100981-05-3Relevant articles and documents
Straightforward synthesis of novel substituted 1,3,4-thiadiazole derivatives in choline chloride-based deep eutectic solvent
Shahcheragh, Seyyed Mohammad,Habibi, Azizollah,Khosravi, Sahar
, p. 855 - 859 (2017)
A one-pot, three-component route for the synthesis of novel 1,3,4-thiadiazole derivatives using a ketene S,S-acetal, a carbonyl compound and thiocarbohydrazide is described. The main advantages of this approach are high yields, short reaction times, simple reaction conditions and a green reaction medium. The 1,3,4-thiadiazole core has been substituted with biologically active groups such as arylhydrazones, coumarin, isatin, Meldrum's acid and barbituric acid. Structures of the thiadiazoles were elucidated from spectroscopic data.
Hydrolysis of α-alkyl-α-(methylthio)methylene Meldrum's acids. A kinetic and computational investigation of steric effects
Bernasconi, Claude F.,Brown, Shoshana D.,Ali, Mahammad,Rappoport, Zvi,Yamataka, Hiroshi,Salim, Hatim
, p. 4795 - 4802 (2006)
The rates of hydrolysis of α-R-α-(methylthio)methylene Meldrum's acids (8-R with R = H, Me, Et, s-Bu, and t-Bu) were determined in basic and acidic solution in 50% DMSO-50% water (v/v) at 20 °C. In basic solution (KOH), nucleophilic attack to form a tetrahedral intermediate (T OH-) is rate limiting for all substrates (κ1OH). In acidic solution (HCl) and at intermediate pH values (acetate buffers), water attack (κ1H2O) is rate limiting for 8-Me, 8-Et, and 8-t-Bu; the same is presumably the case for 8-t-Bu, but rates were too slow for accurate measurements at low pH. For 8-H, water attack is rate limiting at intermediate pH but at pH OH- to products, two of which being unique to hydrolysis reactions and taking advantage of the acidic nature of the OH group in TOH-. This scheme provides an explanation why even at high [KOH] TOH- does not accumulate to detectable levels even though the equilibrium for OH - addition to 8-R is expected to favor TOH, and why at low pH water attack is rate limiting for R = Me, Et, s-Bu, and t-Bu but leaving group departure becomes rate limiting with the sterically small R = H. The trend in the k1OH and k1H2O indicates increasing steric crowding at the transition state with increasing size of R, but this effect is partially offset by a sterically induced twisting of the C=C double bond in 8-R which leads to its elongation and makes the substrate less stable and hence more reactive. Our computational results suggest that this effect becomes particularly pronounced for R = t-Bu and explains why k 1OH for 8-t-Bu is somewhat higher than for the less crowded 8-s-Bu.
Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs
Pirali, Tracey,Ciraolo, Elisa,Aprile, Silvio,Massarotti, Alberto,Berndt, Alex,Griglio, Alessia,Serafini, Marta,Mercalli, Valentina,Landoni, Clarissa,Campa, Carlo Cosimo,Margaria, Jean Piero,Silva, Rangel L.,Grosa, Giorgio,Sorba, Giovanni,Williams, Roger,Hirsch, Emilio,Tron, Gian Cesare
, p. 1542 - 1554 (2017/09/26)
Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor.
For forming the functional polymer film of the coating liquid and functional polymer film forming method
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Paragraph 83; 84, (2017/10/28)
Provided is a coating solution for forming a functional polymer film, said coating solution containing: at least one type of modifying compound selected from the group represented by formula A-D and having at least one Meldrum's acid structural site and a functional structural site which imparts functionality; and a polymer for modification or a monomer for the synthesis of said polymer for modification. Also provided is a functional polymer film obtained by firing a substrate coated using said coating. (In the formulae, the symbols are groups as defined in claim 1.)
Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase
Barbeau, Olivier R.,Cano-Soumillac, Celine,Griffin, Roger J.,Hardcastle, Ian R.,Smith, Graeme C. M.,Richardson, Caroline,Clegg, William,Harrington, Ross W.,Golding, Bernard T.
, p. 2670 - 2677 (2008/03/11)
8-Substituted 2-morpholin-4-yl-quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones with selected aryl and heteroaryl groups as the substituent have been synthesised as potential inhibitors of DNA-dependent protein kinase. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was utilised in the preparation of 8-substituted 2-morpholin-4-yl-quinolin-4-ones. For this purpose 8-bromo-2-morpholin-4-yl- quinolin-4-one was required as an intermediate. This compound was obtained by adapting a literature route in which thermal cyclocondensation of (2-bromoanilino)-morpholin-4-yl-5-methylene-2,2-dimethyl[1,3]dioxane-4,6-dione afforded 8-bromo-2-morpholin-4-yl-quinolin-4-one. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was also utilised to prepare 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones using 9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one O- trifluoromethanesulfonate as an intermediate. 8-Substituted 2-morpholin-4-yl- quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones were both inhibitors of DNA-dependent protein kinase. When the substituent was dibenzothiophen-4-yl, dibenzofuran-4-yl or biphen-3-yl, IC50 values in the low nanomolar range were observed. Interestingly, the pyridopyrimidinones and quinolinones were essentially equipotent with the corresponding 8-substituted 2-morpholin-4-yl-chromen-4-ones previously reported (I. R. Hardcastle, X. Cockcroft, N. J. Curtin, M. Desage El-Murr, J. J. J. Leahy, M. Stockley, B. T. Golding, L. Rigoreau, C. Richardson, G. C. M. Smith and R. J. Griffin, J. Med. Chem., 2005, 48, 7829-7846). The Royal Society of Chemistry.
DNA-PK INHIBITORS
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Page/Page column 50, (2008/06/13)
Compounds of formula: (I) wherein A, B and D are respectively selected from the group consisting of: (i) CH, NH, C; (ii) CH, N, N; and (iii) CH, O, C; the dotted lines represent two double bonds in the appropriate locations; and where Z is selected from S, O, C(=O), CH2 and NH are disclosed for use in inhibiting DNA-PK.
SUBSTITUTED 3-AMINO-THIENO[2,3-B] PYRIDINE-2-CARBOXYLIC ACID AMIDE COMPOUNDS AS IKK INHIBITORS
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Page/Page column 79, (2008/06/13)
Disclosed are compounds of formula (I): wherein the variables R1, R2, R3 and Z are described herein, which are useful as inhibitors of the kinase activity of the IκB kinase (IKK) complex. The compounds are therefore useful in the treatment of IKK mediated diseases including autoimmune diseases inflammatory diseases and cancer. Also disclosed are pharmaceutical compositions comprising these compounds and processes for preparing these compounds.
Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold
Knight, Zachary A.,Chiang, Gary G.,Alaimo, Peter J.,Kenski, Denise M.,Ho, Caroline B.,Coan, Kristin,Abraham, Robert T.,Shokat, Kevan M.
, p. 4749 - 4759 (2007/10/03)
Phosphoinositide 3-kinases (PI3-Ks) are an ubiquitous class of signaling enzymes that regulate diverse cellular processes including growth, differentiation, and motility. Physiological roles of PI3-Ks have traditionally been assigned using two pharmacological inhibitors, LY294002 and wortmannin. Although these compounds are broadly specific for the PI3-K family, they show little selectivity among family members, and the development of isoform-specific inhibitors of these enzymes has been long anticipated. Herein, we prepare compounds from two classes of arylmorpholine PI3-K inhibitors and characterize their specificity against a comprehensive panel of targets within the PI3-K family. We identify multiplex inhibitors that potently inhibit distinct subsets of PI3-K isoforms, including the first selective inhibitor of p110β/p110δ (IC50 p110β = 0.13 μM, p110δ = 0.63 μM). We also identify trends that suggest certain PI3-K isoforms may be more sensitive to potent inhibition by arylmorpholines, thereby guiding future drug design based on this pharmacophore.
Amine catalysis in the vinylic substitution of α-methylthio-α-arylmethylene Meldrum's acids and its absence in the substitution of methyl β-iodo-α-nitrocinnamate by amines
Beit-Yannai,Chen,Rappoport
, p. 1534 - 1545 (2007/10/03)
Substitution of the iodine of (E)- and (Z)-methyl β-iodo-α-nitrocinnamates (5) by amines gives identical (Z)-enamines with aniline (Ani) and piperidine (Pip). No amine catalysis was observed with Pip, Ani, morpholine (Mor), orp-MeOC6H4NHMe (MMA) in MeCN nor with Pip or Mor in EtOH: kPip/kMor = 115-138 (MeCN), 3.3-6.9 (EtOH); kMeCN/kEtOH = 25.5 ± 2.2 (Pip), 0.79-1.16 (Mor); k(Z)-5/k(E)-5 = 1.3-2.9 (13.5 with MMA in MeCN). Replacement of the MeS group in six α-amethylthio-α-arylmethylene Meldrum's acid (6-X) by Pip resulted in amine catalysis in MeCN and EtOH. In EtOH, the p-anisyl derivative (6-MeO) and in MeCN 6-MeO, 6-Me and 6-H displayed second order catalysis in Pip. Other 6-X compounds show orders between one and two in Pip with amine catalyzed (k3B)/non-catalyzed (k2) rate coefficient ratios of 281-731 (EtOH) and 504-635 (MeCN) at 30°C. kMeCN/kEtOH = 3.0-4.9. In MeCN ΔH? = -0.8 to -5.9 kcal mol-1 and ΔS? = -50 to -72 e.u. An intermediate zwitterion, 3a, is formed in all cases. For system 5 the rate of I- expulsion from 3a exceeds its deprotonation rate, and the observed rate coefficient is composite: kobs = k1k2/k-1 in MeCN (k1 = rate coefficient of nucleophilic attack) but kobs = k1 in EtOH. In MeCN the deprotonation is faster than the expulsion rate of MeS-, and more so for 6-X with X = p-Br, p-CF3, m,m′-(CF3)2. Different electrophilicities of 6-X, different extents of hydrogen bonding, steric and electronic effects account for the kinetic differences.
Synthesis of 3-hydroxythiophenes and thiophen-3(2H)-ones by pyrolysis of alkylsulfanylmethylene Meldrum's acid derivatives
Hunter, Gordon A.,McNab, Hamish
, p. 1209 - 1214 (2007/10/02)
3-Hydroxythiophene 1 and a range of its 2-substituted, 2,2-disubstituted and 5-substituted derivatives have been made by flash vacuum pyrolysis (FVP) of an appropriate alkylsulfanylmethylene derivative of Meldrum's acid 3 or 4.These compounds are readily obtained, either by reaction of methoxymethylene Meldrum's acid with alkylthiols in refluxing acetonitrile, or via the bis(methylsulfanyl) compound 18 by known procedures.The pyrolysis proceeds by a hydrogen-transfer-cyclisation mechanism in which thereis extensive loss of configuration of a chiral centre at the reaction site.The NMR and mass spectra of the Meldrum's acid precursors and the mass spectra of the 3-hydroxythiophenes are briefly discussed.
