- METHODS OF TREATMENT WITH MYOSIN MODULATOR
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Disclosed herein are methods of treatment comprising administering a therapeutically effective amount of a myosin modulator or a pharmaceutically acceptable salt thereof to a subject in need thereof and diagnostic methods useful in connection with those treatments. Due to observations unfolding in clinical trials with mavacamten and with mavacamten and other myosin inhibitors in the pre-clinical setting, new insights into how myosin inhibitors can be used beneficially to impact the disease state of HCM and other diseases are provided herein.
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Paragraph 565
(2021/05/15)
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- Catalytic hydration of cyanamides with phosphinous acid-based ruthenium(ii) and osmium(ii) complexes: scope and mechanistic insights
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The synthesis of a large variety of ureas R1R2NC(O)NH2 (R1 and R2 = alkyl, aryl or H; 26 examples) was successfully accomplished by hydration of the corresponding cyanamides R1R2NCN using the phosphinous acid-based complexes [MCl2(η6-p-cymene)(PMe2OH)] (M = Ru (1), Os (2)) as catalysts. The reactions proceeded cleanly under mild conditions (40-70 °C), in the absence of any additive, employing low metal loadings (1 molpercent) and water as the sole solvent. In almost all the cases, the osmium complex 2 featured a superior reactivity in comparison to that of its ruthenium counterpart 1. In addition, for both catalysts, the reaction rates observed for the hydration of the cyanamide substrates were remarkably faster than those involving classical aliphatic and aromatic nitriles. Computational studies allowed us to rationalize all these trends. Thus, the calculations indicated that the presence of a nitrogen atom directly linked to the CN bond depopulates electronically the nitrile carbon by inductive effect when coordinated to the metal center, thus favouring the intramolecular nucleophilic attack of the OH group of the phosphinous acid ligand to this carbon. On the other hand, the higher reactivity of Os vs. Ru seems to be related with the lower ring strain on the incipient metallacycle that starts to form in the transition state associated with this key step in the catalytic cycle. Indirect experimental evidence of the generation of the metallacyclic intermediates was obtained by studying the reactivity of [RuCl2(η6-p-cymene)(PMe2OH)] (1) towards dimethylcyanamide in methanol and ethanol. The reactions afforded compounds [RuCl(η6-p-cymene)(PMe2OR)(NCNMe2)][SbF6] (R = Me (5a), Et (5b)), resulting from the alcoholysis of the metallacycle, which could be characterized by single-crystal X-ray diffraction. This journal is
- álvarez, Daniel,Cadierno, Victorio,Crochet, Pascale,González-Fernández, Rebeca,López, Ramón,Menéndez, M. Isabel
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p. 4084 - 4098
(2020/07/09)
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- TYK2 INHIBITORS AND USES THEREOF
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Described herein are compounds that are useful in treating a TYK2-mediated disorder. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
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Paragraph 00570
(2020/06/10)
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- Myosin inhibitor, as well as preparation method and application thereof
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The invention relates to the field of medicinal chemistry, in particular to a myosin inhibitor, as well as a preparation method and application thereof. The invention provides a compound or pharmacologically acceptable salt, an isomer, a prodrug, a polymorphic substance or a solvate thereof. A chemical structural formula of the compound is as shown in a formula I. Compared with other similar medicines in the prior art, the compound or the pharmacologically acceptable salt, the isomer, the prodrug, the polymorphic substance or the solvate thereof provided by the invention have better activity and a more ideal pharmacokinetics characteristic.
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Paragraph 0111-0114
(2020/02/14)
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- Synthesis and Structure of 1-Substituted Semithioglycolurils
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Two methods for the synthesis of previously unavailable 1-substituted semithioglycolurils were developed. These methods consist of the cyclocondensation of 1-substituted ureas with 4,5-dihydroxy- or 4,5-dimethoxyimidazolidine-2-thione or glyoxal, followed by the reaction of the resulting 1-substituted 4,5-dihydroxyimidazolidine-2-ones with HSCN in a two-step one-pot procedure. Two of the desired semithioglycolurils were obtained as conglomerates.
- Baranov, Vladimir V.,Galochkin, Anton A.,Kravchenko, Angelina N.,Makhova, Nina N.,Nelyubina, Yulia V.
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p. 2563 - 2571
(2020/09/07)
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- A Physical Organic Approach to Tuning Reagents for Selective and Stable Methionine Bioconjugation
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We report a data-driven, physical organic approach to the development of new methionine-selective bioconjugation reagents with tunable adduct stabilities. Statistical modeling of structural features described by intrinsic physical organic parameters was applied to the development of a predictive model and to gain insight into features driving the stability of adducts formed from the chemoselective coupling of oxaziridine and methionine thioether partners through Redox Activated Chemical Tagging (ReACT). From these analyses, a correlation between sulfimide stabilities and sulfimide ν (C=O) stretching frequencies was revealed. We exploited the rational gains in adduct stability exposed by this analysis to achieve the design and synthesis of a bis-oxaziridine reagent for peptide stapling. Indeed, we observed that a macrocyclic peptide formed by ReACT stapling at methionine exhibited improved uptake into live cells compared to an unstapled congener, highlighting the potential utility of this unique chemical tool for thioether modification. This work provides a template for the broader use of data-driven approaches to bioconjugation chemistry and other chemical biology applications.
- Christian, Alec H.,Jia, Shang,Cao, Wendy,Zhang, Patricia,Meza, Arismel Tena,Sigman, Matthew S.,Chang, Christopher J.,Toste, F. Dean
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supporting information
p. 12657 - 12662
(2019/09/04)
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- Regioselective Formal [3+2] Cycloadditions of Urea Substrates with Activated and Unactivated Olefins for Intermolecular Olefin Aminooxygenation
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A new class of intermolecular olefin aminooxygenation reaction is described. This reaction utilizes the classic halonium intermediate as a regio- and stereochemical template to accomplish the selective oxyamination of both activated and unactivated alkenes. Notably, urea chemical feedstock can be directly introduced as the N and O source and a simple iodide salt can be utilized as the catalyst. This formal [3+2] cycloaddition process provides a highly modular entry to a range of useful heterocyclic products with excellent selectivity and functional-group tolerance.
- Wu, Fan,Alom, Nur-E,Ariyarathna, Jeewani P.,Na?, Johannes,Li, Wei
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supporting information
p. 11676 - 11680
(2019/07/31)
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- MAVACAMTEN FOR USE IN THE TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY
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Provided are methods for treating hypertrophic cardiomyopathy and diastolic dysfunction.
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Paragraph 0190
(2019/02/15)
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- A practically simple, catalyst free and scalable synthesis of: N -substituted ureas in water
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A practically simple, mild and efficient method is developed for the synthesis of N-substituted ureas by nucleophilic addition of amines to potassium isocyanate in water without organic co-solvent. Using this methodology, a variety of N-substituted ureas (mono-, di- and cyclic-) were synthesized in good to excellent yields with high chemical purity by applying simple filtration or routine extraction procedures avoiding silica gel purification. The developed methodology was also found to be suitable for gram scale synthesis of molecules having commercial application in large volumes. The identified reaction conditions were found to promote a unique substrate selectivity from a mixture of two amines.
- Tiwari, Lata,Kumar, Varun,Kumar, Bhuvesh,Mahajan, Dinesh
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p. 21585 - 21595
(2018/06/26)
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- Synthesis and Antiangiogenic Properties of Tetrafluorophthalimido and Tetrafluorobenzamido Barbituric Acids
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The development of novel thalidomide derivatives as immunomodulatory and anti-angiogenic agents has revived over the last two decades. Herein we report the design and synthesis of three chemotypes of barbituric acids derived from the thalidomide structure: phthalimido-, tetrafluorophthalimido-, and tetrafluorobenzamidobarbituric acids. The latter were obtained by a new tandem reaction, including a ring opening and a decarboxylation of the fluorine-activated phthalamic acid intermediates. Thirty compounds of the three chemotypes were evaluated for their anti-angiogenic properties in an ex vivo assay by measuring the decrease in microvessel outgrowth in rat aortic ring explants. Tetrafluorination of the phthalimide moiety in tetrafluorophthalimidobarbituric acids was essential, as all of the nonfluorinated counterparts lost anti-angiogenic activity. An opening of the five-membered ring and the accompanying increased conformational freedom, in case of the corresponding tetrafluorobenzamidobarbituric acids, was well tolerated. Their activity was retained, although their molecular structures differ in torsional flexibility and possible hydrogen-bond networking, as revealed by comparative X-ray crystallographic analyses.
- Ambro?ak, Agnieszka,Steinebach, Christian,Gardner, Erin R.,Beedie, Shaunna L.,Schnakenburg, Gregor,Figg, William D.,Gütschow, Michael
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p. 2621 - 2629
(2016/12/09)
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- BICYCLIC-PYRIMIDINEDIONE COMPOUNDS
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The present invention provides novel bicyclic pyrimidinedione compounds that are useful for the treatment of hypertrophic cardiomyopathy (HCM) and conditions associated with left ventricular hypertrophy or diastolic dysfunction. The synthesis and characterization of the compounds is described, as well as methods for treating HCM and other forms of heart disease.
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Paragraph 0143; 0144
(2016/07/27)
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- CYCLOALKYL-SUBSTITUTED PYRIMIDINEDIONE COMPOUNDS
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The present invention provides novel cycloalkyl-substituted pyrimidine dione compounds that are useful for the treatment of hypertrophic cardiomyopathy (HCM) and conditions associated with left ventricular hypertrophy or diastolic dysfunction. The synthesis and characterization of the compounds is described, as well as methods for treating HCM and other forms of heart disease.
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Paragraph 0071
(2015/01/07)
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- PYRIMIDINEDIONE COMPOUNDS AGAINST CARDIAC CONDITIONS
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Provided are novel pyrimidine dione compounds and pharmaceutically acceptable salts thereof, that are useful for the treatment of hypertrophic cardiomyopathy (HCM) and conditions associated with left ventricular hypertrophy or diastolic dysfunction. The synthesis and characterization of the compounds and pharmaceutically acceptable salts thereof, are described, as well as methods for treating HCM and other forms of heart disease.
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Paragraph 0071-0072
(2015/01/07)
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- Carboxylic acid-catalyzed one-pot synthesis of cyanoacetylureas and their cyclization to 6-aminouracils in guanidine ionic liquid
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A novel, one-pot, carboxylic acid-catalyzed synthesis of cyanoacetylureas via in situ generated ureas and their cyclization to 6-aminouracils in the presence of the guanidine-based ionic liquid 1,1,3,3-tetramethylguanidine lactate [TMG][Lac] is described. The ureas were synthesized from amines and potassium cyanate, which on reaction with cyanoacetic acid in the presence of acetic anhydride in the same pot afforded cyanoacetylureas, which undergo cyclization in [TMG][Lac] as solvent as well as catalyst to afford 6-aminouracils. One-pot synthesis of cyanoacetylureas, efficient and rapid cyclization, better yield, shorter reaction time, easy workup procedure, and recyclability of the ionic liquid are some advantages of this procedure.
- Chavan, Sunil S.,Shelke, Rupesh U.,Degani, Mariam S.
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p. 399 - 403
(2013/05/21)
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- PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
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The invention relates to a process for straightening keratin fibres, comprising: (i) a step in which a straightening composition containing at least two denaturing agents is applied to the keratin fibres, (ii) a step in which the temperature of the keratin fibres is raised, using a heating means, to a temperature of between 110 and 250° C.
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- Process for the preparation of asymmetrically substituted ureas, carbamates or thiocarbamates
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Process for the preparation of asymmetrically substituted ureas, carbamates, thiocarbamates or substituted isocyanates by reaction of an adduct of isocyanic acid and a tertiary amine with a primary and secondary amine, an alcohol, a thiol or a compound having one or two non-cumulated olefinic double bonds, and a process for the preparation of N-mono- or N,N-disubstituted ureas by reaction of ammonium isocyanate with a primary or secondary amine in a diluent.
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- Process for the preparation of substituted isocyanates
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Process for the preparation of asymmetrically substituted ureas, carbamates, thiocarbamates or substituted isocyanates by reaction of an adduct of isocyanic acid and a tertiary amine with a primary and secondary amine, an alcohol, a thiol or a compound having one or two non-cumulated olefinic double bonds.
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- Process for the preparation of asymmetrically substituted ureas
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Process for the preparation of asymmetrically substituted ureas by reaction of a gaseous mixture of isocyanic acid and ammonia having a temperature of 260° to 600° C. with a primary or secondary amine.
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- Photo-oxidation of Oxazolidones and Hydantoins in the Presence of Benzophenone
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Irradiation in the presence of benzophenone and oxygen of nitrogen-containing heterocycles having an NCO group yields products arising out of regioselective oxidation α to the nitrogen atom.Direct irradiation (in the absence of benzophenone and oxygen) of 5-methyl- and 5,5-dimethyl-hydantoins yields allophanates.The first step of this reaction involves the homolysis of the C(4) - C(5) bond of the hydantoin.
- Gramain, Jean-Claude,Remuson, Roland
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p. 2341 - 2346
(2007/10/02)
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- SYNTHESIS OF METHYL 3-(N'-ALKYLUREIDO)-2-METHYL-2-PROPENOATES AND THEIR CYCLIZATION TO 3-ALKYL-5-METHYLURACILS
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Stereoisomeric methyl 3-(N'-alkylureido)-2-methyl-2-propenoates (Ia-Id) were prepared by acid-catalyzed reaction of N-alkylureas (R = methyl, benzyl, isopropyl and tert-butyl) with methyl 3-methoxy-2-methyl-2-propenoate (III).Reaction of the ester III with N-tert-butylthiourea afforded the thioureides (E)-Ie and (Z)-Ie.On treatment with sodium methoxide in methanol, compounds Ia-Ic cyclized to the corresponding 3-alkyl-5-methyluracils IIa-IIc whereas compounds Id and Ie underwent only a base catalyzed E/Z isomerization with (E)-isomers predominating.
- Ledvina, Miroslav,Farkas, Jiri
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p. 676 - 688
(2007/10/02)
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- Conformational Preferences in Alkylnitrosoureas
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The spectroscopic properties of several N-alkyl-N-nitrosoureas, N,N'-dialkyl-N-nitrosoureas, and N,N',N'-trialkyl-N-nitrosoureas have been studied in carbon disulfide and chloroform solutions.The NH stretching frequencies in the IR spectra have been observed in both concentrated and dilute solution and in the presence of added dioxane.The results indicate that there is a strong intramolecular hydrogen bond in the mono- and dialkylnitrosoureas.The chemical shifts and line widths of the NMR spectra have also been studied in these solvents.The large chemical shift differences, about 1.3 ppm, for the NH protons in the monoalkylnitrosoureas and other spectroscopic features in the monoalkyl- and dialkylnitrosoureas also indicate that an intramolecular hydrogen bond contributes to a strong conformational preference.The temperature dependence of the NMR spectra of several N,N',N'-trialkyl-N-nitrosoureas establishes that the energy barrier for rotation about the carbon dialkylamide bond is about 13 kcal mol-1.Dipolar resonance interactions are primarily responsible for this barrier.This interaction is augmented by a strong, 8-10 kcal mol-1, hydrogen bond in the mono- and dialkylnitrosoureas.
- Snyder, John K.,Stock, Leon M.
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p. 886 - 891
(2007/10/02)
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- Cyclization of peptides
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The invention disclosed herein relates to the novel method for the preparation of cyclic peptides, wherein a linear peptide is reacted, in solution in a polar organic solvent, with an insoluble, resin-bound carboxyl-activating reagent such as resin-bound isopropylcarbodiimide. Cyclic peptides thus obtained have been found to retain biological activity characteristic of their linear counterparts, with increased biostability; the cyclic peptide, Gramicidin S, which can be prepared by this method, is a valuable antibacterial.
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