- Enantiomeric excess determination of α-amino acids by 19F NMR spectroscopy of their N,N-dimethyl-(2,2,2-trifluoro-1-phenylethyl)amine-C,N)palladium complexes
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The synthesis and resolution of the trifluoromethyl-palladacycle, di-μ-chloro-bis(N,N-dimethyl-(2,2,2-trifluoro-1-phenylethyl)amine-2-C,N) palladium(II) are shown. The utility of the complex and its application in the enantiomeric excess determination of α-amino acids by 19F NMR spectroscopy is demonstrated and X-ray diffraction analysis of one of the diastereomeric complexes, trans-{[(R)-phenylglycinato-N,O][(R)-N,N-dimethyl-(2,2,2-trifluoro-1- phenylethyl)amine-C,N]palladium(II)}, is reported.
- Levrat, Fabrice,Stoeckli-Evans, Helen,Engel, Norbert
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Read Online
- Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R
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Even today, the role of the histamine H2 receptor (H2R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pKi = 8.07) were reported as H2R agonists. However, their applicability to the study of the H2R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H2R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [35S]GTPγS and β-arrestin2 recruitment assays) with human (h) H2R affinities in the one-digit nanomolar range (pKi (139, UR-KAT523): 8.35; pKi (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH2R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD2longR and agonists with high affinity at the hD3R (e.g. pKi (139, UR-KAT523): 7.80; pKi (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H2R and D3R agonists for the application in recombinant systems in which either the H2R or the D3R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H2R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H2R in the CNS.
- Biselli, Sabrina,Bresinsky, Merlin,Buschauer, Armin,Forster, Lisa,Honisch, Claudia,Pockes, Steffen,Tropmann, Katharina,Bernhardt, Günther
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supporting information
(2021/02/12)
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- Discovery of N-Cyano-sulfoximineurea Derivatives as Potent and Orally Bioavailable NLRP3 Inflammasome Inhibitors
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NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases. In this study, rationally designed mimics of sulfonylurea moiety were investigated as NLRP3 inhibitors. Our results culminated into discovery of series of unprecedented N-cyano sulfoximineurea derivatives as potent NLRP3 inflammasome inhibitors. Compound 15 (IC50 = 7 nM) and analogues were found to be highly potent and selective NLRP3 inflammasome inhibitor with good pharmacokinetic profile. These effects translate in vivo, as 15, 29, and 34 significantly inhibit NLRP3 dependent IL-1β secretion in mice.
- Agarwal, Sameer,Sasane, Santosh,Shah, Hardik A.,Pethani, Jignesh P.,Deshmukh, Prashant,Vyas, Vismit,Iyer, Pravin,Bhavsar, Harsh,Viswanathan, Kasinath,Bandyopadhyay, Debdutta,Giri, Poonam,Mahapatra, Jogeswar,Chatterjee, Abhijit,Jain, Mukul R.,Sharma, Rajiv
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supporting information
p. 414 - 418
(2020/03/13)
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- Scope and limitations of reductive amination catalyzed by half-sandwich iridium complexes under mild reaction conditions
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The conversion of aldehydes and ketones to 1° amines could be promoted by half-sandwich iridium complexes using ammonium formate as both the nitrogen and hydride source. To optimize this method for green chemical synthesis, we tested various carbonyl substrates in common polar solvents at physiological temperature (37 °C) and ambient pressure. We found that in methanol, excellent selectivity for the amine over alcohol/amide products could be achieved for a broad assortment of carbonyl-containing compounds. In aqueous media, selective reduction of carbonyls to 1° amines was achieved in the absence of acids. Unfortunately, at Ir catalyst concentrations of 1 mM in water, reductive amination efficiency dropped significantly, which suggest that this catalytic methodology might be not suitable for aqueous applications where very low catalyst concentration is required (e.g., inside living cells).
- Nguyen, Dat P.,Sladek, Rudolph N.,Do, Loi H.
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supporting information
(2020/07/15)
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- IDO inhibitors
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The invention discloses novel compounds used as indoleeamine-pyrrole-2,3-dioxygenase (IDO) inhibitors, and specifically discloses the compounds represented by a formula (I) shown in the description and pharmaceutically-acceptable salts of the compounds. The invention also discloses an application of the compounds represented by the formula (I) and the pharmaceutically-acceptable salts of the compounds in preparation of a medicament for treating tumors.
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Paragraph 0143; 0146; 0147
(2019/01/05)
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- Silver-catalyzed formal [3+2]-cycloaddition of α-trifluoromethylated methyl isocyanides: a facile stereoselective synthesis of CF3-substituted heterocycles
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An Ag-catalyzed formal [3+2]-cycloaddition of α-trifluoromethylated methyl isocyanides with polar double bonds has been developed for the facile access to trifluoromethylated oxazolines, imidazolines and pyrrolines under mild conditions. The practicality of this chemistry is demonstrated by the gram-scale synthesis of oxazolines with excellent yields and facile transformations of the formed oxazolines to trifluoromethylated β-amino alcohols in quantitative yields.
- Zhang, Xue,Wang, Xin,Gao, Yuelei,Xu, Xianxiu
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supporting information
p. 2427 - 2430
(2017/03/01)
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- Economical and practical strategies for synthesis of α-trifluoromethylated amines
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A powerful approach to synthesize α-trifluoromethylated amines has been developed. The method is operationally simple, broad in substrate scope and amenable to scale-up using trifluoroacetic anhydride. Meanwhile, the strategy not only provided a versatile approach to synthesize α-trifluoromethylated amines but also provides a new method for exploring the new reactivity of trifluoroacetic anhydride.
- Jiang,Cheng,Yuan
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p. 2406 - 2408
(2016/05/19)
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- Structure-activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor
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Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicity at the secondary 4-amino group. A stepwise optimization by combination of active fragments led to the discovery of three structures with EGFR IC 50 50 of 0.3 nM towards EGFR and its mutants L858R and L861Q. Studies using human cancer cell lines and an EGFR-L858R reporter cell system revealed good cellular potency, verifying the identified thienopyrimidines as promising lead structures.
- Bugge, Steffen,Kaspersen, Svein Jacob,Larsen, Synne,Nonstad, Unni,Bj?rk?y, Geir,Sundby, Eirik,Hoff, B?rd Helge
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p. 354 - 374
(2014/03/21)
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- Stereoselective transformations of α-trifluoromethylated ketoximes to optically active amines by enzyme-nanometal cocatalysis: Synthesis of (s)-inhibitor of phenylethanolamine n-methyltransferase
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One-pot cascade synthesis of optically active α-trifluoromethylated amines directly from ketoximes was accomplished with the use of Candida antarctica lipase B and catalysts prepared by atomic layer deposition (ALD). Compared to the commercial palladium catalyst, the ALD-prepared catalysts showed much higher activity and afforded various α-trifluoromethylated amides in good yields and with high enantioselectivity. One of the enantiopure amides was further hydrolyzed into the corresponding amine, which was treated as a crucial starting material for total synthesis of (S)-inhibitor of phenylethanolamine N-methyltransferase without loss of chiral information.
- Cheng, Guilin,Wu, Qi,Shang, Zeyu,Liang, Xinhua,Lin, Xianfu
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p. 2129 - 2133
(2014/08/05)
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- Chemoenzymatic dynamic kinetic resolution of α-trifluoromethylated amines: Influence of substitutions on the reversed stereoselectivity
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Enzymatic resolution of α-trifluoromethylated amines via kinetic resolution (KR), dynamic kinetic resolution (DKR) employing CALB-Pd/Al 2O3, and a one-pot sequential process of KR/DKR/KR was investigated comparatively for the first time. Although CALB-catalyzed KR of α-trifluoromethylated amines with substituents of methyl (1a), isopropyl (1c), phenyl (1d) and benzyl group (1e) can provide good stereoselectivity factors E from 31 to >200 respectively, DKR and sequential process of KR/DKR/KR possess better practical application potential because of the higher conversion (62%-84%) and the similar enantiomeric excesses (90%-99%). The enantiopreference and inversion for the α-trifluoromethylated amines displayed by CALB were observed and explained by docking modes. Namely, for 1,1,1-trifluoro-2-propylamine (1a), the product amide with R-configuration was obtained, and the enantiopreference was converted to S for the amines (1b-1e) with substituents larger than methyl group. The catalysts recycle, and scale-up experiments were demonstrated successfully. All these results indicated the high efficiency and green feature of this enzymatic process, and its application significance.
- Cheng, Guilin,Xia, Bo,Wu, Qi,Lin, Xianfu
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p. 9820 - 9828
(2013/09/02)
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- PYRROLO [3, 2 -E] [1,2,4] TRIAZOLO [1,5 -A] PYRIMIDINES DERIVATIVES AS INHIBITORS OF MICROGLIA ACTIVATION
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The invention relates to novel compounds useful in the treatment and prophylaxis of disease. Compounds of the formula (I) wherein X is halogen, independently selected form chlorine and fluorine and n is 0, 1 or 2. and their pharmaceutically acceptable salts are useful in the treatment and prophylaxis of diseases caused by activation of microglia, particularly Alzheimer's disease.
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Page/Page column 15-16
(2011/04/26)
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- Biomimetic reductive amination under the continuous-flow reaction conditions
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This study present a full account of continuous-flow reaction conditions for biomimetic reductive amination of fluorinated carbonyl compounds to corresponding amines and amino acids of biomedical importance. We demonstrate that simple silica-adsorbed DBU can be used as efficient catalysts for on-column 1,3-proton shift reaction, a key transformation in the biomimetic reductive amination process. This new on-column process features operationally convenient conditions, higher chemical yields, enantioselectivity and purity of the corresponding products as compared with traditional in-flask reactions. Moreover the removal of base-catalyst, the most delicate problem of the in-flask reactions, is not an issue in the on-column process, as the silica-adsorbed DBU or polymer-bound guanidine remains on the column and can be reused. This feature renders the overall process substantially more economical and synthetically efficient, in particular, for large-scale synthesis of the corresponding fluorinated amines and amino acids target.
- Soloshonok, Vadim A.,Catt, Hector T.,Ono, Taizo
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body text
p. 261 - 265
(2010/04/05)
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- Diastereoselective alkylation of glycinates by assistance of intramolecular potassium-fluorine interactions
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A study was conducted to demonstrate diatereoselective alkylation of glycinates by assistance of intermolecular potassium-fluorine interactions. Preparation of the starting materials for the investigations was carried out from the readily available fluorinated acetophenones. The investigations focused on finding appropriate alkylation conditions after their transformation to the corresponding enolates. The representative starting material was subjected to a solution of a base in THF at -78°C to generate the enolate. The model electrophile, BnBr was introduced in the investigations after stirring for 0.5 hours at the same temperature.
- Yamazaki, Takashi,Kawashita, Seiji,Kitazume, Tomoya,Kubota, Toshio
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scheme or table
p. 11461 - 11464
(2010/04/24)
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- THIADIAZOLES AS CXC- AND CC- CHEMOKINE RECEPTOR LIGANDS
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Disclosed are novel compounds of Formula (IA) and the pharmaceutically acceptable salts and solvates thereof. Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and ischemia reperfusion injury, pain (e.g., acute pain, acute and chronic inflammatory pain, and neuropathic pain) using a compound of Formula (IA).
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Page/Page column 208
(2010/02/12)
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- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
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There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
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- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
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There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
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Page 122-123
(2008/06/13)
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- THIADIAZOLEDIOXIDES AND THIADIAZOLEOXIDES AS CXC- AND CC-CHEMOKINE RECEPTOR LIGANDS
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Disclosed are novel compounds of the formula (IA) and the pharmaceutically acceptable salts and solvates thereof. Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and cardiac reperfusion injury, acute pain, acute and chronic inflammatory pain, and neuropathic pain using a compound of formula (IA).
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- IL-8 RECEPTOR ANTAGONISTS
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Novel IL-8 receptor antagonists and methods of using them are provided.
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- Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 1. N-cyanoguanidine bioisosteres possessing in vive bladder selectivity
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A structurally novel series of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel openers is described. As part of our efforts directed toward identifying novel, bladder-selective potassium channel openers (KCOs) targeted for urge urinary incontinence (UUI), we found that bioisosteric replacement of the N-cyanoguanidine moiety of pinacidil (1, Figure 1) with a diaminocyclobutenedione template afforded squaric acid analogue 2, the prototype of a novel series of K(ATP) channel openers with unique selectivity for bladder smooth muscle in vive. Further modification of the heterocyclic ring to give substituted aryl derivatives (3) afforded potent KCOs that possessed the desired detrusor selectivity when administered orally. The effects of these potassium channel agonists on bladder contractile function was studied in vitro using isolated rat detrusor strips. Potent relaxants were evaluated in vive in a rat model of bladder instability. Lead compounds were evaluated concomitantly in normotensive rats for their effects on mean arterial blood pressure (MAP) and heart rate as a measure of in vive bladder selectivity. (R)-4-[3,4-Dioxo-2-(1,2,2-trimethyl- propylamino)-cyclobut-1-enyαmino]-3-ethyl-benzonitrile (79) met our potency and selectivity criteria and represents an attractive development candidate for the treatment of UUI. Electrophysiological studies using isolated rat bladder detrusor myocytes have demonstrated that compound 79 produces significant hyperpolarization which is glyburide-reversed, thus consistent with the activation of K(ATP). The design, synthesis, structure-activity relationships (SAR), and pharmacological activity associated with this series of novel KCOs will be discussed.
- Butera, John A.,Antane, Madelene M.,Antane, Schuyler A.,Argentieri, Thomas M.,Freeden, Chris,Graceffa, Russell F.,Hirth, Bradford H.,Jenkins, Douglas,Lennox, Joseph R.,Matelan, Edward,Norton, N. Wesley,Quagliato, Dominick,Sheldon, Jeffrey H.,Spinelli, Walter,Warga, Dawn,Wojdan, Alexandra,Woods, Morgan
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p. 1187 - 1202
(2007/10/03)
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- A convenient preparative method for α-trifluoromethyl amines
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α-Trifluoromethyl amines (IV) were prepared in three steps: preparation of α-trifluoromethyl ketones (I), their conversion to benzyloximes (II), and reduction of the oximes (II) with lithium aluminium hydride and sodium methoxide. For example, α-trifluoromethyltridecylamine was obtained from the reduction of trifluoromethyl dodecyl ketone benzyl oxime. Elsevier Science S.A.
- Watanabe, Shoji,Fujita, Tsutomu,Sakamoto, Masami,Hamano, Hiroyuki,Kitazume, Tomoya,Yamazaki, Takashi
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- Mechanisms of decomposition of (Z)-2,2,2-trifluoro-1-arylethanediazoates in aqueous media
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A study of the kinetics of decay of three (Z)-2,2,2-trifluoro-1-arylethanediazoates at 25°C in aqueous media, 4% 2-propanol by volume, ionic strength 1 M (NaClO4) in the pH range 4-13, as well as the results of experiments to detect deuterium incorporation into products from solvent is reported. It is concluded in the case of the unsubstituted compound that the buffer-independent reaction involves rate-limiting heterolytic bond fission of the diazoic acid to yield a diazonium ion intermediate, and a similar mechanism is indicated for the other two compounds. General acid catalysis of the decay of the diazoic acids at pH 7 is observed, and it is concluded that the reaction involves rate-limiting N-O bond cleavage of the diazoic acid that is concerted with protonation of the leaving hydroxide ion by the catalyst.
- Finneman, Jari I.,Fishbein, James C.
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p. 7134 - 7138
(2007/10/03)
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- A practical route to fluoroalkyl- and fluoroarylamines by base-catalyzed [1,3]-proton shift reaction
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The base-catalyzed [1,3]-proton shift reaction is shown to be an efficient general approach to fluoroalkyl and fluoroaryl amines starting from appropriate carbonyl compounds and benzylamine.
- Soloshonok,Soloshonok, Vadim A.,Kirilenko,Kirilenko, Alexander G.,Kukhar,Kukhar, Valery P.,Resnati,Resnati, Giuseppe
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p. 3119 - 3122
(2007/10/02)
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- OXIMES TRIFLUOROMETHYLEES ET ORGANOMAGNESIENS ALLYLIQUES: SYNTHESE D'HYDROXYLAMINES HOMOALLYLIQUES ET D'AMINES HOMOALLYLIQUES PRIMAIRES
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Les organomagnesiens allyliques s'additionnent aux oximes substituees par un groupement trifluoromethyle, pour conduire a des hydroxylamines avec des rendements eleves.Une telle reaction est particuliere a ces oximes et a ces magnesiens.Les hydroxylamines obtenues ont ete transformees en amines primaires homoallyliques.
- Felix, C.,Laurent, A.,Lesniak, S.,Mison, P.
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p. 301 - 323
(2007/10/02)
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- 19F NMR non-equivalence of diastereomeric amides of 2,2,2-trifluoro-1-phenylethylamine
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An alternate synthesis and resolution is reported for 2,2,2-trifluoro-1-phenylethylamine. The 19F NMR of a series of amide derivatives of chiral acids is described. The diastereomeric non-equivalence of the 19F NMR signals (0.05-0.09 ppm) of these amides permits use of these derivatives for determination of enantiomeric purity of alpha-substituted acids. The potential for configurational correlations is discussed.
- Wang,Mosher
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p. 987 - 990
(2007/10/02)
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- A convenient synthesis of hindered amines and α-trifluoromethylamines from ketones
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Ketones and α-trifluoromethylketones were converted to primary, secondary, and tertiary amines in good to excellent yields by a reductive amination procedure utilizing TiCl4/NaCNBH3. The method provides the first direct route to α-trifluoromethylamines from ketones, and access to hindered amines from ketones which are unobtainable by Borch reductive amination.
- Barney, Charlotte L.,Huber, Edward V.,McCarthy, James R.
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p. 5547 - 5550
(2007/10/02)
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