- PYRIMIDINE-BASED ANTIPROLIFERATIVE AGENTS
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This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
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Page/Page column 172; 209; 210
(2018/02/28)
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- Oxidation of Secondary Methyl Ethers to Ketones
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We present a mild way of converting secondary methyl ethers into ketones using calcium hypochlorite in aqueous acetonitrile with acetic acid as activator. The reaction is compatible with various oxygen- and nitrogen-containing functional groups and afforded the corresponding ketones in up to 98% yield. The use of this methodology could expand the application of the methyl group as a useful protecting group.
- Gilissen, Pieter J.,Blanco-Ania, Daniel,Rutjes, Floris P. J. T.
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p. 6671 - 6679
(2017/07/15)
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- ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF
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Described herein are compounds of Formula (S-I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.
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Paragraph 00519
(2016/04/20)
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- Development and evaluation of ST-1829 based on 5-benzylidene-2-phenylthiazolones as promising agent for anti-leukotriene therapy
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Different inflammatory diseases and allergic reactions are mediated by leukotrienes, which arise from the oxygenation of arachidonic acid catalyzed by 5-lipoxygenase (5-LO). One promising approach for an effective anti-leukotriene therapy is the inhibition of this key enzyme. This study presents the synthesis and development of a potent and direct 5-LO inhibitor based on the well characterized 5-benzylidene-2-phenylthiazolone C06, whose further pharmacological investigation was precluded due to its low solubility. Through optimization of C06, evaluation of structure-activity relationships including profound assessment of the thiazolone core and consideration of the solubility, the 5-benzyl-2-phenyl-4-hydroxythiazoles represented by 46 (ST-1829, 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol) were developed. Compound 46 showed an improved 5-LO inhibitory activity in cell-based (ICinf50/inf values 0.141/4M) and cell-free assays (ICinf50/inf values 0.03 1/4M) as well as a prominent enhanced solubility. Furthermore, it kept its promising inhibitory potency in the presence of blood serum, excluding excessive binding to serum proteins. These facts combined with the non-cytotoxic profile mark a major step towards an effective anti-inflammatory therapy.
- Lill, Andreas P.,R?dl, Carmen B.,Steinhilber, Dieter,Stark, Holger,Hofmann, Bettina
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supporting information
p. 503 - 523
(2014/12/11)
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- Spectroscopic and X-ray crystallographic evidence for electrostatic effects in 4-substituted cyclohexanone-derived hydrazones, imines, and corresponding salts
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The axial conformer of several 4-substituted cyclo-hexanone hydrazone salts was found to predominate in solution. Changes in the charge of the molecule and the polarity of the solvent led to changes in the conformational preference of each molecule that were consistent with electrostatic stabilization of the axial conformer. H NMR spectroscopic analysis was utilized to determine the structure of cyclohexanone-derived substrates by comparison to conformationally restricted trans-decalone derivatives and computational models. X-ray crystallography demonstrated that the axial configuration of a pendant benzyloxy group is the preferred conformation of an iminium ion in the solid state. The structure of a neutral hydrazone was also determined to favor the axial configuration for a pendant benzyloxy group in the solid state.
- Dibble, David J.,Ziller, Joseph W.,Woerpef
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supporting information; experimental part
p. 7706 - 7719
(2011/12/02)
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- Novel Compounds for the Treatment of Diseases Associated with Amyloid or Amyloid-Like Proteins
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The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.
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Page/Page column 72
(2011/11/30)
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- NEW GALLIUM BISAMINOTHIOLATE COMPLEXES FOR MYOCARDIAL IMAGING
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The present invention is directed to compounds of Formula I: and pharmaceutically acceptable salts thereof; wherein A1, A2 and A3 are the same or different cycloalkyl, wherein at least one of A1, A2 or A3 is substituted. R1 through R6 are independently hydrogen or alkyl, R7 and R8 are independently hydrogen or alkyl and RP is hydrogen or sulfhydryl protecting group. This invention is also directed to complexes, wherein said compounds chelate radioactive metal ions, such as Gallium. The complexes of the rpesent invention are useful as myocardial perfusion imaging agents.
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Page/Page column 11
(2008/12/08)
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- BENZIMIDAZOLES WHICH HAVE ACTIVITY AT M1 RECEPTOR AND THEIR USES IN MEDICINE
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Compounds of formula (I), salts and solvates are provided: formula (I), wherein Q, R and R6 are as defined in the claims. Uses of the compounds for therapy, for example in the treatment of psychotic disorders and cognitive impairment, are also disclosed.
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Page/Page column 49
(2008/06/13)
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- BENZIMIDAZOLES WHICH HAVE ACTIVITY AT M1 RECEPTOR AND THEIR USES IN MEDICINE
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Compounds of Formula (I) and salts and solvates are provided; wherein R, R5, R6 and Q are defined as in the claims. Uses of the compounds for therapy, for example in the treatment of psychotic disorders and cognitive impairment, are also disclosed.
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Page/Page column 46-47
(2010/11/28)
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- BENZIMIDAZOLES WHICH HAVE ACTIVITY AT M1 RECEPTOR AND THEIR USES IN MEDICINE
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Compounds of formula (I), salts and solvates are provided, wherein Q, R, R4 - R6 are as def ined in the Claims. Uses of the Compounds for therapy, for example in the treatment of psychotic disorders and cognitive impairment, are also disclosed.
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Page/Page column 45-46
(2010/11/28)
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- Synthesis of 5-substituted 4,5,6,7-tetrahydroindoles from cyclohexanones
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5-Substituted 4,5,6,7-tetrahydroindoles were prepared from 4-substituted cyclohexanones in three steps: conversion to an enol silyl ether, introduction of a formylmethyl group at 2-C, and the Paal-Knorr pyrrole synthesis by reacting the 1,4-dicarbonyl compounds with ammonia. The substituents are H, methyl, ethyl, tert-butyl, methoxy, and phenyl.
- Lee, Chang Kiu,Lee, In-Sook Han,Noland, Wayland
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p. 419 - 428
(2008/02/09)
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- New bioorganic reagents: Evolved cyclohexanone monooxygenase - Why is it more selective?
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Four mutants of the cyclohexanone monooxygenase (CHMO) evolved as catalysts for Baeyer-Villiger oxidation of 4-hydroxycyclohexanone were investigated as catalysts for a variety of 4-substituted and 4,4-disubstituted cyclohexanones. Several excellent catalytic matches (mutant/substrate) were identified. The most important, however, is the finding that, in a number of cases, a mutant with a single exchange, Phe432Ser, was shown to be as robust and more selective as a catalyst than the wild-type CHMO. All biotransformations were performed on a laboratory scale, allowing full characterization of the products. The absolute configurations of two products were established. A model suggesting a possible role of the 432 serine residue in enantioselectivity control is proposed.
- Kayser, Margaret M.,Clouthier, Christopher M.
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p. 8424 - 8430
(2007/10/03)
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- Stereospecific retro-diels-alder fragmentation of stereoisomeric 3- methoxy- and 3,6-dialkoxytricyclo[6.2.2.02,7]dodeca-9-enes upon electron ionization
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The stereoisomeric 2,3-cis- and 2,3-trans-3-methoxytricyclo [6.2.2.02,7]dodeca-9-enes endo-1 and exo-1 (endo and exo refer to the methoxy group) exhibit different behavior under electron ionization (EI): the m/z 80 cyclohexa-1,3-diene radical cation formed by retro-Diels-Alder (RDA) fragmentation is the most abundant ion in the 70 eV mass spectrum of endo-1, whereas exo-1 exhibits preferential formation of an m/z 111 ion corresponding to the O-methylcyclohex-2-en-1-one structure (ion a), which may be obtained by an RDA fragmentation accompanied by a hydrogen migration (RDA - H), with the charge retained in the dienophile moiety. A similar effect has been observed in the EI mass spectra of the four stereoisomeric 3-ethoxy-6- methoxytricyclo[6.2.2.02,7]dodeca-9-enes 2; endo-2, with both endo-alkoxy groups, gives rise to the most abundant m/z 80 ion via the regular RDA process, whereas the other three stereoisomers, with at least one exo-alkoxy group, afford the most abundant m/z 155 ions via the RDA - H process, which correspond to the 4-alkoxy-substituted analogues of the m/z 111 ion a obtained from exo-1. Collision-induced dissociation measurements and a deuterium labeling study showed that the m/z 155 ions obtained from the two trans-diethers (trans-2a and trans-2b) have isomeric structures b and c (a mixture of b and c is formed in the case of exo-2), and that the highly stereospecific RDA - H process involves a double hydrogen transfer, one from position 4 to the diene moiety and the other from position 3 to 4. The above stereospecific behavior shows that the thermodynamically favored RDA - H process has a higher activation energy than the regular RDA fragmentation in the case of endo-1 and endo-2. In all other isomers, which have at least one exo-alkoxyl, the activation energy of the RDA - H process is lower than that of RDA. The latter effect is ascribed to anchimeric assistance of the alkoxyl in the initial C - C bond cleavage in the stepwise RAD - H process, which is possible only when at least one alkoxyl has the exo configuration.
- Morlender-Vais,Mandelbaum
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p. 229 - 241
(2007/10/03)
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- Direct evidence for anchimeric assistance in alcohol elimination from gas-phase MH+ ions of 1,4-dialkoxycyclohexanes under chemical ionisation. Experiment and theory
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trans-1,4-Dialkoxycyclohexanes afford very abundant [MH - ROH]+ ions upon chemical ionisation (CI), in contrast to the cis-isomers, suggesting anchimeric assistance in the alcohol elimination from the MH+ ions of the trans-diethers. Collision induced dissociation (CID) measurements of the [MH - ROH]+ ions, obtained from various suitably deuterium labelled stereoisomeric 1-ethoxy-4-methoxycyclohexanes, indicated fromation of symmetrical bicyclic ethyl and methyl oxonium ions by an anchimerically assisted alcohol elimination from the trans-diethers. On the other hand these measurements suggest that the cis-isomers afford isomeric monocyclic O-protonated 4-alkoxycyclohexene cations, in which the hydrogens at positions 2 and 3 (as well as those at positions 5 and 6, and 1 and 4) are not equivalent. The two results, namely the symmetrical bicyclic structure and the high abundance of the [MH - ROH]+ ions in the CI mass spectra of the trans-diethers, in contrast to the non-symmetrical monocyclic structure and low abundance of these ions in the cis-isomers, are suggested to be direct evidence for anchimeric assistance in a gas-phase ion dissociation process. Ab initio calculations at the MP3/6-31G*//6-31G* level support the anchimerically assisted elimination mechanism observed in trans-1-ethoxy-4-methoxycyclohexane, but also show that the energy difference between the anchimerically assisted and non-assisted elimination mechanisms is small (ca. 2-3 kcal mol-1)(1 cal = 4.184 J).
- Shvily, Ronit,Mueller, Thomas,Apeloig, Yitzhak,Mandelbaum, Asher
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p. 1221 - 1234
(2007/10/03)
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- Enantioselective deprotonation of protected 4-hydroxycyclohexanones
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A series of derivatives of 4-hydroxycyclohexanone (1a-g) with the hydroxy group protected as a silyl ether (1a,b), ether (1d,g), an acetal (1c), or an ester (1e,f) were deprotonated with chiral, optically pure, lithium amides 3-9. The resulting non-racemic enolates were trapped as enol acetates. The enantioselectivity of deprotonation was up to 74percent ee.
- Majewski, Marek,Mackinnon, John
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p. 1699 - 1704
(2007/10/02)
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