921-08-4Relevant articles and documents
CRYSTALLINE FORMS OF A CD73 INHIBITOR
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Page/Page column 21, (2021/03/05)
The present invention relates to crystalline forms of 5-[5-[2-isopropylcyclopropyl] -6-methyl-pyridazin-3-yl]-1H-pyrimidine-2,4-dione, and pharmaceutical compositions comprising them, which inhibit the activity of CD73 and are useful for treating cancer.
A facile microwave assisted synthesis and structure elucidation of (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones by crystallographic, spectroscopic and DFT studies
Raza, Abdul Rauf,Nisar, Bushra,Khalid, Muhammad,Gondal, Humaira Yasmeen,Khan, Muhammad Usman,de Alcantara Morais, Sara Figueirêdo,Tahir, Muhammad Nawaz,Braga, Ataualpa Albert Carmo
, (2020/01/21)
The use of microwave (MW) irradiation in organic synthesis has become increasingly popular within the pharmaceutical and academic arenas because it is a new enabling technology for drug discovery and development. It is a rapid way of synthesis, which involves faster reaction rates and high selectivity to conventional heating method of syntheses. The MW-assisted 7-exo-tet cyclization of N-acylanthranilic acids afforded (3R)-3-alkyl-4,1-benzoxazepines-2,5-diones in very short duration (20 min) with extraordinary high yields in comparison to conventional heating mode of synthesis. The method development, comparative yields of MW-assisted and thermal method of syntheses, crystallographic, spectroscopic and density functional theory (DFT) studies are reported herein. Four novel compounds with chemical formulas C10H9BrClNO3 5m, C19H19NO3 6e, C13H14ClNO3 6h and C12H11Br2NO3 6h were synthesized, validated by 1HNMR, 13CNMR, FT-IR, UVVis, EIMS spectroscopic techniques and confirmed by using single crystal X-ray diffraction (SC-XRD) study. The DFT and TDDFT calculations at B3LYP/6-311 + G(d,p) level of theory were performed for comparative analysis of spectroscopic data, optimized geometries, frontier molecular orbitals (FMOs), natural bond orbital (NBO) analysis and nonlinear optical (NLO) properties of 5m, 6e, 6h and 6o. Overall, experimental findings were supported nicely by corresponding DFT computed results. The NBO analysis confirmed that the presence of non-covalent interactions, hydrogen bonding and hyper- conjugative interactions are pivotal cause for the existence of 5m, 6e, 6h and 6o in the solid-state. NLO analysis showed that 5m, 6e, 6h and 6o have significant NLO properties as compared to prototype standard compound which disclosed their potential for technology related applications.
CD73 INHIBITORS
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Page/Page column 38, (2019/09/18)
The present invention provides 5-[5]-[2-cycloa Ikyl ]-6-pyridazin-3-yl ]- IH-pyrimidine-2,4-dione compounds, or pharmaceutically acceptable salts thereof, that inhibit the activity of CD73 and are useful in treating cancer. (Formula (I))
Total Synthesis and Biological Evaluation of the Glycosylated Macrocyclic Antibiotic Mangrolide A
Hattori, Hiromu,Roesslein, Joel,Caspers, Patrick,Zerbe, Katja,Miyatake-Ondozabal, Hideki,Ritz, Daniel,Rueedi, Georg,Gademann, Karl
supporting information, p. 11020 - 11024 (2018/07/31)
The macrocyclic antibiotic mangrolide A has been described to exhibit potent activity against a number of clinically important Gram-negative pathogens. Reported is the first enantioselective total synthesis of mangrolide A and derivatives. Salient features of this synthesis include a highly convergent macrocycle preparation, stereoselective synthesis of the disaccharide moiety, and two β-selective glycosylations. The synthesis of mangrolide A and its analogues enabled the re-examination of its activity against bacterial pathogens, and only minimal activity was observed.
Di(1-naphthyl) methanol ester of carboxylic acids for absolute stereochemical determination
Zhang, Jun,Sheng, Wei,Gholami, Hadi,Nehira, Tatsuo,Borhan, Babak
supporting information, p. 141 - 146 (2017/11/13)
The absolute stereochemistry of chiral carboxylic acids is determined as a di(1-naphthyl)methanol ester derivative. Computational scoring of conformations favoring either P or M helicity of the naphthyl groups, capable of exciton-coupled circular dichroic coupling, leads to a predicted stereochemistry for the derivatized carboxylic acids.
Enantioselective organocatalytic synthesis of 2-oxopiperazines from aldehydes: Identification of the elusive epoxy lactone intermediate
Kaplaneris, Nikolaos,Spyropoulos, Constantinos,Kokotou, Maroula G.,Kokotos, Christoforos G.
, p. 5800 - 5803 (2016/11/29)
An organocatalytic linchpin catalysis approach was envisaged to convert simple aldehydes into enantioenriched 2-oxopiperazines. A four-step reaction sequence (chlorination, oxidation, substitution, and cyclization) was developed and led to different substitution patterns in high yields and selectivities. The reaction mechanism was studied, and the previously elusive epoxy lactone intermediate was identified by HRMS.
Chiral Pool-Based Synthesis of Naphtho-Fused Isocoumarins
Raza, Abdul Rauf,Saddiqa, Aisha,?akmak, Osman
, p. 951 - 957 (2015/11/16)
A variety of chiral derivatives of benzo[d]naphtho[1,2-b]pyran-6-one were prepared in a single step by Et3N-mediated condensation of homophthalic anhydride with different derivatives of (S)-amino acid chlorides at -5 °C by employing a chiral pool methodology. Chirality 27:951-957, 2015.
Forming Stereogenic Centers in Acyclic Systems from Alkynes
Vabre, Roxane,Island, Biana,Diehl, Claudia J.,Schreiner, Peter R.,Marek, Ilan
supporting information, p. 9996 - 9999 (2015/08/19)
The combined carbometalation/zinc homologation followed by reactions with α-heterosubstituted aldehydes and imines proceed through a chair-like transition structure with the substituent of the incoming aldehyde residue preferentially occupying a pseudo-axial position to avoid the two gauche interactions. The heteroatom in the axial position produces a chelated intermediate (and not a Cornforth-Evans transition structure for α-chloro aldehydes and imines) leading to a face differentiation in the allylation reaction. This method provides access to functionalized products in which three new carbon-carbon bonds and two to three stereogenic centers, including a quaternary one, were created in acyclic systems in a single-pot operation from simple alkynes. All-carbon quaternary stereocenter: The combined carbometalation/zinc homologation of alkynes followed by reactions with α-heterosubstituted aldehydes and imines provides access to functionalized acyclic adducts. These adducts obtained in a single-pot reaction have three new carbon-carbon bonds and two to three stereogenic centers, including a quaternary carbon stereocenter.
Chiron based synthesis of isocoumarins: Reactivity of α-substituted carboxylic acids
Saddiqa, Aisha,Raza, Abdul R.,Black, David Stc.,Kumar, Naresh
, p. 736 - 743 (2014/06/09)
The asymmetric synthesis of a novel (S)-isocoumarin has been attempted in a single step by the coupling of homophthalic acid with (S)-N-protected amino acids and α-chloroacids at high temperature by exploiting a chiral pool methodology. The coupling of homophthalic acid with N-protected (S)-amino acids gave exclusion of the carboxyl/alkyl group. However, coupling of homophthalic acid with α-chloroacids afforded asymmetric isocoumarins in high yield.
Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β2-adrenergic receptor
Plazinska, Anita,Pajak, Karolina,Rutkowska, Ewelina,Jimenez, Lucita,Kozocas, Joseph,Koolpe, Gary,Tanga, Mary,Toll, Lawrence,Wainer, Irving W.,Jozwiak, Krzysztof
, p. 234 - 246 (2014/01/17)
The β2-adrenergic receptor (β2-AR) agonist [3H]-(R,R′)-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4′-methoxyfenoterol analogs in which the length of the alkyl substituent at α′ position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [3H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC50 values, were determined in HEK293 cells expressing the β2-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α′ position. The results also indicate that the Ki values obtained using [3H]-(R,R′)-methoxyfenoterol as the marker ligand modeled the EC50 values obtained from cAMP stimulation better than the data obtained using [3H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β2-AR conformation probed by [3H]-(R,R′)-4′-methoxyfenoterol. The CoMFA model of the agonist-stabilized β2-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β2-AR is governed to a greater extend by steric effects than binding to the [3H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role.
