65715-93-7Relevant articles and documents
Discovery of M3Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease
Armani, Elisabetta,Rizzi, Andrea,Capaldi, Carmelida,De Fanti, Renato,Delcanale, Maurizio,Villetti, Gino,Marchini, Gessica,Pisano, Anna Rita,Pitozzi, Vanessa,Pittelli, Maria Gloria,Trevisani, Marcello,Salvadori, Michela,Cenacchi, Valentina,Puccini, Paola,Amadei, Francesco,Pappani, Alice,Civelli, Maurizio,Patacchini, Riccardo,Baker-Glenn, Charles A.G.,Van De Po?l, Hervé,Blackaby, Wesley P.,Nash, Kevin,Amari, Gabriele
supporting information, p. 9100 - 9119 (2021/07/19)
In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.
Overcoming the Deallylation Problem: Palladium(II)-Catalyzed Chemo-, Regio-, and Stereoselective Allylic Oxidation of Aryl Allyl Ether, Amine, and Amino Acids
Begam, Hasina Mamataj,Jana, Ranjan,Manna, Kartic,Samanta, Krishanu
supporting information, p. 7443 - 7449 (2020/10/09)
We report herein a Pd(II)/bis-sulfoxide-catalyzed intramolecular allylic C-H acetoxylation of aryl allyl ether, amine, and amino acids with the retention of a labile allyl moiety. Mechanistically, the reaction proceeds through a distinct double-bond isomerization from the allylic to the vinylic position followed by intramolecular carboxypalladation and the β-hydride elimination pathway. For the first time, C-H oxidation of N-allyl-protected amino acids to furnish five-membered heterocycles through 1,3-syn-addition is established with excellent diastereoselectivity.
Enantioselective Synthesis of Quaternary Δ4- and Δ5-Dehydroprolines Based on a Two-Step Formal [3+2] Cycloaddition of α-Aryl and α-Alkyl Isocyano(thio)acetates with Vinyl Ketones
Odriozola, Amaiur,Oiarbide, Mikel,Palomo, Claudio
supporting information, p. 12758 - 12762 (2017/09/25)
A divergent synthesis of optically active quaternary Δ4- and Δ5-dehydro prolines is developed based on the first catalytic enantioselective conjugate addition of α-substituted isocyano(thio)acetates to vinyl ketones that is general for both α-aryl and α-alkyl isocyano(thio)acetates. The new tetrasubstituted C?N stereocenter is formed without the need of any metal salt due to a bifunctional tertiary amine/squaramide catalyst, featuring a bulky polyaryl sidearm and an unusually short squaramide diamide H???H interatomic distance in the solid state.
PHENYLETHYLPYRIDINE DERIVATIVES AS PDE4-INHIBITORS
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Page/Page column 79; 80, (2014/06/24)
The invention relates to novel compounds which are both inhibitors of the phosphodiesterase 4 (PDE4) enzyme and muscarinic M3 receptor antagonists, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
NOVEL COMPOUNDS
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Paragraph 0460 - 0462, (2014/06/23)
Compounds of formula (I) defined herein are both inhibitors of the phosphodiesterase 4 (PDE4) enzyme and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of a disease of the respiratory tract characterized by airway obstruction.
Diastereoselective synthesis of aliphatic α,α-difluoro- β3-amino esters via a sonocatalyzed Reformatsky reaction
March, Taryn L.,Johnston, Martin R.,Duggan, Peter J.
supporting information; experimental part, p. 182 - 185 (2012/02/16)
(R)-2-Phenylglycine ethyl ester was found to be a cheap and effective auxiliary for the preparation of aliphatic α,α-difluoro- β3-amino esters via a Reformatsky reaction performed under sonication conditions. The products were obtained in good to high yield and ≥96:4 dr, thus providing a new stereoselective route to this under-represented class of compounds. A facile one-pot removal of the phenylglycine moiety and concomitant Boc protection subsequently afforded the corresponding Boc-protected β3-amino esters in excellent yield.
Haloenol pyranones and morpholinones as antineoplastic agents of prostate cancer
Mock, Jason N.,Taliaferro, John P.,Lu, Xiao,Patel, Sravan Kumar,Cummings, Brian S.,Long, Timothy E.
scheme or table, p. 4854 - 4858 (2012/08/13)
Haloenol pyran-2-ones and morpholin-2-ones were synthesized and evaluated as inhibitors of cell growth in two different prostate human cancer cell lines (PC-3 and LNCaP). Analogs derived from l- and d-phenylglycine were found to be the most effective antagonists of LNCaP and PC-3 cell growth. Additional studies reveal that the inhibitors induced G2/M arrest and the (S)-enantiomer of the phenylglycine-based derivatives was a more potent inhibitor of cytosolic iPLA2β.
The effect of benzyl amine on the efficiency of the base-catalyzed transamination of α-keto esters
Xue, Fazhen,Xiao, Xiao,Wang, Haining,Shi, Yian
scheme or table, p. 6862 - 6867 (2012/08/28)
This paper describes the effect of benzyl amine on the base-catalyzed transamination of α-keto esters. Among various benzyl amines examined, o-HOC6H4CH2NH2 was found to be highly effective for the reaction, affording a wide variety of α-amino esters in good yields. The o-OH group of the benzyl amine facilitates the transamination process likely via H-bond. Moderate enantiomeric excess was obtained for α-amino ester when a quinine derived catalyst was used.
(9H-fluoren-9-yl)methanesuIfonyl (Fms): An amino protecting group complementary to Fmoc
Ishibashi, Yoshitaka,Miyata, Kengo,Kitamura, Masato
experimental part, p. 4201 - 4204 (2010/10/02)
A sulfonamide-based protecting group (PG), (9H-fluoren-9yl)methanesulfonyl (Fms), which can be used in a similar way to the well-established Fmoc PG, was developed. The advantages of this new PG were demonstrated in the successful formation of a phosphonamide between an N-Fmsprotected a-phosphonoalanine monoester and secondary alkylamines, including (R)-2-phenylethylamine, (S)-phenylalanine iert-butyl ester (H-Phe-OtBu), H-Pro-Gly-OtBu, and H-Phe-Phe-OtBu, without formation of oxazaphospholine, which is a serious problem associated with the Fmoc PG. The success should pave the way to the solid-phase synthesis of unnatural peptides substituted with a-amino phosphonic acid (AP) at essentially any arbitrary position without significant modification of the Fmoc-based chemistry that has been accumulated since Carpino's report in 1970. The N-Fms-AP monomer would attract much attention in the field of peptide mimetics.
Copper-catalyzed asymmetric N-H insertion reactions: Couplings of diazo compounds with carbamates to generate α-amino acids
Lee, Elaine C.,Fu, Gregory C.
, p. 12066 - 12067 (2008/03/27)
A Cu/chiral bipyridine catalyst has been developed for the asymmetric insertion of α-diazocarbonyl compounds into the N-H bonds of carbamates to generate an array of easily deprotected arylglycines in good ee. With respect to the reaction partners, as wel
