R20, quinolinyl substituted by R21 or indolyl substituted by R22, are novel effective inhibitors of the type 4 phosphodiesterase.
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Page/Page column 108
(2010/06/15)
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- POLYCYCLIC MOLECULAR COMPOUNDS
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This invention relates to compounds of Formula (I), wherein A is a carboaromatic or heteroaromatic ring having one or more substituents; R6 Formula (A) is optionally substituted with one or more substituents; and n is 0, 1 or an integer greater than 1 and when n is 1 or greater the bond or bonds between the carbon atoms may be saturated or unsaturated, which bind the P2X7 receptor with high affinity. This invention also relates to methods for the diagnosis, treatment or monitoring of disorders in which the P2X7 receptor is implicated, in particular the diagnosis, treatment or monitoring of (the progression of) neuroinflammatory and neurodegenerative disorders in a subject.
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Page/Page column 58
(2008/12/06)
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- Cubyl amides: Novel P2X7 receptor antagonists
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Polycyclic amides 2 and 5-9 were successfully synthesised and their lipophilicity profiles were evaluated using reverse-phase HPLC. All synthesised compounds possessed P2X7R antagonistic properties when tested on rat spinal cord microglia cells. Extensive screening for binding to other neuroreceptor subtypes demonstrated their P2X7 selectivity.
- Gunosewoyo, Hendra,Guo, Jun Liu,Bennett, Maxwell R.,Coster, Mark J.,Kassiou, Michael
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supporting information; experimental part
p. 3720 - 3723
(2009/04/06)
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- The site-selective functionalization of halogen-bearing phenols: An exercise in diversity-oriented organometallic synthesis
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The organometallic approach to diversity-oriented organic synthesis was subjected to a further test, this time in the phenol series. The model compounds selected were 2,3,6-trifluorophenol, the three isomers of (trifluoromethoxy) phenol and the three isomers of chlorophenol. A combination of optionally site selective metalations and protective group-controlled metalations enabled the selective generation of several isomeric intermediates in each case and their subsequent conversion into functionalized derivatives, in particular hydroxybenzoic acids.
- Marzi, Elena,Schlosser, Manfred
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p. 3393 - 3401
(2007/10/03)
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- Substituted phenyl derivatives, their preparation and use
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The present invention discloses compounds having the formula wherein the substituents are defined in the application. The compounds are useful as chloride channel blockers.
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- Kinetics of chlorination of phenol and monosubstituted phenols by t-butyl hypochlorite in aqueous alkaline medium
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The kinetics of chlorination of the parent and sixteen monosubstituted phenols (2-chloro, 2-methyl, 2-carboxy, 2-nitro, 3-chloro, 3-methyl, 3-carboxy, 4-fluoro, 4-chloro, 4-bromo, 4-methyl, 4-ethyl, 4-methoxy, 4-carboxy, 4-acetyl and 4-nitro) by t-BuOCl have been studied in aqueous alkaline medium. The rates of reactions show first order kinetics each in |t-BuOCl| and |XC 6H4OH| and inverse first order in |OH-|. Variation in either ionic strength or addition of reaction product has no significant effect on the rates of reactions, while lowering of the dielectric constant of the medium increases the rate. The rates are measured at different temperatures and the activation parameters for all the phenols computed. A mechanism involving the electrophilic attack of phenoxide ions by HOCl in the rate determining step is suggested. The rates decrease in the order: 3-CH 3 > 2-CH3 > 4-OCH3 > 4-CH3 > 4-C2H5 > H > 3-Cl > 3-COO- > 4-F > 2-COO- > 4-Br > 2-Cl > 4-Cl > 4-COO- > 4-COCH3 > 2-NO2 > 4-NO2. Hammett equation of the type, log k = -3.44 - 2.35 ρ is found to be valid for substituent effects. The enthalpy and entropy of activation are correlated.
- Moodithaya,Gowda, B. Thimme
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p. 420 - 425
(2007/10/03)
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- Substituted phenyl derivatives, their preparation and use
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The present invention discloses compounds having the formula wherein the substituents are defined in the application. The compounds are useful as chloride channel blockers.
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- Kinetics and mechanism of chlorination of phenol and substituted phenols by sodium hypochlorite in aqueous alkaline medium
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The kinetics of chlorination of the parent and thirteen substituted phenols (2-methyl, 2-chloro, 2-carboxy, 3-methyl, 3-chloro, 3-carboxy, 4-methyl, 4-ethyl, 4-chloro, 4-bromo, 4-carboxy, 4-acetyl and 4-nitro phenols) by NaOCl have been studied in aqueous alkaline medium under varying conditions. The rates show first order kinetics each in [NaOCl] and [(X)C6H4(OH)] and inverse first order in [OH-]. Variation in ionic strength of the medium and addition of Cl have no significant effect on the rates of reactions. The rates of the reactions are measured at different temperatures and the activation parameters for all the phenols computed. A mechanism involving the electrophilic attack of the phenoxide ions by NaOCl in the rate determining step has been considered. The values of the pre-equilibrium and the rate determining steps have been calculated for all the phenols. The rates decrease in the order: 3-CH3 >2-CH3 >4-C2H5 = 4-CH3 >phenol >3-COO = 3-Cl > 2-COO >4-COO >2-Cl ? 4-Cl ? 4-Br > 4-COCH3 >4-NO2. Hammett plot of the type, log kobs = -2.88 -3.2980σ is found to be valid. The correlation between the enthalpies and the free energies of activations is reasonably linear with an isokinetic temperature of 300 K. Further, the energies of activation of all the phenols are optimised corresponding to the log A of the parent phenol through the equation, Ea = 2.303 RT (log A - log kobs). Similarly log A values of all the phenols are optimised corresponding to the Ea of PhOH through the equation, log A = log kobs + Ea/2.303RT. Ea increases with the introduction of electron-withdrawing groups into the benzene ring, while the introduction of the electron-releasing groups lowers Ea for the reaction. Similarly log A decreases with the substitution of electron-withdrawing groups, while log A increases on substitution with the electron-releasing groups.
- Gowda,Mary
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p. 1196 - 1202
(2007/10/03)
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- PHOTOREACTION OF BENZOIC ACID WITH SODIUM HYPOCHLORITE IN AQUEOUS ALKALI
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The photoreaction of benzoic acid with sodium hypochlorite in aqueous alkali (pH > 12) has been studied.At a low initial ratio of , e.g, 0.1, hydroxylation and chlorination at the aromatic ring occur simultaneously with ipso-substitution of the carboxylate group to give hydroxy- and chlorobenzoic acids together with phenol.The product distribution depends on the wavelength of the light, which implies the dependence on the concentration of avtive species generated from ClO(1-) and on the light stability of products.At comparable concentrations of ClO(1-) and PhCOO(1-), the products initially formed from the photoreaction react further with ClO(1-) in the dark to give polychlorinated derivatives.The initial steps for the photoreaction are discussed on the basis of the reactivity of the active species, O(3P), O(1D), O(1-)(.), and Cl(.), generated by photolysis of ClO(1-).
- Ogata, Yoshiro,Tomizawa, Kohtaro
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p. 985 - 988
(2007/10/02)
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- Synthesis and properties of nuclear hydroxylated derivatives of flufenamic acid and etofenamate
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Synthesis of six nuclear hydroxylated derivatives of flufenamic acid and etofenamate (5-OH-, 4'-OH and 5,4'-(OH2) on a preparative scale is described. All compounds show low toxicity, by only weak anti-inflammatory activity in the rat paw kaolin edema test as compared to 2-(2-hydroxyethoxy)ethyl-N-(α,α,α-trifluoro-m-tolyl)-anthranilate (etofenamate, active substance of Rheumon Gel).
- Boltze,Backer,Kreisfeld
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p. 183 - 186
(2007/10/02)
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