- Synthesis and morpholinolysis of N,N-diethyl carbamate derivatives of 4- HOAt, 7-HOAt and HOBt
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N,N-Diethyl carbamates of 1-hydroxy-7-azabenzotriazole (7-HOAt), 1-hydroxy-4-azabenzotriazole (4-HOAt), 1-hydroxybenzotriazole (HOBt), and 1-hydroxypyrrolidine-2,5-dione have been synthesised. The reactivities of these active esters have been determined by studying the kinetics and mechanism of their morpholinolysis in acetonitrile at different temperatures.
- Khattab, Sherine N.,Hassan, Seham Y.,Hamed, Ezzat A.,El-Faham, Ayman
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Read Online
- Unwanted hydrolysis or α/β-peptide bond formation: How long should the rate-limiting coupling step take?
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Nowadays, in Solid Phase Peptide Synthesis (SPPS), being either manual, automated, continuous flow or microwave-assisted, the reaction with various coupling reagents takes place via in situ active ester formation. In this study, the formation and stability of these key active esters were investigated with time-resolved 1H NMR by using the common PyBOP/DIEA and HOBt/DIC coupling reagents for both α- and β-amino acids. Parallel to the amide bond formation, the hydrolysis of the α/β-active esters, a side reaction that is a considerable efficacy limiting factor, was studied. Based on the chemical nature/constitution of the active esters, three amino acid categories were determined: (i) the rapidly hydrolyzing ones (t 24 h) in solution. The current insight into the kinetics of this key hydrolysis side reaction serves as a guide to optimize the coupling conditions of α- and β-amino acids, thereby saving time and minimizing the amounts of reagents and amino acids to be used-all key factors of more environmentally friendly chemistry.
- Goldschmidt G?z, Viktória,Nagy, Adrienn,Farkas, Viktor,Keszei, Ern?,Perczel, András
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p. 30720 - 30728
(2019/10/28)
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- Highly efficient one-pot assembly of peptides by double chemoselective coupling
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This study describes a methodological advancement in solution-phase peptide synthesis via the development of a convenient and operational protocol to synthesize oligopeptides in a one-pot three-step cascade method, in which two peptide bonds are introduced chemoselectively. Tri- to hexapeptides were obtained in high global yields (80-95%) with virtually no epimerization as determined via HPLC. The methodology described herein represents a faster, easier and milder approach to the synthesis of peptides, and it operates at equimolar amounts. This protocol comprises the formation of secondary and tertiary amides and is compatible with Z, Boc and Fmoc N-protecting groups as well as the use of d/l and non-proteinogenic amino acids.
- Sampaio-Dias, Ivo E.,Sousa, Carlos A. D.,Silva-Reis, Sara C.,Ribeiro, Sara,García-Mera, Xerardo,Rodríguez-Borges, José E.
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supporting information
p. 7533 - 7542
(2017/09/27)
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- N-aryl benzotriazole type nitrogen oxygen derivative and synthesis method thereof
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The invention discloses an N-aryl benzotriazole type nitrogen oxygen derivative and a synthesis method thereof. The N-aryl benzotriazole type nitrogen oxygen derivative has the structure shown by the formula (I), the preparation method comprises the steps that an N-hydroxybenzotriazole derivative of the structure shown by the formula (II), an organo-boron reagent of the structure shown by the formula (III), cupric salt and an alkaline matter are taken and placed into an organic solvent, reaction is performed under the condition of oxygen, and a target crude product is prepared. The method is easy to control, and the period is short; the prepared crude product has excellent antineoplastic activity. The compounds of the structures shown by the formula (I), the formula (II) and the formula (III) are as below respectively. (Please see the chemical formulas in the description.).
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Paragraph 0040-0042
(2016/11/24)
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- ULTRAVIOLET RADIATION ABSORBING POLYETHERS
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A polymer composition comprising a linear ultraviolet radiation absorbing polyether that comprises a chemically bound UV-chromophore.
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Page/Page column
(2014/02/15)
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- Importance of π-stacking interactions in the hydrogen atom transfer reactions from activated phenols to short-lived N-oxyl radicals
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A kinetic study of the hydrogen atom transfer from activated phenols (2,6-dimethyl- and 2,6-di-tert-butyl-4-substituted phenols, 2,2,5,7,8- pentamethylchroman-6-ol, caffeic acid, and (+)-cathechin) to a series of N-oxyl radical (4-substituted phthalimide-N-oxyl radicals (4-X-PINO), 6-substituted benzotriazole-N-oxyl radicals (6-Y-BTNO), 3-quinazolin-4-one-N-oxyl radical (QONO), and 3-benzotriazin-4-one-N-oxyl radical (BONO)), was carried out by laser flash photolysis in CH3CN. A significant effect of the N-oxyl radical structure on the hydrogen transfer rate constants (kH) was observed with kH values that monotonically increase with increasing NO-H bond dissociation energy (BDENO-H) of the N-hydroxylamines. The analysis of the kinetic data coupled to the results of theoretical calculations indicates that these reactions proceed by a hydrogen atom transfer (HAT) mechanism where the N-oxyl radical and the phenolic aromatic rings adopt a π-stacked arrangement. Theoretical calculations also showed pronounced structural effects of the N-oxyl radicals on the charge transfer occurring in the π-stacked conformation. Comparison of the kH values measured in this study with those previously reported for hydrogen atom transfer to the cumylperoxyl radical indicates that 6-CH3-BTNO is the best N-oxyl radical to be used as a model for evaluating the radical scavenging ability of phenolic antioxidants.
- Mazzonna, Marco,Bietti, Massimo,Dilabio, Gino A.,Lanzalunga, Osvaldo,Salamone, Michela
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p. 5209 - 5218
(2014/06/23)
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- One-step radiosynthesis of 4-nitrophenyl 2-[18F]fluoropropionate ([18F]NFP); Improved preparation of radiolabeled peptides for PET imaging
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The versatile 18F-labeled prosthetic group, 4-nitrophenyl 2-[18F]fluoropropionate ([18F]NFP), was synthesized in a single step in 45 min from 4-nitrophenyl 2-bromopropionate, with a decay corrected radiochemical yield of 26.2% ± 2.2%. Employing this improved synthesis of [18F]NFP, [18F]GalactoRGD - the current 'gold standard' tracer for imaging the expression of αVβ 3 integrin - was prepared with high specific activity in 90 min and 20% decay corrected radiochemical yield from [18F]fluoride. 4-Nitrophenyl 2-[18F]fluoropropionate ([18F]NFP), was synthesized in a single radiochemical step in 45 minutes and 26% d.c. radiochemical yield from 4-nitrophenyl 2-bromopropionate. Employing this improved synthesis of [18F]NFP, [18F]GalactoRGD was prepared with high specific activity in 90 minutes and 20% d.c. radiochemical yield from [18F]fluoride. Copyright
- Haskali, Mohammad B.,Roselt, Peter D.,Karas, John A.,Noonan, Wayne,Wichmann, Christian W.,Katsifis, Andrew,Hicks, Rodney J.,Hutton, Craig A.
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p. 726 - 730
(2014/01/06)
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- METHOD FOR THE MANUFACTURE OF DEGARELIX
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In a step-wise synthesis of degarelix comprising 0.3% by weight or less of 4-([2(5-hydantoyl)]acetylamino)-phenylalanine analog on (solid support)-NH2 a step comprises providing a solution of an amino acid or peptide of which the α-amino group is protected by Fmoc; contacting the support with the solution in the presence of reagent for forming a peptide bond between a carboxyl group of the amino acid or peptide and (solid support)-NH2; removing Fmoc by contacting the support with an organic base, in particular piperidine, in an organic solvent. Also disclosed is degarelix of high purity prepared by the method of the invention and the use of Fmoc in the synthesis of degarelix.
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- Spectrophotometric determination of pKa's of 1-Hydroxybenzotriazole and oxime derivatives in 95% acetonitrile-water
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1-hydroxybenzotriazole derivatives are used with carbodiimide as additives to generate active esters during peptide bond formation. They are also used as additives during the peptide bond formation. Dissociation constants of the 1-hdroxybenzotriazole (HOBt) and its derivatives, 1- hydroxy-6- chlorobenzotriazole, 1-hydroxy-6-trifluoromethylbenzotriazole, 1-hydroxy-6-nitrobenzotriazole were determined spectrophotometrically in 95% acetonitrile-water. In addition, 7-aza-1- hydroxybenzotriazole (7-HOAt) and 4-aza-1-hydroxybenzotriazole (4-HOAt) were also studied. Recently, oxyma was reported as a good replacement for the benzotriazole derivatives. As alcoholic components of active esters, the oximes seem to be good leaving groups. Therefore it was expected, that the strongly acidic and nucleophilic oximes, which possess electron-withdrawing groups in the molecule, are suitable as additives during the peptide bond formation. The dissociation constant of some oximes,such as diethyl 2-(hydroxyimino)malonate, ethyl 2-cyano-2-(hydroxyimino) acetate (oxyma), hydroxycarbonimidoyl dicyanide and N-hydroxypicolinimidoyl cyanide in 95% acetonitrile-water are reported.
- Fathalla, Magda Fouad,Khattab, Sherine Nabil
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experimental part
p. 324 - 332
(2012/05/04)
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- Discovery of 1H-benzo[d][1,2,3]triazol-1-yl 3,4,5-trimethoxybenzoate as a potential antiproliferative agent by inhibiting histone deacetylase
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Twenty-one benzotriazoles (3-16 and 18-24) were synthesized and half of them (5, 8-16, 20, and 21) were reported for the first time. Their antiproliferative activities against three human cancer cells were assayed. It revealed that 1H-benzo[d][1,2,3]triazol-1-yl 3,4,5-trimethoxybenzoate (9) showed considerable activity against three human cancer cell lines with the half maximal inhibitory concentration (IC50) values of 1.2-2.4 nM, which were close to the value of the positive control, doxorubicin. Further investigation indicated compound 9 was a potential histone deacetylase inhibitor (IC50 = 9.4 μM) and its binding mode was simulated using docking method.
- Fu, Jie,Yang, Ying,Zhang, Xue-Wei,Mao, Wen-Jun,Zhang, Zhi-Ming,Zhu, Hai-Liang
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experimental part
p. 8457 - 8462
(2011/02/26)
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- Synthesis and aminolysis of N,N-diethyl carbamic ester of HOBt derivatives
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The reaction of N,N-diethyl carbamates of 1H-[1,2,3]triazolo[4,5-b]pyridin- 1-ol (4-HOAt) 7, 3H-[1,2,3]triazolo[4,5- b]pyridin-3-ol (7-HOAt) 8, 1H-benzo[d][1,2,3]triazol-1-ol (HOBt) 9, 6-chloro-1H-benzo[d][1,2,3]triazol-1-ol (Cl- HOBt) 10, 6-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-1-ol (CF3 3-HOBt) 11, and 6-nitro-1H-benzo[d][1,2,3]triazol- 1-ol (NO2 2-HOBt) 12 with morpholine and piperidine in CH3CN underwent acyl nucleophilic substitution to give the corresponding carboxamide derivatives. The reactants and products were identified by elemental analysis, IR and NMR. We measured the kinetics of these reactions spectrophotometrically in CH3 3CN at a range of temperatures. The rates of morpholinolysis and piperidinolysis were found to fit the Hammett equation and correlated with s-Hammett values. The values were 1.44 - 1.21 for morpholinolysis and 1.95 - 1.72 for piperidinolysis depending on the temperature. The Bronsted-type plot was linear with a βlg = -0.49 ± 0.02 and -0.67 ± 0.03. The kinetic data and structure-reactivity relationships indicate that the reaction of 9-12 with amines proceeds by a concerted mechanism. The deviation from linearity of the correlation ?H# vs. ?S# and plot of logkpip vs. logkmorph and Bronsted-type correlation indicate that the reactions of amines with carbamates 7 and 8 is attributed to the electronic nature of their leaving groups.
- Khattab, Sherine Nabil,Hassan, Seham Yassin,Hamed, Ezzat Awad,Albericio, Fernando,Ayman, El-Faham
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experimental part
p. 75 - 81
(2010/07/15)
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- PEPTIDE COMPOUND AND USE THEREOF
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The present invention provides a method for the prophylaxis or treatment of cancer in a mammal, comprising administering a therapeutically effective amount of CBP501, a prodrug thereof or a pharmaceutically acceptable salt thereof to the mammal, wherein CBP501, a prodrug thereof or a pharmaceutically acceptable salt thereof is administered simultaneously with or before administration of a nucleic acid damaging agent.
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- Nucleophilic iron catalysis in transesterifications: Scope and limitations
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Figure presented The ester bond is one of the most common structural motifs found in nature. Apart from the condensation between an acid and an alcohol, transesterifications represent another mechanistic alternative for the preparation of this compound class. The present paper summarizes our most recent investigations in this field, using nucleophilic iron complexes as catalysts for transesterifications under neutral conditions. This new type of metal catalyst complements the existing methodologies, which rely on Lewis acidic metal complexes. Investigations on scope and limitations, stereochemical course, and chemoselectivities will be presented.
- Magens, Silja,Plietker, Bernd
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supporting information; experimental part
p. 3715 - 3721
(2010/08/07)
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- PROCESS FOR THE PRODUCTION OF INTERMEDIATES FOR THE PREPARATION OF TRICYCLIC IMIDAZOPYRIDINES
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The invention relates to a process for the synthesis of compounds of the formula (1-a) and compounds of the formula (1-b). The compounds of the formula 1-a and the compounds of the formula 1-b, in which the substituents R1, R2, R3, and Arom have the meanings indicated in the description, are valuable intermediates for the preparation of pharmaceutically active compounds.
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Page/Page column 67
(2010/11/29)
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- Antiinflammatory and antinociceptive activities of some benzotriazolylalkanoic acids.
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Sets of benzotriazol-1/2-ylalkanoic acids (1, 2, 3) and benzotriazol-1-yloxyalkanoic acids (4, 5) were prepared and tested for antiinflammatory activity; when significant activity was observed also the antinociceptive activity was explored. While the acids of structure 1, 4 and 5 were devoid of antiinflammatory action, most 2-(benzotriazol-1/2-yl)propionic acids (2, 3) exhibited significant activity as antiinflammatory and antinociceptive agents, with compound 2c and 3a being the most active in the two assays, respectively. The dextrorotatory enantiomer of 2c ((+)-2c) was also prepared and found to be practically as active as the racemic mixture, though some differences in the steepness of the dose-response curves were observed.
- Boido, Alessandro,Vazzana, Iana,Mattioli, Francesca,Sparatore, Fabio
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- Isoquinoline derivatives and isoquinoline combinatorial libraries
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The present invention provides the synthesis of heterocyclic compounds based on the isoquinoline ring. More specifically, the invention provides novel isoquinoline derivatives as well as novel libraries comprised of such compounds.
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- STAUROSPORIN DERIVATIVES
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The present invention provides an antitumor agent comprising a staurosporin derivative or a pharmaceutically acceptable salt thereof, as an active ingredient, which is represented by the general formula (I): wherein R1 represents hydrogen, hydroxy or lower alkoxy, R2 and R3 are the same or different and represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, halogen, nitro, formyl, etc., R4 represents hydrogen; etc., R5 represents NR11AR12A (wherein R11A and R12A represent hydrogen, substituted or unsubstituted lower alkyl, etc.), provided that R2 and R3 are not simultaneously hydrogen.
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- Novel stabilized activated derivatives of carbamic acid, their process of preparation and their use for the preparation of ureas
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Process for the preparation of stable activated derivatives of carbamic acid, comprising at least one protected amino group and an activated carbamic acid function, from an amino acid derivative in which the amino group is protected. The process includes: a) a step of transformation of the —COOH group of the amino acid derivative into a —CON3 group to obtain an acyl azide; b) a step of transformation of the —CON3 group of the acyl azide into a —NCO group to obtain an isocyanate; c) a step of treating the isocyanate to obtain a stable derivative of carbamic acid.
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- Cyclic AMP-specific phosphodiesterase inhibitors
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Novel pyrrolidine compounds that are potent and selective inhibitors of PDE4, as well as methods of making the same, are disclosed. Use of the compounds in the treatment of inflammatory diseases and other diseases involving elevated levels of cytokines, as well as central nervous system (CNS) disorders, also is disclosed.
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- Treatment of congestive heart failure with growth hormone secretagogues
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The present invention is directed to methods for the modulation of cardiac function which comprise the administration of certain compounds, as defined herein, having growth hormone secretagogue activity.
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- Comparison of the effects of 5- and 6-HOAt on model peptide coupling reactions relative to the cases for the 4- and 7-isomers
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(equation presented) Synthesis of 5- and 6-HOAt has completed the full set of the four HOAt isomers derived from HOBt by insertion of a single nitrogen atom in the benzenoid nucleus. Comparison of the reactivity of all four isomers in model peptide coupling reactions has confirmed the unique character of the 7-isomer in promoting selectivity and maintaining configuration at the reactive carboxylic acid residue.
- Carpino, Louis A.,Imazumi, Hideko,Foxman, Bruce M.,Vela, Michael J.,Henklein, Peter,El-Faham, Ayman,Klose, Jana,Bienert, Michael
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p. 2253 - 2256
(2007/10/03)
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- Sulphonamide derivatives
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The present invention relates to the potentiation of glutamate receptor function using certain sulphonamide derivatives. It also relates to novel sulphonamide derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
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- Non-explosive preparations of 1-hydroxybenzotriazole
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Preparations consisting of 5 to 90%, relative to the total weight of the preparations, of mainly neutralized 1-hydroxy-benzotriazole of the formula STR1 in which R1 and R2, independently of one another, represent hydrogen or methyl and M≈ is one equivalent of an alkali metal or alkaline earth metal cation or H≈, whereby M≈ is present in the range of 85-100 equivalent-% as alkali metal or alkaline earth metal cation and in the range of 15-0 equivalent-% as H≈, and the remainder to 100% of water, whereby the water containing preparations have a pH value of from 3 to 11 are nonexplosive and can be handled without danger. For the preparation, unsubstituted 1-hydroxy-benzotriazole is neutralized with an aqueous solution or suspension of a hydroxide, bicarbonate or carbonate of an alkali metal or alkaline earth metal. These preparations may be present as solutions, suspensions or pastes.
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- Inhibitors of peptide binding to MHC class II proteins
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Compounds of the formula STR1 are inhibitors of peptide binding to major histocompatibility complex type II proteins and may be used in the treatment and prevention of autoimmune diseases including: rheumatoid arthritis, Type I diabetes, multiple sclerosis, lupus erythematosis, Graves disease and pemphigus. The present invention also provides novel compositions, methods of treatment employing compounds of the present invention and methods of manufacture of the compounds of structural formula (I).
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- 4-HYDROXY-BENZOPYRAN-2-ONES AND 4-HYDROXY-CYCLOALKYL[B]PYRAN-2-ONES USEFUL TO TREAT RETROVIRAL INFECTIONS
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The present invention relates to compounds of formula I which are 4-hydroxy-benzopyran-2-ones and 4-hydroxy-cycloalkyl[b]pyran-2-ones useful for inhibiting a retrovirus in a mammalian cell infected with said retrovirus. STR1 Wherein R 10 and R 20 taken together are: STR2
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- Benzo-fused lactams promote release of growth hormone
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There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused lactams as the active ingredient therefore are also disclosed.
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- CYCLIC HEXAPEPTIDE OXYTOCIN ANTAGONISTS
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Disclosed are cyclic hexapeptides of the formula: STR1 These compounds are antagonists of oxytocin and are useful in the treatment of preterm labor and dysmenorrhea, and for stoppage of labor prepatory to Caesarian delivery. Also disclosed are pharmaceutical compositions containing the compounds of formula I and methods of preparing these compounds.
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- Synthesis of Oligoribonucleotides by the Hydroxybenzotriazole-Activated Phosphotriester/Dicyclohexylcarbodiimide System
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Addition of dicyclohexylcarbodiimide stabilized the benzotriazole-activated phosphotriester intermediates in which were used oligoribonucleotide synthesis.By this system, two oligoribonucleotides, r(CGAAAGC) and r(GCGAAAGC), were synthesized for structural comparison with d(GCGAAAGC) whose structure was unusually stable.Electrophoretic experiments showed r(GCGAAAGC) to behave differently from d(GCGAAAGC), although each had the same base sequence.
- Hirao, Ichiro,Miura, Kin-ichiro
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p. 1799 - 1802
(2007/10/02)
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- β-Lactam antibiotics and compositions containing the same
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β-Lactam antibiotics of the formula STR1 in which A is a hydrogen atom, an optionally substituted alkyl, alkenyl, alkinyl or cycloalkyl group, a substituted or unsubstituted phenyl ring, a polycyclic aromatic ring or an optionally substituted heterocyclic 5-membered or 6-membered ring with 1 to 4 hetero-atoms, Y is STR2 X is a sulphur or oxygen atom, T is an organic radical, and Z is a hydrogen atom or a C1 to C6 alkoxy group, or an ester or salt thereof.
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- Synthetically modified trypsin inhibitors and process for preparing them
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Modified trypsin-callicrein inhibitor wherein the five carboxyl groups present in the unmodified material are amidated by--(R)(R) X W groups,Wherein R is prolyl or EQU1 X is an integer from 1 to 10, Y is hydrogen, alkyl, or substituted alkyl and W is --OH, --NH 2, --NHC 2 H 5, --OCH 3, or --OC 2 H 5. Method for making trypsin-callicrein inhibitor so modified by amidation.
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