Synthesis of 4,5-diazaspiro[2.3]hexanes and 1,2-diazaspiro[3.3]heptanes as hexahydropyridazine analogues

4,5-Diazaspiro[2.3]hexanes are made by dihalocarbene addition across the exocyclic double bond of readily accessible 3-alkylidene-1,2-diazetidines. Using difluorocarbene, generated from TMSCF3/NaI, these spirocycles were produced in yields up to 97% by stereospecific addition across the alkene. Lower yields (up to 64%) were observed using more reactive dichlorocarbene, due to competitive insertion of the carbene into the N–N bond. Larger 1,2-diazaspiro[3.3]heptanes are produced by [2+2] cycloaddition of 3-alkylidene-1,2-diazetidines with tetracyanoethylene (TCNE) in up to 99% yield. These additions work with di-, tri- and tetrasubstituted alkenes, offering a practical route to rigidified analogues of the medicinally important hexahydropyridazines

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.

The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer

Process for the preparation of Risdiplam and its intermediates

The present application relates to a process for the preparation of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido-4H-[1,2-a]pyrimidin-4-one of formula-1 and its intermediate compounds. Formula-1

Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity

This work was funded by Italian Minister of University and Research project PRIN 2017-201744BN5T. Grant funding (VKA): National Institutes of Health-National Eye Institute-R01EY029409, P30EY00179, National Institutes of Neurological Disorders and Stroke R01NS124784, Unrestricted Grant, Research to Prevent Blindness, New York, NY. This study was partially supported by the Spanish State Research Agency (10.13039/501100011033) under the auspices of MINECO (grant number PID2019-108691RB-I00) and the Andalusian Regional Government (grant CTS109).The design and synthesis of a series of 2,7-diazaspiro[4.4]nonanederivatives as potent sigma receptor (SR) ligands, associated withanalgesic activity, are the focus of this work. In this study, affinitiesat S1R and S2R were measured, and molecular modeling studies wereperformed to investigate the binding pose characteristics. The mostpromising compounds were subjected to in vitro toxicitytesting and subsequently screened for in vivo analgesicproperties. Compound 9d (AD258) exhibitednegligible in vitro cellular toxicity and a highbinding affinity to both SRs (K (i)S1R =3.5 nM, K (i)S2R = 2.6 nM), but not for otherpain-related targets, and exerted high potency in a model of capsaicin-inducedallodynia, reaching the maximum antiallodynic effect at very low doses(0.6-1.25 mg/kg). Functional activity experiments showed thatS1R antagonism is needed for the effects of 9d and thatit did not induce motor impairment. In addition, 9d exhibiteda favorable pharmacokinetic profile.Ministry of Education, Universities and Research (MIUR) PRIN 2017-201744BN5TUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Eye Institute (NEI) R01EY029409, P30EY00179United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Neurological Disorders & Stroke (NINDS) R01NS124784Unrestricted Grant, Research to Prevent Blindness, New York, NYSpanish Government PID2019-108691RB-I00Andalusian Regional Government CTS10

New spirohydantoin derivatives : synthesis, pharmacological evaluation and molecular modeling study

A series of new arylpiperazinylpropyl derivatives of 8/6-phenyl-1,3-diazaspiro[4.5]decan-2,4-dione and spiro[imidazolidine-4,1í-indene/naphthalene]-2,5-dione was synthesized and their affinity was evaluated toward serotonin 5-HT1A, 5-HT2A, 5-HT7 receptors, dopaminergic D2, D3 receptors, adrenergic α1 receptors, and serotonin transporter (SERT). The highest affinity for serotonin 5-HT1A/2A/7 receptors was found for compounds containing a tetralin or indane moiety in the imide part. Among these, two compounds (19, 20) were selected for further pharmacological in vivo studies. A binding mode of representative molecule 19, which behaved as a 5-HT1A agonist and weak 5-HT7 antagonist in the site of 5-HT1A/7, was also analyzed in computationa studies. Moreover, two highly selective (9 and 11) 5-HT2A receptor antagonists were obtained

New spiro (thio) barbiturates based on cyclohexanone and bicyclo [3.1.1]heptan-6-one by nonconcerted [1+5] cycloaddition reaction and their conformational structures

Crossed-aldol condensation reaction of aromatic aldehydes with ketones such as; acetone and cyclohexanone leads to the efficient formation of cross conjugated α,β-unsaturated ketones in excellent yield. The intermolecular and then intramolecular Michael addition reaction of α,β-unsaturated ketones derived from acetone and cyclohexanone with (thio)barbituric acids lead to synthesis new type of 7,11-diaryl-2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraone and 2,4-diaryl-1'H-spiro[bicyclo[3.3.1]nonane-3,5'-pyrimidine]-2',4',6',9(3'H)-tetraone, respectively in good yield. Structure elucidation is carried out by 1H NMR, 13C NMR, FT-IR, UV-Visible, mass spectroscopy and X-ray crystallography techniques. A possible mechanism of the formation is discussed. The structural conformation also demonstrated by coupling constants derived from dihedral angles between vicinal and geminal protons. The 1H NMR spectra of NH protons of spiro compounds derived from barbituric acid show a broad singlet peak instead, these protons in the spiro compounds derived from thiobarbituric acid show two distinct peaks. KEY WORDS: Crossed-aldol condensation, Michael addition, [1+5] Cycloaddition, Barbituric acid, Conformation, Spiro barbiturate Bull. Chem. Soc. Ethiop. 2014, 28(3), 423-440.DOI: http://dx.doi.org/10.4314/bcse.v28i3.1

Access to Spiropyrazolone-butenolides through NHC-Catalyzed [3 + 2]-Asymmetric Annulation of 3-Bromoenals and 1H-Pyrazol-4,5-diones

Producción CientíficaThe stereoselective synthesis of spirocyclic pyrazo- lin-5-ones by N-heterocyclic carbene (NHC) organocatalysis has been less studied so far. For this reason and considering the interest of this class of compounds, here, we present the NHC-catalyzed [3 + 2]-asymmetric annulation of β-bromoenals and 1H-pyrazol-4,5- diones that achieves to produce chiral spiropyrazolone-butenolides. The synthesis is general for aryl and heteroaryl β-bromo-α,β- unsaturated aldehydes and 1,3-disubstituted pyrazolones. The spirobutenolides have been obtained in good yields (up to 88%) and enantioselectivities (up to 97:3 er). This constitutes the first described example using pyrazoldiones as the starting materials for this class of spiro compounds.Junta de Castilla y León predoctoral fellowship (EDU/556/2019

Experimental and theoretical DFT investigations in the [2, 3]-wittig-type rearrangement of propargyl/allyl-oxy-pyrazolones

Here we report the synthesis of interesting 3-alkyl-4-hydroxy-1-aryl-4-(propa-1,2-dienyl)1H-pyrazol-5(4H)-ones and 9-alkyl-7-aryl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-dien-6-ones, starting from 1,2-diaza-1,3-dienes (DDs) and propargyl alcohol. The reaction proceeds through a sequence Michael-type nucleophilic attack/cyclization/[2,3]-Wittig rearrangement. In the same way, the reaction between the aforementioned DDs and allyl alcohol furnished 4-allyl-4-hydroxy-3-alkyl-1-aryl-1H-pyrazol-5(4H)-ones. A DFT study was also carried out, in order to have decisive clarifications about the mechanism