- Synthesis of 5 H -Pyrrolo[3,4- b ]pyrazine-Based Peptidomimetics
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A range of 5H-pyrrolo[3,4-b]pyrazine-based peptidomimetics were designed, and their efficient synthesis starting from 5-imino-5H-pyrrolo[3,4-b]pyrazin-7-amine by subsequent interaction with N-protected amino acid hydrazides and amino acid esters with N,N-carbonyldiimidazole as the coupling agent was elaborated.
- Biitseva, Angelina V.,Rudenko, Igor V.,Hordiyenko, Olga V.,Omelchenko, Iryna V.,Arrault, Axelle
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- Unveiling the active isomer of cycloalanopine, a cyclic opine from: Lactobacillus rhamnosus LS8, through synthesis and analog production
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Opines are widely distributed natural products formed by the reductive condensation of amino acids with α-keto acids or carbonyls of carbohydrates. They have important biological roles in bacteria, higher plants, fungi, invertebrates and mammals, including humans. An unusual cyclic opine of undefined stereochemistry, cycloalanopine, was previously isolated from Lactobacillus rhamnosus LS8 and reported to have antimicrobial activity against both Gram-negative and Gram-positive bacteria. In this work, we report a three-step strategy to synthetically access pure isomers of this cyclic compound and analogs thereof. In the key step, acyclic bis-hydrazides can be oxidized with (diacetoxyiodo) benzene to corresponding cyclic N,N-diacylhydrazides. The three cycloalanopine isomers, along with several analogs, were synthesized and tested against a panel of Gram-positive and Gram-negative bacteria. We identified the active isomer as the meso compound: (4R,6S)-4,6-dimethyl-1,2,5-triazepan-3,7-dione. Additionally, a glycine derivative, (R)-4-methyl-1,2,5-triazepan-3,7-dione, was ascertained to be more potent. This compound was active against both Gram-positive and Gram-negative organisms with the strongest potency against Escherichia coli and Acinetobacter baumannii, an opportunistic pathogen found in hospital-derived infections.
- Antwi, Isaac,Chiorean, Sorina,Van Belkum, Marco J.,Vederas, John C.
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supporting information
p. 528 - 531
(2020/05/13)
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- Amino Acid Functionalized Organotin Trichlorides and Their Tin Sulfide Clusters
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We present a new synthesis of functionalized tin sulfide clusters via organotin trichlorides with boc-protected amino acids (RAAcSnCl3). In this work we used non-polar (alanine, valine, leucine, phenylalanine and methionine), polar/neutral (serine and tyrosine) and basic (histidine) amino acids. We obtained single crystals from a Boc-protected valine derivative of the originally used organotin trichloride R1SnCl3 [R1 = CMe2CH2C(O)Me] and determined its structure by means of X-ray diffraction. A subsequent reaction with sulfide sources led to a variety of respective cluster structures. By using either (Me3Si)2S or Na2S, the reaction product turns out to be the defect-heterocubane cluster [(RAAcSn)3S4Cl] or the “doppeldecker”-type cluster [(RAAcSn)4S6], respectively, according to 119Sn NMR spectroscopy.
- Engel, Annikka,Dehnen, Stefanie
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- 2,4,5-TRISUBSTITUTED 1,2,4-TRIAZOLONES USEFUL AS INHIBITORS OF DHODH
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The present invention provides triazolone compounds compounds of general formula (I) : in which R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.
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Page/Page column 251
(2018/05/24)
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- 1,3-THIAZOL-2-YL SUBSTITUTED BENZAMIDES
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The present invention relates to 1,3-thiazol-2-yl substituted benzamide compounds of general formula (I) as described and defined herein, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neurogenic disorder, as a sole agent or in combination with other active ingredients.
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- New tetrahydropyrido pyrimidinecarboxylic compound or salt thereof
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To provide a compound having an inhibitory activity for an androgen receptor. A tetrahydropyridopyrimidine compound represented by the following general formula (I) or a pharmaceutically acceptable thereof (in the formula, X and R are as defined in the specification).
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Paragraph 0248
(2016/10/08)
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- NOVEL PYRROLIDINE DERIVED BETA 3 ADRENERGIC RECEPTOR AGONISTS
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The present invention provides compounds of Formula (I), pharmaceutical compositions thereof, and method of using the same in the treatment or prevention of diseases mediated by the activation of β3-adrenoceptor.
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Page/Page column 65
(2015/04/22)
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- P2X3 AND/OR P2X2/3 COMPOUNDS AND METHODS
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The present application provides novel compounds and methods for preparing and using these compounds. In one embodiment, the compounds are of the structure of formula (I), wherein R1-R4 are defined herein. In a further embodiment, these compounds are useful in method for regulating one or both of the P2X3 or P2X2/3 receptors. In another embodiment, these compounds are useful for treating pain in patients by administering one or more of the compounds to a patient.
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Paragraph 0209; 0214; 0215
(2015/07/07)
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- 3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH
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The invention is directed to a formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are described herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant I DH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
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Page/Page column 42
(2014/09/29)
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- 3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH
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The invention is directed to a formula (I), or a pharmamceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
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Page/Page column 108; 109
(2014/09/29)
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- SGC STIMULATORS
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Compounds of Formulae (I') and (I) are described, which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.
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Paragraph 00274
(2014/09/29)
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- 3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH
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The invention is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-R6 are defined herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formual (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer
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Page/Page column 87
(2013/04/13)
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- Synthesis and Antitubercular Activity of Novel Amino Acid Derivatives
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In this work, 17 new N-acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. The compounds 8b, 8e, 8f, 9a-d, and 10c exhibited an important minimum inhibitory concentration activity between 12.5 and 50μg/mL, which can be compared with that of the tuberculostatic drug d-cycloserine (20μg/mL). In this work 17 new N-acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Eight compounds were non-cytotoxic and exhibited an important MIC activity between 12.5 and 50μg/mL, which can be compared with that of the tuberculostatic drug d-cycloserine (20μg/mL).
- Da Costa, Cristiane F.,Pinheiro, Alessandra C.,De Almeida, Mauro V.,Lourenco, Maria C.S.,De Souza, Marcus V.N.
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experimental part
p. 216 - 222
(2012/04/23)
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- Synthesis of α-hydrazino phosphonates from l-amino acid- and l-glutathione-derived hydrazones
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[Tetra(tert-butyl)phthalocyanine]aluminum chloride catalyzed hydrophosphorylation of cyclic ketone hydrazones, which were derived from hydrazides of l-amino acids and glutathione, resulted in polyfunctional α-hydrazino phosphonates.
- Matveeva,Kolesnikova,Zefirov
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experimental part
p. 248 - 253
(2011/11/05)
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- Design, synthesis and biological evaluation of a library of thiocarbazates and their activity as cysteine protease inhibitors
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Recently, we identified a novel class of potent cathepsin L inhibitors, characterized by a thiocarbazate warhead. Given the potential of these compounds to inhibit other cysteine proteases, we designed and synthesized a library of thiocarbazates containing diversity elements at three positions. Biological characterization of this library for activity against a panel of proteases indicated a significant preference for members of the papain family of cysteine proteases over serine, metallo-, and certain classes of cysteine proteases, such as caspases. Several potent inhibitors of cathepsin L and S were identified. The SAR data were employed in docking studies in an effort to understand the structural elements required for cathepsin S inhibition. This study provides the basis for the design of highly potent and selective inhibitors of the papain family of cysteine proteases.
- Liu, Zhuqing,Myers, Michael C.,Shah, Parag P.,Beavers, Mary Pat,Benedetti, Phillip A.,Diamond, Scott L.,Smith, Amos B.,Huryn, Donna M.
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experimental part
p. 337 - 351
(2010/09/04)
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- Antiviral Agents
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A compound of formula (I) and pharmaceutically acceptable salts thereof; compositions containing it and its use in medicine, particularly for the treatment or inhibition of HCV infections, and processes for making it are disclosed.
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Page/Page column 19
(2010/06/22)
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- Synthesis of GABAA receptor agonists and evaluation of their α-subunit selectivity and orientation in the GABA binding site
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Drugs used to treat various disorders target GABAA receptors. To develop α subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [3H]muscimol binding and in patch-clamp experiments with heterologously expressed GABAA αiβ 3γ2 receptors (i = 1-6). The effects of 5-aminomethyl-3H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all α subunit isoforms. 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-one 5a and 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-thione 6a were weak agonists at α2-, α3-, and α5-containing receptors. When coapplied with GABA, they were antagonistic in α2-, α4-, and α6-containing receptors and potentiated α3-containing receptors. 6a protected GABA binding site cysteine-substitution mutants α1F64C and α1S68C from reacting with methanethiosulfonate-ethylsulfonate. 6a specifically covalently modified the α1R66C thiol, in the GABA binding site, through its oxadiazolethione sulfur. These results demonstrate the feasibility of synthesizing α subtype selective GABA mimetic drugs.
- Jansen, Michaela,Rabe, Holger,Strehle, Axelle,Dieler, Sandra,Debus, Fabian,Dannhardt, Gerd,Akabas, Myles H.,Lüddens, Hartmut
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supporting information; experimental part
p. 4430 - 4448
(2009/06/06)
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- TRIAZOLE DERIVATIVE
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An object of the present invention is to provide a compound having an action of inhibiting binding between S1P and its receptor, Edg-1 (S1P1), and is useful as a pharmaceutical compound. A compound or a pharmaceutically acceptable salt thereof, which compound is represented by the formula below (where A represents an oxygen atom, a sulfur atom, a group represented by Formula -SO-, a group represented by Formula -SO2-, or the like, R1 represents a hydrogen atom, an alkyl group having 1-6 carbon atoms, or the like, R1A represents a hydrogen atom or the like, R2 represents an alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, or the like, R3 represents an aryl group, R4 represents a hydrogen atom or an alkyl group having 1-6 carbon atoms and optionally substituted with a carboxyl group, and R5 represents an alkyl group having 1-10 carbon atoms, a cycloalkyl group having 3-8 carbon atoms, an aryl group which is optionally substituted, or the like).
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Page/Page column 26-27
(2008/12/08)
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- CHEMICAL COMPOUNDS
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The invention relates to chemical compounds of formula (I) and (II) or pharmaceutically acceptable salts thereof, which possess Edg-1 antagonistic activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.
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Page/Page column 61-62
(2010/11/28)
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- TRIAZOLE DERIVATIVE
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A compound represented by the formula (I) below or a pharmaceutically acceptable salt thereof has an effect of inhibiting binding between S1P and its receptor Edg-1(S1P1), and is useful as a pharmaceutical product. (I) (In the formula, A represents a sulfur atom, an oxygen atom, a formula -SO- or a formula -SO2-; R1 represents a hydrogen atom, an alkyl group having 1-6 carbon atoms or the like; R2 represents an alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-8 carbon atoms or the like; R3 represents a hydrogen atom or an alkyl group having 1-6 carbon atoms; R4 represents a hydrogen atom, an alkyl group having 1-6 carbon atoms, a phenyl group or the like; R5 represents a hydrogen atom or an alkyl group having 1-6 carbon atoms; and R6 represents an alkyl group having 1-6 carbon atoms, a phenyl group or a substituted phenyl group.)
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Page/Page column 28-29
(2008/06/13)
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- Novel semicarbazide-derived inhibitors of human dipeptidyl peptidase I (hDPPI)
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Human dipeptidyl peptidase I (hDPPI, cathepsin C, EC 3.4.14.1) is a novel putative drug target for the treatment of inflammatory diseases. Using 1 as a starting point (IC50 > 10 μM), we have improved potency by more than 500-fold and successfully identified novel inhibitors of DPPI via screening of a one-bead-two-compounds library of semicarbazide derivatives. Selected compounds were shown to inhibit intracellular DPPI in RBL-2H3 cells. These compounds were further characterized for adverse effects on HepG2 cells (cytotoxicity and viability) and their metabolic stability in rat liver microsomes was estimated. One of the most potent inhibitors, 8 (IC50 = 31 ± 3 nM; Ki = 45 ± 2 nM, competitive inhibition), is selective for DPPI over other cysteine and serine proteases, has a half-life of 24 min in rat liver microsomes, shows approximately 50% inhibition of intracellular DPPI at 20 μM and is noncytotoxic.
- Bondebjerg, Jon,Fuglsang, Henrik,Valeur, Kirsten Rosendal,Kaznelson, Dorte Wissing,Hansen, Johnny Arnsdorf,Pedersen, Rene Orup,Krogh, Berit Olsen,Jensen, Bo Skaaning,Lauritzen, Conni,Petersen, Gitte,Pedersen, John,Naerum, Lars
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p. 4408 - 4424
(2007/10/03)
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- PROTEASE INHIBITORS
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A monoacyl semicarbazide of the general formula (I): (I), or a pharmaceutically acceptable salt or ester thereof, is capable of selectively inhibiting dipeptidyl-peptidase I (DPP-I), also known as cathepsin C. A compound of the invention is useful as an active substance for the treatment of inflammation, type 2 diabetes, asthma, severe influenza, respiratory syncytial virus infection, CD8 T cell inhibition, inflammatory bowel diseases, psoriasis, atopic dermatitis, Papillon Lefevre syndrome, Haim Munk syndrome, gum disease, periodontitis, rheumatoid arthritis, Huntington’s disease, Chaga’s disease, Alzheimer’s disease, sepsis or for application in target cell apoptosis.
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- Orally bioavailable small molecule ketoamide-based inhibitors of cathepsin K
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An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P1 and P 1′ elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors.
- Barrett, David G.,Catalano, John G.,Deaton, David N.,Long, Stacey T.,Miller, Larry R.,Tavares, Francis X.,Wells-Knecht, Kevin J.,Wright, Lois L.,Zhou, Hui-Qiang Q.
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p. 2543 - 2546
(2007/10/03)
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- New system for peptide synthesis using N-acylpyrazoles
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New system of peptide synthesis was described. The extension of one amino acid unit on the peptide chain was constituted from only 2 reaction steps, the conversion from esters to the corresponding N-acylpyrazoles and the subsequent aminolysis with amino esters. This new system was distinctive from the conventional peptide synthesis, which was consisted of 3 steps of the deprotection, the activation and the condensation. Moreover, the key intermediate N-acylpyrazoles exhibited the excellent properties of high sensitivity and separability for the chiral column on HPLC using the UV detector.
- Kashima, Choji,Tsuruoka, Shiro,Mizuhara, Saori
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p. 413 - 424
(2007/10/03)
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- Synthesis of 1,2,4-Oxadiazole-, 1,3,4-Oxadiazole-, and 1,2,4-Triazole-Derived Dipeptidomimetics
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Three series of heterocyclic dipeptidomimetics have been synthesized.The compounds were designed as amino acid-glycine mimetics containing 1,2,4-oxadiazole, 1,3,4-oxadiazole, and 1,2,4-triazole ring systems, useful as building blocks in the synthesis of m
- Borg, Susanna,Estenne-Bouhtou, Genevieve,Luthman, Kristina,Csoeregh, Ingeborg,Hesselink, Willy,Hacksell, Uli
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p. 3112 - 3120
(2007/10/02)
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- Hydantoin derivatives, salts thereof and maillard reaction inhibitors comprising the same
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There are described hydantoin derivatives of formula (I), salts and use thereof. The derivatives and salts show an inhibition to Maillard reaction of proteins in a living body, which reaction causes a modification of the protein. Some of the derivatives are novel.
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- p-AZOBENZENECARBOXAMIDOMETHYL ESTERS - NEW COLORED HYDROPHOBIC CARBOXYL PROTECTING GROUPS IN PEPTIDE SYNTHESIS
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p-Azobenzenecarboxamidomethyl esters (OAbc esters) of several α-amino acids have been synthesized and characterized.Their application in peptide chemistry as a colored alkali labile carboxyl protecting group was demonstrated.The esters are compatible with
- Zhuravlev, Valentin G.,Mazurov, Anatolii A.,Andronati, Sergei A.
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p. 1495 - 1504
(2007/10/02)
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- N-BENZHYDRYL-GLYCOLAMIDE ESTERS (OBg ESTERS) AS CARBOXYL PROTECTING GROUPS IN PEPTIDE SYNTHESIS
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N-benzhydryl-glycolamide esters (OBg esters) of various N-protected amino acids have been synthesized.In order to demonstrate their usefulness in peptide chemistry, the syntheses of For-Met-Leu-Phe-OH (chemiotactic peptide) and Pro-Leu-Gly-NH2 (MIF) have been carried out.OBg esters are compatible with commonly used protecting groups and are cleanly and selectively removed in mild alkaline conditions without any side reaction, except for β-benzyl aspartyl containing sequences.
- Amblard, Muriel,Rodriguez, Marc,Martinez, Jean
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p. 5101 - 5108
(2007/10/02)
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- PROTECTION OF THE CARBOXY GROUP IN THE FORM OF THE 2-CYANOETHYL ESTERS IN SYNTHESIS OF PEPTIDES
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With the aim of studying the suitability of the 2-cyano group for the protection of carboxylic functions in peptide synthesis, we have obtained the 2-cyanoethyl esters of a number of amino acids and have studied their behavior under the conditions of peptide synthesis.The synthesis of the pentapeptide leucine-enkephalin has been performed with the use of 2-cyanoethyl protection for C-terminal carboxy groups throughout.The physicochemical characteristics of the compounds synthesized are given.
- Kalashnikov, V. V.,Samukov, V. V.
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p. 351 - 354
(2007/10/02)
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