- 1,1′-Dicarbodiimidoferrocenes: Synthesis, Characterization, and Group IV 1,1′-Bisguanidinateferrocene Complexes
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We report the two-step one-pot preparation of a series of bulky substituted 1,1′-dicarbodiimidoferrocene proligands. In solution the compounds achieve equilibrium with the corresponding 2,4-diimino-1,3-azetidine products which exhibit distinct spectroscopic and electrochemical features. Metalation of the carbodiimides with M(NMe2)4 (M = Zr, Hf) leads to fluxional six-coordinate compounds that exhibit intermediate Bailar twist features in solution and in the solid state. Coordination of the 2,4-diimino-1,3-diazetidines to Zr(NMe2)4 results in a metal-mediated carbodiimide metathesis into two zirconium guanidinate complexes, which can be rationalized by a two-step reaction mechanism.
- Palomero, Orhi Esarte,Jones, Richard A.
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- Isocyanate deinsertion from κ1-O amidates: facile access to perfluoroaryl rhodium(i) complexes
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Reaction of the amidate ligand salt, Na[N(Dipp)C(O)C6F5] (1) (Dipp = 2,6-diisopropylphenyl) with [Rh(NBD)Cl]2 (NBD = norbornadiene) results in formation of the dirhodium(i) complex [Rh2{μ2-N,O-N(Dipp)C(O)C6F5}2(NBD)2] (2). Reaction of 2 with PCy3 at room temperature provides an equilibrium mixture of the geometric isomers (E/Z)-[Rh{κ1-O-N(Dipp)C(O)C6F5}(NBD)(PCy3)] (E/Z-3). Treatment of 2 with 3 equiv. of CNXyl (Xyl = 2,6-dimethylphenyl) gives the κ1-O complex [Rh{κ1-O-N(Dipp)C(O)C6F5}(CNXyl)3] (6) while use of 3 equiv. of PPh3 provides the κ2-complex [Rh{κ2-N,O-N(Dipp)C(O)C6F5}(PPh3)2] (8). For complex κ2-N,O8, an equilibrium results with free PPh3 giving the κ1-O complex [Rh{κ1-O-N(Dipp)C(O)C6F5}(PPh3)3] (9). Heating a tol-d8 solution of E/Z-3, 6, or 8/9 results in 2,6-diisopropylphenylisocyanate extrusion providing the corresponding [Rh]-C6F5 complex in good yield.
- Drover, Marcus W.,Schafer, Laurel L.,Love, Jennifer A.
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- Stability and lifetime of quadruply hydrogen bonded 2-Ureido-4[1H]-pyrimidinone dimers
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2-Ureido-4[1H]-pyrimidinones are known to dimerize via a strong quadruple hydrogen bond array. A detailed study of the dimerization constant and lifetime of the dimer is presented here. Excimer fluorescence of pyrene-labeled 2-ureido-4[1H]-pyrimidinone 1b was used to determine a dimerization constant K(dim) of 6 x 107 M-1 in CHCl3, 1 x 107 M-1 in chloroform saturated with water, and 6 x 108 M-1 in toluene (all at 298 K). Under these conditions, the preexchange lifetime of the similar dimers of both 1d and 1e is 170 ms in CDCl3, 80 ms in wet CDCl3, and 1.7 s in toluene-d8, as determined by dynamic NMR spectroscopy. Association rate constants were calculated from the K(dim) values and the preexchange lifetimes. The resulting values are significantly lower than the diffusion-controlled association rate constants calculated using the Stokes-Einstein and the Debeije equations. This difference is ascribed to a tautomeric equilibrium of the monomer between the dimerizing 4[1H]-pyrimidinone and nondimerizing 6[1H]-pyrimidinone tautomers, which is unfavorable for dimerization.
- Soentjens, Serge H. M.,Sijbesma, Rint P.,Van Genderen, Marcel H. P.,Meijer
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- SULFONIMIDAMIDE COMPOUNDS AS NLRP3 MODULATORS
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Described herein are compounds of Formula (I), Formula (I-A), and Formula (I-B), solvates thereof, tautomers thereof, and pharmaceutically acceptable salts of the foregoing, Further described herein are methods of inhibiting NLRP3 using said compounds, and methods of and compositions useful in treating NLRP3-dependent disorders.
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Paragraph 0432
(2021/07/31)
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- NOVEL SULFONAMIDE CARBOXAMIDE COMPOUNDS
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The present invention relates to compounds of formula (I) wherein Q is selected from O or S; R1 is a non-aromatic heterocyclic group comprising at least one ring nitrogen atom, wherein R1 is attached to the sulfur atom of the sulfonylurea group by a ring carbon atom, and wherein R1 may optionally be substituted; and R2 is a cyclic group substituted at the α-position, wherein R2 may optionally be further substituted. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP3.
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Page/Page column 108; 109
(2019/01/21)
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- ENHANCED BIOAVAILABILITY OF N-(2,6-BIS(1-METHYLETHYL) PHENYL)-N'-((1-(4-(DIMETHYLAMINO)-PHENYL)CYCLOPENTYL) METHYL)UREA HYDROCHLORIDE
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Methods for enhancing the bioavailability of N-(2,6-bis(1-methylethyl)phenyl)-N'-((1-(4-(dimethylamino)phenyl)cyclopentyl)-methyl)urea hydrochloride (ATR-101)through administration with food, and compositions and kits related thereto.
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Page/Page column 17-18
(2017/02/09)
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- SOLID DRUG FORM OF N-(2,6-BIS(1-METHYLETHYL)PHENYL)-N'-((1-(4-(DIMETHYLAMINO)PHENYL)CYCLOPENTYL)METHYL)UREA HYDROCHLORIDE AND COMPOSITIONS, METHODS AND KITS RELATED THERETO
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A novel solid drug form of N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride (also referred to “ATR-101”) suitable for oral dosing, and to compositions, methods and kits relating thereto. ATR-101 has particular utility in the treatment of, for example, aberrant adrenocortical cellular activity, including adrenocortical carcinoma (ACC), congenital adrenal hyperplasia (CAH) and Cushing's syndrome.
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Page/Page column 19; 20
(2016/04/26)
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- Terminal imido rhodium complexes
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Compounds of the late transition metals with M≡X multiple bonds (X=CR2, NR, O) represent a synthetic challenge, partly overcome by preparative chemists, but with noticeable gaps in the second- and third-row elements. For example, there are no isolated examples of terminal imido rhodium complexes known to date. Described herein is the isolation, characterization, and some preliminary reactivity studies of the first rhodium complexes [Rh(PhBP3)(NR)] (PhBP3=PhB{CH2PPh 2}3) with a multiple and terminal Rh≡N bond. These imido compounds result from reactions of organic azides with the corresponding rhodium(I) complex having a labile ligand, and display a pseudo-tetrahedral core geometry with an almost linear Rh-N-C arrangement [177.5(2)°]] and a short Rh-N bond [1.780(2) A]. We also show that the Rh≡N bond undergoes protonation at the nitrogen atom or addition of H2, and also engages in nitrene-group transfer and cycloaddition reactions. A missing link: Terminal imido rhodium complexes with a Rh≡N multiple bond have been prepared, thus providing compounds which have been elusive to synthesis. Preliminary studies indicate rhodium imides are somewhat ambiphilic and can therefore undergo protonation at the nitrogen atom, as well as hydrogenation at the Rh≡N bond. These systems also engage in nitrene-group transfer and cycloaddition reactions.
- Geer, Ana M.,Tejel, Cristina,Lopez, Jose A.,Ciriano, Miguel A.
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supporting information
p. 5614 - 5618
(2014/06/10)
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- Synthesis of ureas from titanium imido complexes using CO2 as a C-1 reagent at ambient temperature and pressure
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The coordinatively unsaturated 12-electron complex dichloro t-butylimido bispyridine titanium(iv) (2a) has been shown to react with CO2 to give N,N-bis-t-butyl urea. Two analogous sterically hindered coordinatively saturated 14-electron complexes dichloro t-butylimido trispyridine titanium(iv) (10a) and dichloro 2,6-(i-Pr)2phenylimido trispyridine titanium(iv) (10b) also gave their corresponding symmetrical ureas upon treatment with CO2. Further experiments support the intermediary of metallocycles formed from heterocumulene metathesis reactions. The unsymmetrical urea N-benzyl, N-t-butyl urea (11) was produced from treatment of 2,6-(i-Pr) 2phenylimido trispyridine titanium(iv) (10b) with CO2 and interception with BnNH2. Equimolar quantities of N,N- bistrimethylsilybenzylamine or N,N-bistrimethylsilyphenethylamine were shown to promote the reaction between t-butylimido bispyridine titanium(iv) (2a) and CO2 to give near quantitative yields of symmetrical urea. Other symmetrical ureas could be produced from TiCl4, amine and CO 2 in moderate to quantitative yields depending on the stoichiometry of amine present.
- Anderson, James C.,Moreno, Rafael Bou
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body text
p. 1334 - 1338
(2012/04/10)
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- Mechanistic study of the palladium - Phenanthroline catalyzed carbonylation of nitroarenes and amines: Palladium - Carbonyl intermediates and bifunctional effects
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Palladium - phenanthroline complexes catalyze both the nitroarene carbonylation reaction and the amine oxidative carbonylation reaction to give, depending on the conditions, carbamates and ureas. There is evidence that the key step in both processes is the amine carbonylation. Here, we show that when the reaction is run in methanol key intermediate compounds have the general formula [Pd(RPhen)(COOMe)2] (1) (RPhen = l,10-phenanthroline or one of its substituted derivatives). The kinetics of the reaction of 1 with toluidine in the presence of a carboxylic or phosphorus acid is firstorder with respect to complex, acid, and toluidine. A CO atmosphere is also required for the reaction to proceed. Acid dimerization was shown not to be influential under the concentration conditions examined, but reaction between the acid and toluidine is not negligible and a correction has to be applied. Diphenylphosphinic acid is more effective than any carboxylic acid in promoting this reaction, as also observed under catalytic conditions. A series of equilibria and an irreversible acid-assisted proton transfer explain the observed data. Formation of an adduct between complexes of the kind 1 and CO was spectroscopically observed when RPhen = 2,9-Me2Phen. Several analogous complexes were also spectroscopically characterized and the X-ray structure of [Pd(2,9Me2Phen)Cl2(CO)] was solved. This shows an asymmetric coordination of the nitrogen ligand. Kinetic measurements were also conducted under catalytic conditions. An Eyring plot shows that the effect of the acidic promoter is to decrease the ?S * value, whereas no positive effect is observed on ?H*. A temperature-dependent correction for the reaction between the acid and aniline and phenanthroline present under the reaction conditions has to be applied. Comparison of the results obtained under stoichiometric and catalytic conditions strongly supports the view that 1 is involved even in the latter and that the acid is acting as a bifunctional promoter.
- Ragaini, Fabio,Gasperini, Michela,Cenini, Sergio,Arnera, Lucia,Caselli, Alessandro,Macchi, Piero,Casati, Nicola
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supporting information; scheme or table
p. 8064 - 8077
(2010/03/31)
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- Structural optimization of a CXCR2-directed antagonist that indirectly inhibits γ-secretase and reduces Aβ
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Amyloid β (Aβ), a key molecule in the pathogenesis of Alzheimer's disease (AD), is derived from the amyloid precursor protein (APP) by sequential proteolysis via β- and γ-secretases. Because of their role in generation of Aβ, these enzymes have emerged as important therapeutic targets for AD. In the case of γ-secretase, progress has been made towards designing potent inhibitors with suitable pharmacological profiles. Direct γ-secretase inhibitors are being evaluated in clinical trials and new strategies are being explored to block γ-secretase activity indirectly as well. In this regard, we have previously reported an indirect regulation of γ-secretase through antagonism of CXCR2, a G-protein coupled receptor (GPCR). We demonstrated that N-(2-hydroxy-4-nitrophenyl)-N′-(2-bromophenyl)urea (SB225002), a selective inhibitor of CXCR2 also plays a role in an indirect inhibition of γ-secretase. Furthermore, we reported a ～5-fold difference in the selective inhibition of APP versus Notch processing via γ-secretase following treatment with SB225002. Herein we describe the synthesis and optimization of SB225002. By determination of the structure-activity relationship (SAR), we derived small molecules that inhibit Aβ40 production with IC50 values in the sub-micromolar range in a cell-based assay and also validated the potential of CXCR2 as a new target for therapeutic intervention in AD.
- Bakshi, Pancham,Jin, Chao,Broutin, Pierre,Berhane, Beniam,Reed, Jon,Mullan, Michael
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experimental part
p. 8102 - 8112
(2010/03/24)
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- Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton.
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Potent, specific, chemically stable and non-peptide/small-molecular inhibitors of puromycin-sensitive aminopeptidase, such as 3-(2,6-diethylphenyl)-2,4(1H,3H)-quinazolinedione (PAQ-22, 5), were prepared by the structural development of a potent PSA inhibitor, 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22, 4). The design was carried out partly by applying electrostatic potential field information obtained from PIQ-22 (4) and its derivatives based on thalidomide (2). This information revealed that a positive electrostatic potential field around the benzylic methylene in the tetrahydroisoquinoline ring is necessary for potent activity. Lineweaver-Burk plot analysis showed that PAQ-22 (5) and its derivatives inhibit puromycin-sensitive aminopeptidase (PSA) in a non-competitive manner. These potent and specific PSA inhibitors showed dose-dependent cell invasion-inhibitory activity in a Matrigel assay using mouse melanoma B16F10/L5 cells, in spite of their low cell toxicity.
- Kakuta, Hiroki,Tanatani, Aya,Nagasawa, Kazuo,Hashimoto, Yuichi
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p. 1273 - 1282
(2007/10/03)
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- Isocyanate and carbodiimide synthesis by nitrene-group-transfer from a nickel(II) imido complex
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The imido complex (dtbpe)Ni{N(2,6-(CHMe2)2C6H3)} reacts with CO and CNCH2Ph with addition at the Ni-N bond to give (dtbpe)Ni{C,N:η2-C(O)N(2,6-(CHMe2)2C 6H3)} and (dtbpe)Ni{C,N:η2-C(NCH2Ph)N(2,6-(CHMe2) 2C6H3)}; both) complexes react further with CO to liberate the isocyanate and carbodiimide ligands with formation of (dtbpe)-(Ni(CO)2.
- Mindiola, Daniel J.,Hillhouse, Gregory L.
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p. 1840 - 1841
(2007/10/03)
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- Preparation of isocyanates from primary amines and carbon dioxide using Mitsunobu chemistry
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Primary alkylamines 1 and hindered arylamines 1 give high yields of isocyanates 5 when reacted with carbon dioxide and the Mitsunobu zwitterions 4 generated from dialkyl azodicarboxylates and Bu3P in dichloromethane at - 78°C. Use of Ph3P still gave high yields of isocyanates from reactions of primary alkylamines, but only low yields were obtained from reactions of aromatic amines. Reactions which failed to give high yields of isocyanates gave either carbamoylhydrazines 6 and/or dicarbamoylhydrazines 10 and/or triazolinones 7. The triazolinones were shown to arise from reactions of reactive aryl isocyanates with the Mitsunobu zwitterion. The carbamoylhydrazines were shown not to arise from reaction of isocyanate with reduced dialkyl azodicarboxylates, and a mechanism for their formation is proposed. Single-crystal X-ray analyses confirmed the structures of 6, 7, and 10.
- Saylik, Dilek,Horvath, Michael J.,Elmes, Patricia S.,Jackson, W. Roy,Lovel, Craig G.,Moody, Keith
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p. 3940 - 3946
(2007/10/03)
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- A Mitsunobu-based procedure for the preparation of alkyl and hindered aryl isocyanates from primary amines and carbon dioxide under mild conditions
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A Mitsunobu-based procedure for the preparation of alkyl and hindered aryl isocyanates in excellent yields from primary amines and carbon dioxide under very mild conditions is described.
- Horvath,Saylik,Elmes,Jackson,Lovel,Moody
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p. 363 - 366
(2007/10/03)
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- Reactivity of Carbamoyl Radicals. A New, General, Convenient Free-Radical Synthesis of Isocyanates from Monoamides of Oxalic Acid
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A new, general, simple synthesis of isocyanates was developed by oxidation of monoamides of oxalix acid with peroxydisulfate catalyzed by Ag and Cu salts.The reaction was carried out in a two-phase system (water and an organic solvent), and it is suitable also for practical applications, due to the simple experimental conditions and the inexpensive as well as nontoxic reagents.The first example of homolytic intramolecular aromatic carbamoylation is also reported.
- Minisci, Francesco,Fontana, Francesca,Coppa, Fausta,Yan, Yong Ming
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p. 5430 - 5433
(2007/10/02)
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- Neue Methode zur Synthese von Isocyanaten unter milden Bedingungen
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Keywords: Arendiyldiisocyanate; Di-tert-butyldicarbonat; 4-Dimethylaminopyridin; Isocyanate
- Knoelker, Hans-Joachim,Braxmeier, Tobias,Schlechtingen, Georg
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p. 2746 - 2749
(2007/10/03)
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- N-phenyl-N'-pyridinylureas as anticonvulsant agents
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A series of N-phenyl-N'-pyridinylureas was examined for anticonvulsant activity. Extensive structure/activity investigations revealed optimal activity in the N-(2,6-disubstituted-phenyl)-N'-(4-pyridinyl)urea series, with 37 exhibiting the best overall anticonvulsant profile. Compound 37 was effective against seizures induced by maximal electroshock but did not protect mice from clonic seizures produced by the convulsant pentylenetetrazol. The overall pharmacological profile suggests that 37 would be of therapeutic use in the treatment of generalized tonic-clonic and partial seizures. Compound 37 was selected for Phase 1 clinical trials.
- Pavia,Lobbestael,Taylor,Hershenson,Miskell
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p. 854 - 861
(2007/10/02)
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- A Convenient Method for the Synthesis of Sterically Hindered Aryl Isocyanates
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Reaction of a sterically hindered aniline with a sterically non-hindered arylisocyanate produces the sterically hindered aryl isocyanate in good yields besides the urea derived from the unhindered aryl isocyanate. - Key words: Metathesis of Isocyanates, NMR Spectra
- Habib, Nargues S.,Rieker, Anton
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p. 1593 - 1597
(2007/10/02)
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