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Lack of effect of the length of oligoglycine- and oligo(ethylene glycol)-derived para-substituents on the affinity of benzenesulfonamides for carbonic anhydrase II in solution
Using 1H NMR spectroscopy, values of T2 have been determined for the methylene protons of the oligoglycine moieties of para-substituted benzenesulfonamides having structures H2NO2SC6H4CO(Gly)(n)OH (n = 1-6) bound at the active site of bovine carbonic anhydrase II (CA, EC 4.2.1.1). These values have been correlated with measurements of dissociation constants of these complexes, in order to infer motion of these ligands when bound to the enzyme. Motion of glycines 1-3 (those closest to the aryl ring) is hindered by their proximity to the protein; motion of glycines 4-6 is relatively unhindered. Despite the restriction to motion inferred for glycines 1-3, the values of K(d) for the six compounds (n = 1-6, 1-6) are indistinguishable within experimental uncertainty (± 20%): K(d) in μM (n) 0.30 (1); 0.26 (2); 0.33 (3); 0.37 (4); 0.37 (5); 0.34 (6). There is, therefore, an unexpected compensation of the loss in conformational entropy on binding by another contributor to the free energy.
Jain, Ahamindra,Huang, Shaw G.,Whitesides, George M.
p. 5057 - 5062
(1994)
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Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and N-Propargyl Handles for Drug-Activation
The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.
Oliveira, Bruno L.,Stenton, Benjamin J.,Unnikrishnan,De Almeida, Cátia Rebelo,Conde, Jo?o,Negr?o, Magda,Schneider, Felipe S.S.,Cordeiro, Carlos,Ferreira, Miguel Godinho,Caramori, Giovanni F.,Domingos, Josiel B.,Fior, Rita,Bernardes, Gon?alo J. L.
p. 10869 - 10880
(2020)
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HYDROLYSIS OF N-SALICYLIDENE-2-METHOXYETHYLAMINE. INTRAMOLECULAR GENERAL BASE CATALYSIS AND SPECIFIC EFFECTS OF BORIC ACID.
Hydrolysis of N-salicylidene-2-methoxyethylamine is kinetically investigated at 30 degree C. Intramolecular general base catalysis by the o-O** minus substituent takes place in the neutral pH region. Nucleophilic catalysis by morpholine was also found to be operative. Added boric acid accelerates the hydrolysis above pH 5. 5 while it decelerates the hydrolysis below pH 5. 5. The hydrolysis rate as the function of the boric acid concentration follows a saturation curve in harmony with a reaction sequence involving a rapid equilibrium formation of a borate-substrate complex followed by its breakdown. The morpholine catalysis is inhibited by boric acid in accord with the slow reaction of morpholine with the complex.
Nagamatsu,Okuyama,Fueno
p. 2502 - 2507
(1984)
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Nucleophilic Catalysis of Hydrolysis of a Schiff Base by Amines. Intramolecular Catalysis of Transimination
Certain groups of amines were found to catalyze hydrolysis of N-(o-methoxybenzylidene)-2-methoxyethylamine through transimination.The rate-determining transimination was followed by rapid hydrolysis of an intermediate Schiff base.Rate constants for the transimination with simple, but less basic, amines change sigmoidally with pH and are buffer-dependent in accord with a mechanism involving a trapping of the incipient tetrahedral intermediate T+1 by a proton transfer to acids or bases.Morpholine behaved similarly.In the reaction with bifunctional amines carrying an internal amino group, rates are independent of both pH and buffer concentrations.Initial nucleophilic attack of these amines is rate determining in the whole pH range examined because of the rapid trapping of T+1 by an intramolecular proton transfer.
Okuyama, Tadashi,Nagamatsu, Hiroaki,Kitano, Masakazu,Fueno, Takayuki
p. 1516 - 1521
(1986)
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INFLUENCE OF BORIC ACID ON THE HYDROLYSIS RATE OF A HYDROXY SCHIFF BASE.
Effects of boric acid on the rate of hydrolysis of a Schiff base derived from alpha -hydroxyisobutyrophenone and 2-methoxyethylamine were examined in the pH range 4. 2-10. 4 at 30 degree C. The rate increased above pH 7 but decreased below pH 7 with increasing borate concentration following a saturation curve. This is consistent with a reaction sequence involving a preequilibrium formation of a borate-substrate complex followed by its rate-determining decay to the hydrolysis products. The formation constant of the complex showed a bell-shaped change with pH but the rate constant for the complex decay was constant above pH 7, a small change being observed at lower pH. A mechanism involving an intramolecular transfer of the boron-coordinated hydroxide ion to the imine carbon within the complex is presented.
Matsuda,Nagamatsu,Okuyama,Fueno
p. 500 - 505
(1984)
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Simple and efficient: Ethylene glycol isonitrile gold(I) chlorides for the formation and stabilization of gold nanoparticles
Ethylene glycol isonitriles C≡N(CH2CH2O) nCH3 (5a, n = 1; 5b, n = 3; 5c, n = 4) with different chain lengths were prepared by using straightforward synthesis methodologies including the Gabriel synthesis and an Appel-type reaction protocol. Upon treatment with [AuCl(SMe)2], compounds 5a-c gave the corresponding isocyanide gold(I) chlorides [AuCl{C≡N(CH2CH2O) nCH3}] (7a, n = 1; 7b, n = 3; 7c, n = 4). Single-crystal X-ray diffraction studies reveal a polymeric (7a) or dimeric (7c) structure with aurophilic interactions. Gold(I) complexes 7a-c were applied in the formation and stabilization of gold nanoparticles (AuNPs). The isonitriles with their ethylene glycol functionalities, which provide multiple donating capabilities, are able to stabilize the encapsulated gold colloids. The reduction of 7a-c by the addition of Na[BH4] in tetrahydrofuran or methanol produces AuNPs without the further addition of any stabilizer, since metal-organic 7a-c combine the stabilizing component and gold source in one molecule. The dependency of different solvents, concentrations, and varying ethylene glycol chain lengths on the NP size and size distribution is reported. Characterization by TEM, UV/Vis spectroscopy, and XRPD revealed that AuNPs are formed with a size between 6.4(±1.4) to 9.5(±2.3) nm in methanol and 18.2(±2.3) to 27.2(±3.5) nm in tetrahydrofuran. Copyright
Tuchscherer, Andre,Schaarschmidt, Dieter,Schulze, Steffen,Hietschold, Michael,Lang, Heinrich
p. 4421 - 4428
(2011)
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Preparation method of 2-methoxyethylamine
The invention relates to a preparation method of 2-methoxyethylamine in the technical field of organic synthesis chemical industry. The preparation method comprises the following steps: dissolving N,N'-bis(2-methoxyethyl)thiourea as an initial raw material in a solvent, and carrying out an oxidation reaction in the presence of an oxidant to prepare 2-methoxyethylamine. The method provided by the invention has the advantages of short route steps, mild conditions and high product yield, and provides a universal new method for preparation of 2-methoxyethylamine.
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Paragraph 0029-0061

(2021/05/08)

Indirect reduction of CO2and recycling of polymers by manganese-catalyzed transfer hydrogenation of amides, carbamates, urea derivatives, and polyurethanes
The reduction of polar bonds, in particular carbonyl groups, is of fundamental importance in organic chemistry and biology. Herein, we report a manganese pincer complex as a versatile catalyst for the transfer hydrogenation of amides, carbamates, urea derivatives, and even polyurethanes leading to the corresponding alcohols, amines, and methanol as products. Since these compound classes can be prepared using CO2as a C1 building block the reported reaction represents an approach to the indirect reduction of CO2. Notably, these are the first examples on the reduction of carbamates and urea derivatives as well as on the C-N bond cleavage in amides by transfer hydrogenation. The general applicability of this methodology is highlighted by the successful reduction of 12 urea derivatives, 26 carbamates and 11 amides. The corresponding amines, alcohols and methanol were obtained in good to excellent yields up to 97%. Furthermore, polyurethanes were successfully converted which represents a viable strategy towards a circular economy. Based on control experiments and the observed intermediates a feasible mechanism is proposed.
Liu, Xin,Werner, Thomas
p. 10590 - 10597
(2021/08/20)

Synthesis of oxalamides by acceptorless dehydrogenative coupling of ethylene glycol and amines and the reverse hydrogenation catalyzed by ruthenium
A sustainable, new synthesis of oxalamides, by acceptorless dehydrogenative coupling of ethylene glycol with amines, generating H2, homogeneously catalyzed by a ruthenium pincer complex, is presented. The reverse hydrogenation reaction is also accomplished using the same catalyst. A plausible reaction mechanism is proposed based on stoichiometric reactions, NMR studies, X-ray crystallography as well as observation of plausible intermediates.
Ben-David, Yehoshoa,Diskin-Posner, Yael,Milstein, David,Zhou, Quan-Quan,Zou, You-Quan
p. 7188 - 7193
(2020/07/23)

Method for preparing 2-methoxyethylamine through direct catalytic amination of ethylene glycol monomethyl ether
The invention discloses a method for preparing 2-methoxyethylamine through direct catalytic amination of ethylene glycol monomethyl ether. The method comprises the following steps: continuously inputting raw materials such as ethylene glycol monomethyl ether, ammonia and hydrogen into a tubular fixed bed reactor filled with a catalyst and directly performing amination reaction to prepare the 2-methoxyethylamine. The catalyst takes gamma-aluminum oxide as a carrier; the loaded active metal components are one or a mixture of any of copper, cobalt, nickel, chromium, cerium, silver or ruthenium; and the theoretical load quantity of the active components is 15 to 35 percent of the mass of the catalyst. The method provided by the invention has the advantages of simple process, mild reaction conditions, high yield of 2-methoxyethylamine, low cost and the like.
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Paragraph 0028-0039; 0040-0043

(2019/05/08)

Manganese catalyzed hydrogenation of carbamates and urea derivatives
We report the hydrogenation of carbamates and urea derivatives, two of the most challenging carbonyl compounds to be hydrogenated, catalyzed for the first time by a complex of an earth-abundant metal. The hydrogenation reaction of these CO2-derived compounds, catalyzed by a manganese pincer complex, yields methanol in addition to amine and alcohol, which makes this methodology a sustainable alternative route for the conversion of CO2 to methanol, involving a base-metal catalyst. Moreover, the hydrogenation proceeds under mild pressure (20 bar). Our observations support a hydrogenation mechanism involving the Mn-H complex. A plausible catalytic cycle is proposed based on informative mechanistic experiments.
Das, Uttam Kumar,Kumar, Amit,Ben-David, Yehoshoa,Iron, Mark A.,Milstein, David
supporting information
p. 12962 - 12966
(2019/08/26)

Structure-Activity Relationships of Fish Oil Derivatives with Antiallergic Activity in Vitro and in Vivo
A series of unsaturated fatty acids in fish oil and their corresponding ethanolamide metabolites were explored to find active fish oil components of antiallergic activity in vitro. Ethanolamides of omega-3 fatty acids (α-linolenic acid, EPA, and DHA) were found to possess promising antiallergic activity, whereas free fatty acids and ethanolamides of other fatty acids exhibited no or weak potency. Based on this finding, structure-activity relationships of DHA-ethanolamide (DHEA) derivatives were investigated to yield better fatty acid derivatives with enhanced antiallergic activity in vitro and in vivo. When the ethanolamide moiety of DHEA was replaced by the substituted sulfonamide functionality, highly promising potency was provided in vitro. Compound 59 showed improved antiallergic activity in vivo over DHEA. The results indicate that optimized DHEA derivatives have enhanced antiallergic activity in vitro and in vivo, and the resulting structures will be an important basis for further development of bioavailable derivatives with promising allergy suppressive activity.
Kim, In-Hae,Kanayama, Yoshiki,Nishiwaki, Hisashi,Sugahara, Takuya,Nishi, Kosuke
p. 9576 - 9592
(2019/11/11)

Versatile Dynamic Covalent Assemblies for Probing π-Stacking and Chirality Induction from Homotopic Faces
Herein we report for the first time the use of dynamic covalent reactions (DCRs) for building a π-stacking model system and further quantifying its substituent effects (SEs), which remain a topic of debate despite the rich history of stacking. A general DCR between 10-methylacridinium ion and primary amines was discovered, in which π-stacking played a stabilizing role. Facile quantification of SEs with in situ competing π-stacking systems was next achieved in the form of amine exchange exhibiting structural diversity by simply varying components. The linear correlation with σm in Hammett plots indicates the dominance of purely electrostatic SEs, and the additivity of SEs is in line with the direct interaction model. With α-chiral amines π-stacking within the adduct enabled chirality transfer from homotopic faces. The strategy of dynamic covalent assembly should be appealing to future research of probing weak interactions and manipulating chirality.
Ye, Hebo,Hai, Yu,Ren, Yulong,You, Lei
supporting information
p. 3804 - 3809
(2017/03/27)

HIV INTEGRASE INHIBITORS
The present invention features compounds that are HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.
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(2015/09/22)

Probing the nature of the Co(III) ion in corrins: Comparison of reactions of aquacyanocobyrinic acid heptamethyl ester and aquacyano-stable yellow cobyrinic acid hexamethyl ester with neutral N-donor ligands
Equilibrium constants (log K) for substitution of coordinated H 2O in aquacyanocobyrinic acid heptamethyl ester (aquacyanocobester, ACCbs) and aquacyano-stable yellow cobyrinic acid hexamethyl ester (aquacyano-stable yellow cobester, ACSYCbs), in which oxidation of the C5 carbon of the corrin interrupts the normal delocalized system of corrins, by neutral N-donor ligands (ammonia, ethanolamine, 2-methoxyethylamine, N-methylimidazole, and 4-methylpyridine) have been determined spectrophotometrically as a function of temperature. Log K values increase with the basicity of the ligand, but a strong compensation effect between ΔH and ΔS values causes a leveling effect. The aliphatic amines with a harder donor atom produce ΔH values that are more negative in their reactions with ACSYCbs than with ACCbs, while the softer, aromatic N donors produce more negative ΔH values with ACCbs than with ACSYCbs. Molecular modeling (DFT, M06L/SVP, and a quantum theory of atoms in molecules analysis of the electron density) shows that complexes of the aliphatic amines with SYCbs produce shorter and stronger Co-N bonds with less ionic character than the Co-N bonds of these ligands with the cobester. Conversely, the Co-N bond to the aromatic N donors is shorter, stronger, and somewhat less ionic in the complexes of the cobester than in those of the SYCbs. Therefore, the distinction between the harder Co(III) in ACSYCbs and softer Co(III) in ACCbs, reported previously for anionic ligands, is maintained for neutral N-donor ligands.
Chemaly, Susan M.,Kendall, Louise,Nowakowska, Monika,Pon, Dale,Perry, Christopher B.,Marques, Helder M.
p. 1077 - 1083
(2013/03/13)

Unprecedented catalytic hydrogenation of urea derivatives to amines and methanol
Indirect CO2 hydrogenation: Hydrogenation of urea derivatives to the corresponding amines and methanol is reported (see picture). The reaction is catalyzed by a bipyridine-based tridentate PNN Ru(II) pincer complex and proceeds under mild, neutral conditions using 13.6 atm of H2. A mild approach is offered for the indirect hydrogenation of CO2 to methanol as urea derivatives are available from CO2. Copyright
Balaraman, Ekambaram,Ben-David, Yehoshoa,Milstein, David
supporting information; experimental part
p. 11702 - 11705
(2012/01/05)

PROCESS FOR PREPARING AMINES FROM ALCOHOLS AND AMMONIA
The present invention provides novel ruthenium based catalysts, and a process for preparing amines, by reacting a primary alcohol and ammonia in the presence of such catalysts, to generate the amine and water. According to the process of the invention, primary alcohols react directly with ammonia to produce primary amines and water in high yields and high turnover numbers. This reaction is catalyzed by novel ruthenium complexes, which are preferably composed of quinolinyl or acridinyl based pincer ligands.
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Page/Page column 24; 31; 32

(2010/04/03)

Synthesis of nonsymmetrical dialkylamines on the basis of diphenylphosphinic amides
A facile method for the synthesis of nonsymmetrical dialkylamines (C nH2n+1)2NH (n = 1-12) using the Ph 2P(O) protecting group was developed. The method includes successive transformation of monoalkylamines to primary diphenylphosphinic N-alkylamides Ph2P(O)NHR' (R' = CnH2n+1, n = 1-12) by the Todd-Atherton reaction, phase transfer N-alkylation of these compounds, and hydrolysis of the secondary amides Ph2P(O)NR'R″ thus formed. When the (EtO)2P(O) and Bu2P(O) protecting groups are used, N-alkylation of primary amides is accompanied by the formation of Et-O and P-N bond cleavage products, respectively. A study of the stability of the N-alkylamides R2P(O)NHR' (R = Ph, p-MeC6H4, p-CIC6H4, Bu) under strong alkaline conditions used in the phase transfer N-alkylation showed that an increase in the electron-donating ability of substituents at both the nitrogen atom and the phosphorus atom results in a decrease in the degree of P-N bond cleavage. The primary and secondary diphenylphosphinic amides containing a β-hydroxyethyl group at the nitrogen atom are extremely unstable under the alkaline conditions and are converted quantitatively to the diphenylphosphinic acid salt.
Bondarenko,Kharlamov,Vendilo
experimental part
p. 1872 - 1885
(2011/01/06)

An Air/water-stable tridentate N-heterocyclic carbene-palladium(II) Complex: Catalytic C-H activation of hydrocarbons via hydrogen/deuterium exchange process in deuterium oxide
While developing novel catalysts for carbon-carbon or carbon-heteroatom coupling (nitrogen, oxygen, or fluorine), we were able to introduce tridentate N-heterocyclic carbene (NHC)-amidate-alkoxide palladium(II) complexes. In aqueous solution, these NHC-Pd(II) complexes showed high ability for C-H activation of various hydrocarbons (cyclohexane, cyclopentane, dimethyl ether, tetrahydrofuran, acetone, and toluene) under mild conditions.
Lee, Joo Ho,Yoo, Kyung Soo,Park, Chan Pil,Olsen, Janet M.,Sakaguchi, Satoshi,Prakash, G. K. Surya,Mathew, Thomas,Jung, Kyung Woon
scheme or table
p. 563 - 568
(2009/11/30)

Selective synthesis of primary amines directly from alcohols and ammonia
(Chemical Equation Presented) Air stable and waterproof: Selective and efficient synthesis of primary amines directly from alcohols and ammonia is achieved under mild conditions (see scheme). The reaction is homogenously catalyzed by a novel air-stable ruthenium pincer complex and can proceed in toluene or even in the absence of solvent or "on water".
Gunanathan, Chidambaram,Milstein, David
supporting information; experimental part
p. 8661 - 8664
(2009/05/15)

N-SUBSTITUTED-AMINOMETHYLENE BRIDGED BICYCLIC NUCLEIC ACID ANALOGS
Provided herein are bicyeMc nucleosides comprising a substituted amino group in the bridge, oligomeric compounds having at least one of these bi cyclic nucleosides and methods of using the oligomeric compounds. The bicyclic nucleosides comprising a substituted amino group in the bridge are useful for enhancing properties of oligomeric compounds including nuclease resistance, in certain embodiments, the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
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Page/Page column 50

(2009/01/24)

Production of catalyst
Disclosed are catalysts, the catalytically active mass of which contains 22 to 40 percent by weight of oxygen-containing compounds of zirconium, calculated as ZrO2, 1 to 30 percent by weight of oxygen-containing compounds of copper, calculated as CuO, 15 to 50 percent by weight of oxygen-containing compounds of nickel, calculated as NiO, the molar ratio between nickel and copper being greater than 1, 15 to 50 percent by weight of oxygen-containing compounds of cobalt, calculated as CoO, and less than 1 percent by weight of an alkali metal, calculated as alkali metal oxide, prior to being treated with hydrogen. Also disclosed is a method for the production of amines by reacting primary and secondary alcohols, aldehydes, or ketones with hydrogen and nitrogen compounds selected from the group ammonia, primary and secondary amines, in the presence of said catalysts at an elevated temperature and an elevated pressure.
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Page/Page column 19; 22

(2008/06/13)

Pyrazolopyrimidines as therapeutic agents
The present invention is directed to pyrazolopyrimidine derivatives of formula (I) wherein the substituents are defined herein, which are useful as kinase inhibitors and as such are useful for affecting angiogenesis and diseases and conditions associated with angiogenesis.
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(2008/06/13)

Amine compounds, resist compositions and patterning process
Amine compounds having a cyano group are useful in resist compositions for preventing a resist film from thinning and also for enhancing the resolution and focus margin of resist.
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(2008/06/13)

Pharmaceutically active pyrrolidine derivatives as bax inhibitors
The present invention is related to new substituted pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of neurodegenerative disorders, diseases associated with polygultamine tracts, epilepsy, ischemia, infertility, cardiovascular disorders renal hypoxia, hepatitis and AIDS. Said pyrrolidine derivatives display a modulatory and most notably a down-regulating-up to an inhibitory-activity with respect to the cellular death agonist Bax and/or the activation pathways leading to Bax and allows therefore to block the release of cytochrome (c). The present invention is furthermore related to novel pharmaceutically activity substituted pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of O, S, CRR, NOR, NNRR; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2-, —SO2NH—; —CH2-; B is either a group —(C═O)—NRR or represents a heterocyclic residue having the formula (II) wherein Q is NR, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
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(2008/06/13)

Pharmaceutically active pyrrolidine derivatives
The present invention is related to pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including premature labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of CR6R7, NOR6, NNR6R7; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO22—, —SO2NH—, —CH2—,B is either a group —(C═O)—NR8R9 or represents a heterocyclic residue having the formula (a) wherein Q is NR10, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
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(2008/06/13)

SUBSTITUTED QUINAZOLINE DERIVATIVES AND THEIR USE AS INHIBITORS
The use of a compound of formula (I) 1 or a salt, ester or amide thereof; where X is O, or S, S(O) or S(O)2, or NR6 where R6 is hydrogen or C1-6 alkyl,; R5 is an optionally substituted 5-membered heteroaromatic ring, R1, R2 ,R3, R4 are independently selected from various specified moieties, in the preparation of a medicament for use in the inhibition of aurora 2 kinase. Certain compounds are novel and these, together with pharmaceutical compositions containing them are also described and claimed
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(2008/06/13)

Fluorobenzamides and uses thereof
The invention relates to fluorobenzamide derivatives of the formula wherein R1, R2, R3 R4, R5, R6 and R7 are as defined herein. =, The compounds of the invention are selective monoamine oxidase B inhibitors and therefore they are suitable for the treatment of diseases mediated by monoamine oxidase B, such as Alzheimer's disease or senile dementia.
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(2008/06/13)

Orally active iron (III) chelators
A compound of formula I wherein R is hydrogen or a group that is removed by metabolism in vivo to provide the free hydroxy compound, R1is an aliphatic hydrocarbon group or an aliphatic hydrocarbon group substituted by a hydroxy group or a carboxylic acid ester, sulpho acid ester or a C1-6alkoxy, C6-aryloxy or C7-10aralkoxy ether thereof, and R3is selected from hydrogen and C1-6alkyl; characterized in that R2is selected from groups (i) —CONH—R5(ii)—CR6R6OR7(iii) —CONHCOR5and (iv) —CON(CnH2n+1)2 R4is selected from hydrogen, C1-6alkyl and a group as described for R2; R5is selected from hydrogen and optionally hydroxy, alkoxy, aryloxy or aralkoxy substituted C1-13alkyl, aryl and C7-13alkyl R6is independently selected from hydrogen and C1-13alkyl, R7is selected from hydrogen, C1-13alkyl, aryl and C7-13aralkyl or a pharmaceutically acceptable salt of any such compound and CnH2n+1is C1-6alkyl with the proviso that the compound is not one of 1-ethyl-2-(1′-hydroxyethyl)-3-hydroxypyridin-4-one and 1-methyl-2-hydroxymethyl-3-hydroxypyridoin-4-one.
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(2008/06/13)

Pyrazolopyrimidines as therapeutic agents
The present invention provides compounds of Formula I, including pharmaceutically acceptable salts and/or prodrugs thereof, where G, R2, and R3 are defined as described herein.
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(2008/06/13)

2-aminobenzoxazole derivatives and combinatorial libraries thereof
The present invention relates to novel 2-aminobenzoxazole derivative compounds of the following formula: wherein R1 to R4 and Z have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminobenzoxazole derivative compounds.
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(2008/06/13)

2-aminopyridine derivatives and combinatorial libraries thereof
The present invention relates to novel 2-aminopyridine derivative compounds of the following formula: wherein R1to R5have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminopyridine derivative compounds.
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(2008/06/13)

4-unsubstituted dihydroisoquinolinone derivatives and combinatorial libraries thereof
The present invention relates to novel dihydroisoquinolinone (DHQ) derivative compounds of the following formula: wherein R1to R7, X, Y, Z, b, c and d have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing DHQ derivative compounds.
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(2008/06/13)

Benzothiazole derivatives with activity as adenosine receptor ligands
The present invention relates to substituted benzothiazole derivitives and to their pharmaceutically acceptable salts useful for the treatment of diseases related to the adenosine receptor.
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(2008/06/13)

Mechanisms of acid decomposition of dithiocarbamates. 1. Alkyl dithiocarbamates
The acid decomposition of some substituted methyldithiocarbamates was studied in water at 25°C in the range of rio -5 and pH 5. The pH-rate profiles showed a bell-shaped curve from which were calculated the acid dissociation constants of the free and conjugate acid species and the specific acid catalysis rate constants k(H). The Bronsted plot of k(H) vs pK(N), the dissociation constant of the conjugate acid of the parent amine, suggests that the acid cleavage occurs through two mechanisms that depend on the pK(N). The plot presents a convex upward curve with a maximum at pK(N) 9.2, which is consistent with the cleavage of the dithiocarbamate anion through a zwitterion intermediate and two transition states. For pK(N) 9.2, the C-N bond breakdown is the slowest step, and according to the inverse SIE, the transition state changes rapidly with the increase of pK(N) to a late transition state. The plot shows a minimum at pK(N) ?10, indicating that a new mechanism emerges at higher values, and it is postulated that it represents a path of intramolecular S to N proton-transfer concerted with the C-N bond breakdown. The thiocarbonyl group acts as a powerful electron- withdrawing group, decreasing the basicity of the nitrogen of the parent amine by 14.1 pK units.
Humeres, Eduardo,Debacher, Nito A.,Marta de S. Sierra,Franco, Jose Dimas,Schutz, Aldo
p. 1598 - 1603
(2007/10/03)

Process for the preparation of 2-nitrobenzaldehydes
The new process for the preparation of 2-nitrobenzaldehydes of the general formula STR1 in which X1 and X2 either independently of one another represent hydrogen or halogen or one of the substituents represents nitro and the other substituent then represents hydrogen, by oxidation of 2-nitrotoluenes of the general formula STR2 in which X1 and X2 have the meaning indicated above is characterized in that the oxidation with oxygen or an oxygen-containing gas is carried out in the presence of at least one alkoxyalkylamine as a solvent and in the presence of strong bases.
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(2008/06/13)

Kinetics of reversible carbon deprotonation of 2-nitroethanol and 2-nitro-1,3-propanediol by hydroxide ion, water, amines, and carboxylate ions. A normal br?nsted α despite an imbalanced transition state
Rates of reversible carbon deprotonation of 2-nitroethanol (2) and 2-nitro-1,3-propanediol (3) by hydroxide ion, water, amines, and carboxylate ions and pKa values for the ionization at carbon (pKaCH) and oxygen (pKaOH) and ionization of the aci-forms (pKaNOH) were determined in aqueous solution at 25 °C. The pKaCH values for 2 and 3 are 8.60 and 7.68, respectively, as compared to 10.22 for CH3NO2. The acidifying effect of the CH2OH groups is attributed to a combination of inductive electron withdrawal and hyperconjugative stabilization of the respective nitronate ions, possibly coupled with intramolecular hydrogen bonding stabilization of this ion. The higher acidity of 2-nitroethanol compared to nitromethane is reflected in higher rates of proton transfer from 2-nitroethanol, implying a "normal" Br?nsted α between 0 and 1. This contrasts with the negative α value based on the reaction of OH- with nitromethane, nitroethane, and 2-nitropropane (Kresge, A. J. Can. J. Chem. 1974, 52, 1897). Reasons why a normal α value is observed in the current system are discussed.
Bernasconi, Claude F.,Panda, Markandeswar,Stronach, Michael W.
p. 9206 - 9212
(2007/10/03)

Triphendioxazine dyestuffs
The novel triphendioxazine dyestuffs of the formula STR1 in which the substituents R, R', T1, T2, X, Y and n have the meanings given in the description are highly suitable for the dyeing and printing of cellulose-containing or amido-containing material.
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(2008/06/13)

Mixtures of hexahydrotriazines useful as H2 S scavengers
A mixture of amines made by reacting an amine compound with an aldehyde compound has been found to reduce the levels of H2 S in liquid or gaseous hydrocarbon streams. At least one of the compounds must have an alkoxyalkylene radical. In one embodiment of the invention, the mixture of amines contains at least one hexahydrotriazine compound of the formula: STR1 where R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen and an alkyl radical, including substituted alkyl radicals, of 1 to 5 carbon atoms; where at least one of the groups is an alkoxyalkylene group. In another embodiment of the invention, the amine mixture may contain other by products, such as the monomers which make up the hexahydrotriazine, with or without the hexahydrotriazine being present. These materials are selective to the reduction of H2 S levels in hydrocarbon or aqueous streams in the presence of CO2 which does not compromise their performance.
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(2008/06/13)

Highly Sterically hindered Carbon Acids: The Intrinsic Reactivity of 5,5',5''-Trimethyl- and 3,3',3'',5,5',5''-Hexamethyl-2,2',2'',4,4',4''-Hexanitrotriphenylmethanes
Rate constants (kpB,kpBH) for the reversible deprotonation of 5,5',5''-trimethyl- and 3,3',3'',5,5',5''-hexamethyl-2,2',2'',4,4',4''-hexanitrotriphenylmethanes (2 and 3) by primary aliphatic amines, piperidine and morpholine as well as by phenoxide anions and hydroxide anion have been measured in H2O-Me2SO (20:80) at 25 deg C.Comparison of the results obtained with those for 2,2',2'',4,4',4''-hexanitrotriphenylmethane (1a) shows that the introduction of methyl groups in positions adjacent to the nitro groups decreases markedly the thermodynamic acidity of theexocyclic CH group: ΔpK2a1a = 1.68; ΔpK3a1a = 6.48.It is suggested that these decreases are very likely the reflection of a twisting of the nitro groups out of their attached aromatic planes and therefore of a reduced resonance stabilization of the conjugated carbanions C-2 and C-3.Other important steric effects are operating in the ionization of 2 and 3.These arise from the accumulation of ortho-nitro groups in the triphenylmethane system which makes the approach of the base reagents from the exocyclic carbon of 2 and 3 very difficult.The finding of extremely low intrinsic reactivities for 2 and 3 and the observation of a much greater catalytic efficiency of primary amines than of secondary amines in assisting the proton transfers are the two most striking manifestations of these F-strain effects.
Terrier, Francois,Xiao, Lan,Farrell, Patrick G.,Moskowitz, Danielle
p. 1259 - 1263
(2007/10/02)

Kinetics of Amine Addition to Benzylidenemalonodialdehyde in 50percent Me2SO-50percent water
The kinetics of the reaction of benzylidenemalonodialdehyde with piperidine, morpholine, n-butylamine, 2-methoxyethylamine, glycinamide, glycine ethyl ester, cyanomethylamine, and semicarbazide have been determined in 50percent aqueous Me2SO at 20 deg C.The reaction leads to a zwitterionic adduct, PhCH(RR'NH(1+))C(CHO)2(1-) (TA(+/-)), that is in fast acid-base equilibrium with the anionic adduct, PhCH(RR'N)C(CHO)2(1-) (TA(1-)).With strongly basic amines at high pH there is also attack of the amine on one of the carbonyl groups, which acts as a rapid preequilibrium.Rate constants for the formation of TA(+/-) (k1) and its reverse (k-1), as well as equilibrium constants (K1 = k1/k-1) and the pKa of TA(+/-) were determined for all the amines.Intrinsic rate constants (k0 = k1 = k-1 when K1 = 1) were calculated.The intrinsic rate constants are lower than those for amine addition to benzylidene Meldrum's acid.This is consistent with the greater role played by resonance in stabilizing TA(+/-) derived from benzylidenemalonodialdehyde.However, k0 for piperidine/morpholine addition to benzylidenemalonodialdehyde is much higher than for the reaction of benzylideneacetylacetone with the same amines, indicating that the rate-depressing effect of intramolecular hydrogen bonding in TA(+/-) derived from benzylidenemalonodialdehyde is much smaller than that in TA(+/-) derived from benzylideneacetylacetone.Even though semicarbazide is an α-effect nucleophile, no enhancement of k1 was observed, but K1, estimated on the basis of a structure-reactivity relationship, is larger than expected based on the pKa of the amine.This result is attributed to a low νnucn value.
Bernasconi, Claude F.,Stronach, Michael W.
p. 1993 - 2001
(2007/10/02)

Kinetics of Amine Addition to Benzylidene-1,3-indandione and Other Vinylic β-Diketones. Effect of Cyclic Structure and Steric Strain on Intrinsic Rate Constants
The kinetics of the reactions of benzylidene-1,3-indandione (4) with piperidine, morpholine, n-butylamine, 2-methoxyethylamine, glycinamide, and cyanomethylamine and the reactions of benzylidene-3,5-heptanedione (5), benzylidene-2,6-dimethyl-3,5-heptanedione (6), and benzylidenedibenzoylmethane (7) with piperidine and morpholine have been measured in 50% Me2SO-50% water (v/v) at 20 °C and 0.5 M ionic strength. The reactions lead, in all cases, to the reversible formation of the zwitterionic adduct PhCH(RR′NH+)C(COX)2- (TA±) that is in fast equilibrium with its anion PhCH(RR′N)C-(COX)2-(TA-). Rate constants for nucleophilic addition (k1) and its reverse (k-1) as well as the pKa, of TA± were determined for all reactions. The intrinsic rate constant (k0 = k1 = k-1 when K1 = 1) for amine addition to 4 is abnormally high, whereas k0 for the reactions of 5-7 are abnormally low and similar to k0 in magnitude for amine addition to benzylideneacetylacetone reported previously. The terms "abnormally high" and "abnormally low" refer to positive and negative deviations, respectively, from a plot of log k0 for amine addition to a series of electrophilic olefins of the type PhCH=CYY′ vs log k0 for deprotonation of carbon acids of the type CH2YY′. The high k0 for the reaction of 4 is attributed to its cyclic structure, which assures that the π-overlap required for the stabilization of the adduct is strongly developed in the transition state. The low k0 values for the reactions of 5-7 arise from intramolecular hydrogen bonding, which is strong in TA± but poorly developed in the transition state, and from steric strain in the adduct, which is strongly developed in the transition state. All these effects can be viewed as manifestations of the principle of nonperfect synchronization (PNS).
Bernasconi, Claude F.,Stronach, Michael W.
p. 2222 - 2227
(2007/10/02)

Triazinyl reactive dyestuffs in which triazinyl group is further substituted with a beta-chloroethylsulfonyl- or vinylsulfonylbutyrylamino moiety
Reactive dyes of the formula STR1 in which D is the radical of an organic dye of the monoazo, polyazo, metal complex azo, anthraquinone, phthalocyanine, formazan, azomethine, dioxazine, phenazine, stilbene, triphenylmethane, xanthene, thioxanthrone, nitroaryl, naphthoquinone, pyrenequinone or perylenetetracarbimide series, R is hydrogen or substituted or unsubstituted C1-4 -alkyl, X is a substituent which is detachable as an anion, B is a radical of the formula STR2 R1 and R2, independently of each other, are hydrogen or substituted or unsubstituted C1-4 -alkyl or phenyl, A is a substituted or unsubstituted aliphatic or aromatic bridge member, Y is a --CO--Z or --SO2 --Z radical, Z is an aliphatic, aromatic or heterocyclic reactive radical, and n is 1 or 2, are suitable for dyeing or printing cellulose-containing and nitrogen-containing materials and in high dyeing yield produce dyeings and prints having good fastness properties.
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(2008/06/13)

Iodide Reduction of Sulfilimines. 2. Evidence for Concurrent Stepwise and Concerted Mechanisms for the Decomposition of Sulfurane Intermediates
The iodide reduction of N-(substituted ethyl or phenyl)-S,S-dimethylsulfilimmonium salts (aqueous solution, 25 deg C, μ = 1.0 with KCl) is first order in proton activity and iodide concentration in the pH range 0.5-5.The solvent deuterium isotope effects for the reduction reaction vary in the range kH/kD = 0.26-0.48 as the nitrogen substituent is changed from ethyl- to trifluoroethylamine.Electron-withdrawing groups in the leaving group decrease the rate of the reaction and give βl.g. values of ca. 0.7 for cyanoethyl- and trifluoroethylamine leaving groups and ca. 0.1 for the more basic ethylamine derivatives; a βl.g. of 0.58 is observed for aniline derivatives.General acid catalysis is observed in the reduction of the acidic ethylamine and aniline derivatives with Broensted α values of 0.59 and 0.39 for cyanoethyl- and trifluoroethylamine leaving groups, respectively; for anilines, the Broensted α values decreased from 0.67 to 0.50 as the leaving group is changed from 4-methyl- to 3-nitroaniline.The value of βl.g. decreases with decreasing strength of the catalyzing acid and the term pxy = (δβl.g./δpKaHA) = (δα/δKal.g.) ca. -0.06 to -0.1.The solvent deuterium isotope effect on the general catalyzed reduction reaction increases with increasing acid strength; for the cyanoethylamine derivative, kBH/kBD = 1.47-2.32 for acetic and chloroacetic acids, respectively.A mechanism is suggested involving concurrent stepwise and concerted mechanisms for the reduction reaction; the mechanism observed seems to depend on the nature of the catalyzing acid.
Young, Paul R.,Huang, H. C.
p. 1805 - 1809
(2007/10/02)

Fiber-reactive disazo brown dye having vinylsulfone-type reactive group
A compound, or a salt thereof, represented by the following formula, STR1 wherein A is a substituted or unsubstituted phenylene or naphthylene group, B is STR2 in which R3 is a hydrogen atom or a lower alkyl, lower alkoxy, acylamino or ureido group, and R4 is a hydrogen atom or a lower alkyl or lower alkoxy group, R1 and R3 are independently a hydrogen atom or a substituted or unsubstituted lower alkyl group, X is a substituted or unsubstituted amino, lower alkoxy, substituted phenoxy or sulfo group, Y is --SO2 CH=CH2 or --SO2 CH2 CH2 Z, in which Z is a group capable of being split by the action of an alkali, and m is 2 or 3, which is useful for dyeing hydroxyl group- or amide group-containing fiber materials to give dyed products of a brown color having excellent fastness properties with good build-up property.
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(2008/06/13)

Iodide Reduction of Sulfilimines. Evidence for the Partitioning of Sulfurane Intermediates
The iodide reduction of N-(substituted phenyl)-S,S-dimethylsulfilimmonium salts (aqueous solution, 25 deg C, μ = 1.0 with KCl) is firts order in proton activity in the pH range 0.5-3.0.The reduction of N-phenyl-S,S-dimethylsulfilimmonium chloride is also catalyzed by general acids with a Broensted α of 0.7.Electron-donating groups on the aniline leaving group accelerate the rate of the reduction with a βlg = 0.54.Rate constants for the reduction of sulfilimines derived from higher pKa amines are also linear with proton activity.For N-benzyl-S,S-dimethylsulfilimmonium chloride, no general catalysis is observed.For sulfilimines with unhindered primary amines as leaving group, a small βlg of about -0.1 is observed.For sulfilimines with benzamide and sulfonamide leaving groups the proton-catalyzed reaction contains both first- and second-order terms in proton activity.The rate of the reduction of the sulfilimine ylide is accelerated by electron-withdrawing substituents with βlg = -0.5.These data are interpreted in terms of a mechanism involving rate-limiting partitioning of a common tetracoordinate sulfurane intermediate.For aniline leaving groups, proton transfer to the neutral sulfurane is suggested to be rate limiting.For higher pKa leaving groups, the protonated sulfurane is solvent equilibrated and breakdown of this intermediate becomes rate limiting.For sulfilimines with very low pKa leaving groups, the predominant pathway is suggested to involve uncatalyzed breakdown of the neutral sulfurane intermediate with expulsion of sulfonamide anion.A parallel pathway involving the general catalyzed breakdown of the neutral sulfurane is also suggested to account for the greater than first-order proton dependence.
Young, Paul R.,McMahon, Patrick E.
p. 7572 - 7577
(2007/10/02)

The influence of a base on the methylation of aminoalchols
A selective methylation towards N and O atoms on aminoalcohols was observed using metal hydride reagents as the base, and the predominant factors for the selectivity were investigated in detail.
Kashima, Choji,Harada, Kazuo,Omote, Yoshimori
p. 288 - 290
(2007/10/02)

Fibre-reactive dyes, containing both chloro and fluoro triazine radicals
Fibre-reactive dyes of the formula STR1 wherein D is the radical of a benzene or naphthalene azo dye which contains sulpho groups, each of R1, R2 and R3 is a hydrogen atom, B is an arylene group and A is an amino group.
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(2008/06/13)

Mechanism of β-lactam ring opening in cephalosporins
The mechanism of the aminolysis of cephalosporins is a stepwise process. A tetrahedral intermediate is formed by the reversible addition of the amine to the beta -lactam carbonyl carbon. Expulsion of the attacking amine from the tetrahedral intermediate occurs faster than fission of the beta -lactam C-N bond. The reaction proceeds by trapping the intermediate with base. Expulsion of a leaving group at C-3 prime in cephalosporins is not concerted with nucleophilic attack of the amine on the beta -lactam carbonyl carbon and makes little difference to the rate of beta -lactam C-N bond fission.
Page,Proctor
p. 3820 - 3825
(2007/10/02)

Structural effects on reactivity in intramolecular catalysis. The hydrolysis of N-alkylated monoamides derived from norbornene-2,3-dicarboxylic acid
Monoamides of 2,3-endo-cis-5-norbornene dicarboxylic acid (compounds 1-5) were prepared by addition of primary alkyl amines (n-propyl-, 2-methoxyethyl-, 2-fluoroethyl-, 2,2-difluoroethyl-, 2,2,2-trifluoroethyl-) to 2,3-endo-cis-5-norbornene dicarboxylic anhydride.The rates of hydrolysis of each compound in solutions whose acid concentration ranged from 0.01 M to 9 M were determined.Rates increase with acidity above 0.1 M until a maximum rate is achieved in strong acid.The results are consistent with a mechanism involving intramolecular catalysis of the hydrolysis of the amide by the adjacent carboxylic acid.The dependence of rate on acidity can be interpreted in terms of a multistep mechanism involving formation of an intramolecular tetrahedral adduct, tautomerization of the adduct, and expulsion of the amine to give the anhydride.The identity of the rate-determining step is a function of the basicity of the substrate and the acidity of the medium.Analysis of the data in terms of the proposed mechanism suggests that the effective molarity of the groups involved in tautomerization of the tetrahedral internal addition intermediate is higher than in other rigid systems which lack the norbornene structure.It is proposed that ring strain and rotational entropy control cyclization and elimination steps.Interactions of the solvent with the entire substrate control reorganization of the intermediate.Conjugation of the interacting functional groups does not appear to have a significant effect upon their reactivity.
Kluger, Ronald,Brandl, Michael
p. 2515 - 2520
(2007/10/02)