- Two birds with one stone: The detection of nerve agents and AChE activity with an ICT-ESIPT-based fluorescence sensor
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Nerve agents are among the world's deadliest poisons, and the target enzyme is acetylcholinesterase (AChE). To better diagnosis nerve agent poisonings, a reliable diagnostic method for both nerve agents and AChE is desirable. Herein, we synthesized a series of fluorescent sensors for both real nerve agents and acetylcholinesterase activity detection. Among these sensors, HBQ-AE exhibited a fast response rate (within 10 s for nerve agent and 8 min for AChE), good sensitivity (the limit of detection is 6 nM and 0.2 U/mL) and a high off/on contrast. To the best of our knowledge, HBQ-AE is the first fluorescence sensor for nerve agents and AChE activity detection. The fluorescent change of HBQ-AE from nonfluorescence to blue fluorescence (nerve agent) or orange fluorescence (AChE) by excitation at 365 nm can be easily observed with the naked eye. HBQ-AE was successfully applied to image nerve agents and AChE activity in living cells. Moreover, HBQ-AE is the vital member to construct a test paper that can be employed to detect and diagnose chemical warfare agents.
- Meng, Wenqi,Pei, Zhipeng,Wang, Yurun,Sun, Mingxue,Xu, Qingqiang,Cen, Jinfeng,Guo, Kai,Xiao, Kai,Li, Zhenjiang
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Read Online
- New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi
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An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.
- Bergé, Justine,Bonduelle, Colin,Boudot, Clotilde,Bourgeade-Delmas, Sandra,Boutet-Robinet, Elisa,Brossas, Jean-Yves,Corvaisier, Sophie,Courtioux, Bertrand,Deraeve, Céline,Destere, Alexandre,Fairlamb, Alan H.,Malzert-Fréon, Aurélie,Mazier, Dominique,Milne, Rachel,Paris, Luc,Pedron, Julien,Pinault, Emilie,Pratviel, Geneviève,Since, Marc,Sournia-Saquet, Alix,Stigliani, Jean-Luc,Tronnet, Antoine,Valentin, Alexis,Verhaeghe, Pierre,Wyllie, Susan
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Read Online
- UDP GLYCOSYLTRANSFERASE INHIBITORS AND METHODS OF USE
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Described herein is a compound of Formula (I), and pharmaceutically acceptable salts thereof. Also described herein are compositions and the use of such compositions in methods of treating a variety of diseases and conditions, in particular Krabbe's Disease (KD) and Metachromatic leukodystrophy (MLD).
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- REGIO-SELECTIVE SYNTHESIS OF IMIDAZO[1,2-A]PYRIMIDINES
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A method of regio-selectively synthesizing an imidazo-pyrimidine compound of formulae (XXa) or (XXb) comprising a step of coupling a first compound of formula XX-P1a or XX-P1b with a second compound of formula XX-P2. This annulation reaction between β-ethoxy acrylamides and phosphorylated aminoimidazoles to furnish imidazo[1,2-a]pyrimidin-amines relies on steering effects from endocyclic and exocyclic phosphorylated aminoimidazoles. The reaction furnishes either 2-amino or 4-amino constitutional isomers of imidazo[1,2-a]pyrimidines with good yields and ranges of 90:10 – 99:1 regio-selectivity. The reaction is useful in the synthesis of various tracer molecules used in the study of neurological conditions such as where R3 and R4 together with the imidazole ring atoms to which they are bonded form a phenyl ring and the products are substituted benzimidazopyrimidines. The reaction can be generalized to form imidazo[1,2-a]pyrimidines substituted at either of their 2- and 4- positions by alkoxy or thioalkyl groups.
- -
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Paragraph 0067; 0073; 0075
(2020/11/23)
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- Pyrimidine quinoline derivatives, and preparation method and applications thereof
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The invention discloses pyrimidine quinoline derivatives, a prodrug, and preparation method and applications thereof. The structure of the pyrimidine quinoline derivatives is represented by formula I, wherein R1 is used for representing hydrogen, C1-4 alkyl, C1-4 halogenated alkyl, C4-7 heterocyclic aryl, C4-7 substituted heterocyclic aryl, benzyl, or substituted benzyl, glycosyl, and amino acid; R2, R3, R4, and R5 are used for independently representing hydrogen, C1-4 alkyl, C1-4 alkyloxy, hydroxyl, amino, or substituted amino, C1-4 halogenated alkyl or halogen, glycosyl, and amino acid; R6 is used for representing substituted or non-substituted five-membered heterocycle, substituted or non-substituted six-membered heterocycle, substituted or non-substituted C8-12 fused heterocycle. The pyrimidine quinoline derivatives possess excellent inhibition effect on five kinds of cancer cells, the inhibition IC50 value of most compounds is lower than 20M, the IC50 value of a part of the compounds is even lower than 5M, the inhibition effect is extremely obvious, and the compounds can be prepared into anti-tumor drugs for applications.
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Paragraph 0159-0163
(2019/10/01)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
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Compounds of formula (I') and methods of their use and preparation, as well as compositions comprising compounds of formula (I').
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- Synthesis and antiviral evaluation of cyclopentyl nucleoside phosphonates
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The synthesis of both 2?-hydroxy-3?-deoxy and 2?-deoxy-3?-hydroxy cyclopentyl nucleoside phosphonates with the natural nucleobases adenine, thymine, cytosine and guanine from a single precursor has been performed. The guanine containing analogues showed antiviral activity. Especially the 3?-deoxy congener 23 was active, displaying an EC50 of 5.35 μM against TK+ VZV strain and an EC50 of 8.83 μM against TK? VZV strain, besides lacking cytotoxicity. However, the application of phosphonodiamidate prodrug strategy did not lead to a boost in antiviral activity.
- Wang, Mengmeng,Srivastava, Puneet,Liu, Chao,Snoeck, Robert,Andrei, Graciela,De Jonghe, Steven,Herdewijn, Piet
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p. 616 - 625
(2018/03/21)
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- HETEROCYCLIC COMPOUNDS USEFUL AS ANTI-BACTERIAL AGENTS AND METHOD FOR PRODUCTION THEREOF
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The present disclosure relates to compounds of Formula I, or their stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof, and pharmaceutical compositions containing them as the active ingredient which can be used as medicaments. The aforementioned substances can also be used in the manufacture of medicaments for treatment, prevention or suppression of diseases, and conditions mediated by microbes. The present disclosure also relates to the synthesis and characterization of aforementioned substances.
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Paragraph 000209
(2019/01/06)
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- BICYCLIC HETEROCYCLE DERIVATIVES AS BROMODOMAIN INHIBITORS
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The invention relates to novel bicyclic heterocycle derivatives of formula (I) wherein Cy1,Cy2, R1,R2 and L have the meaning given in the specification, and pharmaceutically acceptable salts thereof. The compounds of formula (I) are usefulas bromodomain inhibitors in the treatment or prevention of diseases or disorders where bromodomain inhibition is desired.
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- INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
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The present disclosure is directed to compounds of formula I and methods of their use and preparation, as well as compositions comprising compounds of formula I.
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- Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins
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The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral bioavailability.
- Igoe, Niall,Bayle, Elliott D.,Tallant, Cynthia,Fedorov, Oleg,Meier, Julia C.,Savitsky, Pavel,Rogers, Catherine,Morias, Yannick,Scholze, Sarah,Boyd, Helen,Cunoosamy, Danen,Andrews, David M.,Cheasty, Anne,Brennan, Paul E.,Müller, Susanne,Knapp, Stefan,Fish, Paul V.
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supporting information
p. 6998 - 7011
(2017/09/07)
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- High-affinity recognition of the human C-reactive protein independent of phosphocholine
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A high-affinity polypeptide conjugate 4-C25L22-DQ, has been developed for the molecular recognition of the human C-reactive protein, CRP, a well-known inflammation biomarker. CRP is one of the most frequently quantified targets in diagnostic applications and a target in drug development. With the exception of antibodies, most molecular constructs take advantage of the known affinity for CRP of phosphocholine that depends on Ca2+ for its ability to bind. 4-C25L22-DQ which is unrelated to phosphocholine binds in the absence of Ca2+ with a dissociation constant of 760 nM, an order of magnitude lower than that of phosphocholine, the KD of which is 5 μM. The small organic molecule 2-oxo-1,2-dihydroquinoline-8-carboxylic acid (DQ) was designed based on the structural similarities between three hits from a set of compounds selected from a building block collection and evaluated with regards to affinity for CRP by NMR spectroscopy. 4-C25L22-DQ was shown in a competition experiment to bind CRP three orders of magnitude more strongly than DQ itself, and in a pull-down experiment 4-C25L22-DQ was shown to extract CRP from human serum. The development of a robust and phosphocholine-independent recognition element provides unprecedented opportunities in bioanalytical applications in vivo and in vitro under conditions where the concentration of Ca2+ ions is low, or where Ca2+ binding agents such as EDTA or heparin are needed to prevent blood coagulation. The identification from a compound library of a small organic molecule and its conjugation to a small set of polypeptides, none of which were previously known to bind CRP, illustrates a convenient and general route to selective high-affinity binders for proteins with dissociation constants in the μM to nM range for which no small molecule ligands are known.
- Yang, Jie,Gustavsson, Anna-Lena,Haraldsson, Martin,Karlsson, G?ran,Norberg, Thomas,Baltzer, Lars
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supporting information
p. 4644 - 4654
(2017/07/10)
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- CRYSTALLINE FORMS OF N-(2-CHLORO-6-METHY]PHENVN-2-[F6-[4-(2-HVDROXVETHVL)-L- PIPERAZINVIL-2-METHVL-4-PVRIMIDINVLLAMINOL-5-THIAZOLECARBOXAMIDE AND THEIR PROCESS THEREOF
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The present invention relates to crystalline 1,2-Propanediol solvate of N-(2-chloro-6- methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]ainino]-5- thiazolecarboxamide compound of formula- lb, its process for the preparation and its use in the preparation of anhydrous crystalline form (N-6) and monohydrate of N-(2-chloro-6- methy lphenyl)-2- [ [6- [4-(2 -hydroxy ethyl)- 1 -piperazinyl] -2-methyl-4-pyrimidinyl]amino] -5 - thiazolecarboxamide. [formula] 1,2-Propanediol solvate Formula- lb
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Page/Page column 17; 18
(2017/01/26)
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- PROCESSES FOR THE PREPARATION OF IVACAFTOR
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The present invention provides processes for the preparation of ivacaftor using novel intermediates and a process for its preparation.
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Page/Page column 51
(2017/03/21)
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- BICYCLIC HETEROCYCLIC DERIVATIVES AS BROMODOMAIN INHIBITORS
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The present disclosure provides bicyclic heterocyclic derivatives of formula (I), which may be therapeutically useful, more particularly as bromodomain inhibitors; (I), in which R1, R2, R3, R4, L1, L2, Cy1, Cy2, X, n, and dotted line have the same meaning given in the specification, and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof that are useful in the treatment and prevention of diseases or disorders, in particular their use in diseases or disorders associated as bromodomain inhibitors. The present disclosure also provides preparation of compounds and pharmaceutical formulations comprising at least one of bicyclic heterocyclic derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent, or excipient.
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- ANTI-ANGIOGENESIS COMPOUND, INTERMEDIATE AND USE THEREOF
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Disclosed are an anti-abnormal proliferation of angiogenesis compound represented by formula I, use and intermediate thereof. The compound has good effect against abnormal proliferation of angiogenesis, and the activity of the compound is produced by inhibiting VEGFR2. The compound can be used for treating diseases, such as wet macular degeneration, inflammation, malignant tumor and the like, caused by abnormity of angiogenesis and protein kinases such as VEGFR2, FGFR2 and the like.
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Paragraph 0068; 0069
(2016/04/10)
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- TETRAZOLINONE COMPOUND AND USE THEREOF
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A tetrazolinone compound represented by formula (1): wherein Q represents a divalent 5-membred aromatic heterocyclic group optionally having one or more atoms or groups selected from Group P2; A represents a 5- to 10-membered monocyclic or fused ring heterocyclic group optionally having one or more atoms or groups selected from Group P1; R1 and R2 each represents a hydrogen atom, etc.; R3 represents a C1-C6 alkyl group optionally having one or more halogen atoms, etc.; R4, R5, and R6 each represents a hydrogen atom, etc.; and X represents an oxygen atom or a sulfur atom, has excellent control activity against pests.
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Paragraph 0642; 0643; 0644
(2016/07/27)
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- 2-Aminoxazole and 2-Aminothiazole Dasatinib Derivatives as Potent Inhibitors of Chronic Myeloid Leukemia K562 Cells
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Dasatinib is an important drug against chronic myeloid leukemia (CML). In this paper, we describe the preparation and anti-CML activity of 2-aminoxazole and 2-aminothiazole dasatinib derivatives. Biological activity was measured by the inhibition of proliferation of human CML K562 cells. The 2-aminoxazole derivatives had similar activities as the 2-aminothiazole derivatives. All newly synthesized compounds demonstrated more potent antiproliferative activity than imatinib. A few compounds (8b, 8c, 9b) showed nanomolar inhibitory activity, similar to that of dasatinib.
- Chai, Xing-Xing,Cai, Zhi-Ping,Yang, Mian-Tian,Zhou, Ying,Fu, Ying-Jun,Xiong, Yuan-Zhen
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p. 523 - 531
(2016/08/10)
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- Tetrazolinone compound and use thereof
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A tetrazolinone compound represented by formula (1) [wherein Q represents a bivalent 5-membered aromatic heterocyclic group which may have at least one atom or group selected from the group P2; A represents a 5- to 10-membered monocyclic or condensed-cyclic heterocyclic group which may have at least one atom or group selected from the group P1; R1 and R2 independently represent a hydrogen atom or the like; R3 represents a C1-C6 alkyl group which may have at least one halogen atom or the like; R4, R5 and R6 independently represent a hydrogen atom or the like; and X represents an oxygen atom or a sulfur atom] has an excellent controlling effect on harmful organisms.
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Paragraph 1087; 1088; 1089; 1090; 1091
(2016/10/08)
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- 2,3-dimethyl-6-urea -2H-indazoles and its preparation method and application
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The invention discloses a 2, 3-dimethyl-6-urea-2H-indazole compound shown by the following general formula (I), medicinal salt or a solvent compound thereof, wherein Ar is substituted or unsubstituted phenyl or aromatic matrix. The invention also discloses a preparation method and application of the compound. The compound can regulate signal transduction of tyrosine kinase, inhibit bad cellular proliferation, and particularly has obvious curative effect for tumors.
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Paragraph 0221-0224
(2016/10/09)
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- Six-membered c-n-linked aryl sulfide derivatives and aryl sulfoxide derivatives as pest control agents
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The present application relates to new heterocyclic compounds of formula (I), wherein D stands for a substructure of formula (I-A), a method for the production thereof and the use thereof for combatting animal pests, including arthropods and in particular insects and acarides.
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Paragraph 0677; 0678; 0681; 0682
(2016/10/08)
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- BICYCLIC HETEROCYCLIC DERIVATIVES AS BROMODOMAIN INHIBITORS
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The present invention provides bicyclic heterocyclic derivatives of formula (I), which may be therapeutically useful, more particularly as bromodomain inhibitors; (I), in which R1, R2, R3, R4, L1, L2, Cy1, Cy2, X, n and dotted line are have the same meaning given in the specification, and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated as bromodomain inhibitors. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of bicyclic heterocyclic derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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- ANTI-ANGIOGENESIS COMPOUND, INTERMEDIATE AND USE THEREOF
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Disclosed are an anti-abnormal proliferation of angiogenesis compound represented by formula I, use and intermediate thereof. The compound has good effect against abnormal proliferation of angiogenesis, and the activity of the compound is produced by inhibiting VEGFR2. The compound can be used for treating diseases, such as wet macular degeneration, inflammation, malignant tumor and the like, caused by abnormity of angiogenesis and protein kinases such as VEGFR2, FGFR2 and the like.
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Paragraph 0079-0082; 0140
(2016/11/02)
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- Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor
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Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl-aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13.
- Dziedzic, Pawel,Cisneros, José A.,Robertson, Michael J.,Hare, Alissa A.,Danford, Nadia E.,Baxter, Richard H. G.,Jorgensen, William L.
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supporting information
p. 2996 - 3003
(2015/03/18)
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- ANTHELMINTIC COMPOUNDS AND COMPOSITIONS AND METHOD OF USING THEREOF
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The present invention relates to novel anthelmintic compounds of formula (I) below: wherein Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X1, X2, X3, X4, X5, X6, X7 and X8 are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.
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Paragraph 0464; 0465
(2014/05/25)
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- TETRAZOLINONE COMPOUNDS AND ITS USE AS PESTICIDES
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The present invention provides a compound having an excellent efficacy for controlling pests. A tetrazolinone compound of a formula (1): [wherein R1 represents an C6-C16 aryl group, an C1-C12 alkyl group, or a C3-C12 cycloalkyl group, etc., which each optionally be substituted; R2, R3, R4 and R5 represent independently of each other a hydrogen atom, a halogen atom or an C1-C3 alkyl group, etc.; R6 represents an C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogen atom, a C1-C6 haloalkyl group, an C2-C6 alkenyl group, an C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, etc.; R7, R8 and R9 represent independently of each other a hydrogen atom, a halogen atom, or an C1-C4 alkyl group, etc.; X represents an oxygen atom or a sulfur atom; and R10 represents an C1-C6 alkyl group, etc.] shows an excellent controlling efficacy on pests.
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Page/Page column 970
(2013/11/18)
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- Design, synthesis and antiproliferative activity of 2-acetamidothiazole-5- carboxamide derivatives
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In order to develop a new series of dual inhibitors of SRC and ABL, and to investigate whether the pyrimidin-4-ylamino moiety is critical for dasatinib's activity, acetyl substitution was adopted as alternate scaffold at the 2-amino group. Eighteen novel dasatinib derivatives were developed by a parallel synthesis approach and evaluated for their antiproliferative effects. Preliminary tests showed that some of the target compounds IId, IIe and IIf manifested strong antiproliferative activity against MCF-7, MDA-MB 231 and HT-29 cells. Easpecially IId proved to be the most potent compound. Structure-activity relationship studies indicate that the introduction of acetyl substitution as alternate scaffold of pyrimidin-4-ylamino reduced the activity.
- Liu, Wukun,Zhou, Jinpei,Zheng, Yu,Qi, Fan,Zhang, Huibin,Qian, Hai,Wang, Jing,Cheng, Yanhua,Gust, Ronald
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scheme or table
p. 587 - 594
(2012/09/08)
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- The stability and reactivity of activated acryloylcarbamates as reagents for the synthesis of N-1 substituted thymine and uracil - An NMR and DFT study
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The mechanism of the decomposition of acryloylcarbamates 7a-b yielding highly reactive isocyanates 3a-b was proposed based on NMR measurements and quantum chemical calculations. A good agreement between the experimental kinetic data and DFT calculations allowed us to demonstrate that the stability of 7a-d depends on the presence of methyl in the acryloyl moiety and the position of the nitro group in the nitrophenolic part of the molecule. Furthermore, the reactivity of 7a-d with weakly nucleophilic and sterically hindered 2,4,6-tri-tert-butylaniline was explored by 1H NMR demonstrating the usefulness of reagents 7a-d offering access to a variety of 1-N-substituted uracils and thymines with potentially interesting biological properties. Copyright
- Pohl, Radek,Rulisek, Lubomir,Rejman, Dominik
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scheme or table
p. 423 - 430
(2011/11/14)
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- Synthesis and cytotoxicity of novel 2-amino-5-thiazolecarboxamide derivatives
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A series of novel 2-amino-5-thiazolecarboxamide derivatives have been designed and synthesised. All the compounds were evaluated for their antiproliferative activity against human leukaemia cancer HL 60 and K562 cell lines by standard MTT assay in vitro. Some of these compounds showed moderate cytotoxic potencies. Structure-activity relationships suggested that the piperazine moiety in the side chain of 2-amino-5-thiazolecarboxamide was associated with an increase in the cytotoxicity.
- Li, Hu,Yue, Yun,Hu, Xiao-Jun,Zhao, Sheng-Yin
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scheme or table
p. 416 - 419
(2011/10/08)
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- Total synthesis of (±)-streptonigrin: De novo construction of a pentasubstituted pyridine using ring-closing metathesis
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The synthesis of the potent antitumor agent (±)-streptonigrin has been achieved in 14 linear steps and 11% overall yield from ethyl glyoxalate. The synthesis features a challenging ring-closing metathesis reaction, followed by elimination and aromatization, to furnish a key pentasubstituted pyridine fragment.
- Donohoe, Timothy J.,Jones, Christopher R.,Barbosa, Luiz C. A.
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supporting information; experimental part
p. 16418 - 16421
(2011/11/29)
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- Synthesis and biological activities of 2-amino-thiazole-5-carboxylic acid phenylamide derivatives
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In an attempt to develop potent and selective anti-tumor drugs, a series of novel 2-amino-thiazole-5-carboxylic acid phenylamide derivatives were designed based on the structure of dasatinib. All compounds were synthesized by a systematic combinatorial chemical approach. Biological evaluation revealed that N-(2-chloro-6-methylphenyl)-2-(2-(4-methylpiperazin-1-yl)acetamido) thiazole-5-carboxamide (6d) exhibited high antiproliferative potency on human K563 leukemia cells comparable to dasatinib. Against mammary and colon carcinoma cells 6d was either inactive (MDA-MB 231) or distinctly less active (MCF-7 and HT-29: IC50=20.2 and 21.6μM, respectively). Dasatinib showed at each cell line IC501μM. The results of this structure activity relationship study clearly documented that the pyrimidin-4-ylamino core of dasatinib is responsible for the anti-tumor activity against non-leukemia cell lines.
- Liu, Wukun,Zhou, Jinpei,Qi, Fan,Bensdorf, Kerstin,Li, Zhiyu,Zhang, Huibin,Qian, Hai,Huang, Wenlong,Cai, Xueting,Cao, Peng,Wellner, Anja,Gust, Ronald
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experimental part
p. 451 - 458
(2012/02/01)
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- TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
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The present invention comprises inter alia compounds as shown in formula (I) or a pharmaceutically acceptable salt thereof.
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- GLUCAGON RECEPTOR ANTAGONISTS, COMPOSITIONS, AND METHODS FOR THEIR USE
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The present invention relates to compounds of general formula (I), wherein ring A, ring B, R1, R2, R3, Z, and L1 are selected independently of each other and are as defined herein, to compositions comprising the compounds, and methods of using the compounds as glucagon receptor antagonists and for the treatment or prevention of type 2 diabetes and conditions related thereto.
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Page/Page column 118-119
(2009/12/23)
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- TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
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The invention provides for Triazine derivatives and their use to modulate protein kinase activity in a variety of conditions and diseases.
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Page/Page column 53
(2008/12/06)
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- Synthesis of enantiomerically pure (S)-methanocarbaribo uracil nucleoside derivatives for use as antiviral agents and P2Y receptor ligands
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(Chemical Equation Presented) We have developed an approach toward enantiomerically pure (S)-methanocarba ribonucleosides based on several functional group transformations on a sensitive bicyclo[3.1.0]-hexane system. D-Ribose was transformed into methanocarba alcohol 3 followed by conversion of the OH group to a nitrile with inversion of configuration at C4. The nitrile group was subsequently reduced in two stages to the 5′-hydroxymethyl group. An ester group appended to a tertiary carbon (Cl) was transformed to an amino group as a nucleobase precursor.
- Melman, Artem,Zhong, Minghong,Marquez, Victor E.,Jacobson, Kenneth A.
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p. 8085 - 8088
(2008/12/22)
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- Thiazolinone 2-substituted quinolines
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Thiazolinone substituted quinoline derivatives where the quinoline ring is substituted at the 2 position which derivatives demonstrates CDK1 antiproliferative activity and are useful as anti-cancer agents.
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Page/Page column 9
(2010/10/20)
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- 2-(4-Alkylpiperazin-1-yl)quinolines as a new class of imidazole-free histamine H3 receptor antagonists
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With the aim of identifying structurally novel, centrally acting histamine H3 antagonists, a series of 2-(4-alkylpiperazin-1-yl)quinolines was prepared. Systematic variation of the substituents led to highly potent histamine H3 antagonists with low polar surface area and appropriate log P for blood-brain barrier penetration.
- Zaragoza, Florencio,Stephensen, Henrik,Peschke, Bernd,Rimvall, Karin
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p. 306 - 311
(2007/10/03)
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- Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity
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The highly potent, selective, and brain-penetrant metabotropic glutamate subtype 5 (mGlu5) receptor antagonists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl) benzonitrile (47) and 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are reported. Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED50 = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing.
- Roppe, Jeffrey,Smith, Nicholas D.,Huang, Dehua,Tehrani, Lida,Wang, Bowei,Anderson, Jeffrey,Brodkin, Jesse,Chung, Janice,Jiang, Xiaohui,King, Christopher,Munoz, Benito,Varney, Mark A.,Prasit, Petpiboon,Cosford, Nicholas D. P.
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p. 4645 - 4648
(2007/10/03)
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- Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
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The present invention relates to alkyne compounds of general formula I wherein the groups and residues A, B, W, X, Y, Z, R1 and R2 have the meanings given in claim 1. The invention further relates to pharmaceutical compositions containing at least one alkyne according to the invention. In view of their MCH-receptor antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, anorexia, hyperphagia and diabetes.
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- Method for producing 1-substituted 5-Hydroxypyrazoles
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The invention relates to a process for preparing 1-substituted 5- and/or 3-hydroxypyrazoles of the formulae I and II in which R1 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl or C1-C4-alkoxy, where these groups may be substituted by halogen, C1-C4-alkoxy, phenoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthiocarbonyl or by a cyclic ring system having 3-14 ring atoms, which comprises reactingan alkyl 3-alkoxyacrylate of the formula III in which R2, R3 independently of one another are C1-C6-alkyl or C3-C6-cycloalkyl with a hydrazine of the formula IV in which R1 is as defined abovea) at a pH of 6-11 to give 5-hydroxypyrazoles of the formula I orb) at a pH of 11-14 to give 3-hydroxypyrazoles of the formula II.
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- Method for the production of 1-substituted 5-hydroxypyrazoles
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The invention relates to a method for the production of 1-substituted 5-hydroxypyrazoles of formula (I) wherein R1is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl or C1-C4-alkoxy, whereby these groups can be substituted by halogen, C1-C4-alkoxy, phenoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthiocarbonyl or a cyclic ring system with 3-14 ring atoms, by reacting a) an alkylvinylether of general formula (III) wherein R2is C1-C6-alkyl or C3-C6-cycloalkyl, with phosgene (IVa), “diphosgene” (IVb) or “triphosgene” (IVc) to form acid chlorides of formula (V), b) transforming said acid chlorides by eliminating hydrogen chloride into the corresponding 3-alkoxyacrylic acid chloride of formula (VI) and c) reacting said acid chloride with hydrazines of formula (VII) wherein R1has the above cited meaning, to form 5-hydroxypyrazoles of formula (I).
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- A short, efficient synthesis of substituted uracil: An indane carbocyclic nucleoside
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(±)-cis-1-(3-Hydroxymethyl-1-indanyl)-1,2,3,4-tetrahy-dropyrimidine-2, 4-dione (1) was synthesised in two steps and with an overall yield of 51percent from (±)-cis-3-amino-1-indanylmethanol (4) and 3-ethoxy-2-propenoyl isocyanate (3). The isocyanate 3 was prepared in 76percent overall yield by reacting silver cyanate with 3-ethoxy-2-propenoyl chloride (2), which was obtained in one pot from ethyl vinyl ether and oxalyl chloride. The aminoalcohol (4) was prepared from phenylsuccinic anhydride in four steps.
- Ferna?ndez,Garci?a-Mera,Morales,Rodri?guez-Borges
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p. 239 - 242
(2007/10/03)
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- Synthesis of 6,6'-diamino-2,2'-biquinoline and 2,2'-bi-1,6- naphthyridine
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High-yield synthesis and characterization of the new heterocycles 6,6'- diamino-2,2'-biquinoline (3), 6,6'-bis(N,N-dimethyl-amino)-2,2'-biquinoline (4), and 2,2'-bi-1,6-naphthyridine (5) are described. The preparation of 3 and 4 is based on the coupling of 2-amino-6-chloroquinoline and 2-chloro-6- dimethylaminoquinoline in the presence of NiCl2·6H2O/PPh3/Zn in DMF (NiCRA). Compound 5 was synthesized through a condensation reaction of 4- aminopyridine-3-carbaldehyde and butane-2,3-dione.
- Janiak, Christoph,Deblon, Stephan,Uehlin, Lars
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p. 959 - 964
(2007/10/03)
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- Synthesis of Cyclopropyl-Fused Carbocyclic Nucleosides via the Regioselective Opening of Cyclic Sulfites
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The syntheses of some carbocyclic nucleosides that are conformationally locked as "northern" mimics of antiviral active, ring-expanded oxetanocin analogues are reported. The target compounds derived their rigid conformation from a common bicyclo[3.1.0]hexane template. The uracil (3a), cytosine (3b), and adenine (3c) analogues were synthesized from an intermediate cyclic sulfite (12a) that underwent selective ring opening with nucleophiles. Reaction of 12a with sodium azide provided access to the uracil and cytosine analogues (3a and 3b) after construction of the pyrimidine rings, and reaction with the sodium salt of adenine provided an efficient convergent approach to 3c. The preponderance of the undesired N-7 regioisomer obtained from the coupling of 12a with 2-amino-6-chloropurine was unanticipated. Hence, the diol derivative 11 was selectively protected and coupled under Mitsunobu conditions to give, after deprotection, the desired guanine analogue 3d. With the exception of the guanine analogue, the cyclic sulfite chemistry described here represents a useful alternative as a general approach to carbocyclic nucleosides. None of the target nucleosides 3a-d demonstrated significant antiviral activity against HIV-1, HSV-1, HSV-2, and HCMV. Relative to other conformationally rigid, northern carbocyclic analogues that have shown good anti-HSV and anti-HCMV activities, it is concluded that the hydroxymethyl group is a poor substitute for the hydroxyl group in these rigid bicyclic nucleoside templates.
- Moon, Hyung Ryong,Kim, Hea Ok,Chun, Moon Woo,Jeong, Lak Shin,Marquez, Victor E.
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p. 4733 - 4741
(2007/10/03)
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- Preparation of α,β-unsaturated β-oxycarboxylic acid chlorides
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A process for the preparation of α,β-unsaturated β-oxycarboxylic acid chlorides of the formula I STR1 where R1 is a C-organic radical, and R2 and R3, independently of one another, are hydrogen or a C-organic radical, comprises carrying out the addition reaction of an enol derivative of the formula II STR2 with a compound of the formula IIIa, IIIb or IIIc STR3 and converting the resultant acid chloride of the formula STR4 into I by elimination of hydrogen chloride (HCl).
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- Synthesis of racemic carbocyclic cyclopropanoid nucleoside analogues
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As further representatives of a novel class of carbocyclic nucleoside analogues (±)-cis- and (±)-trans-(2-hydroxymethylcyclopropyl)-uracil, -thymine, and -inosine were synthesized from the corresponding dialkyl 1,2-cyclopropane dicarboxylates.
- Csuk, Rene,Von Scholz, Yvonne
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p. 7193 - 7206
(2007/10/02)
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- Synthesis of isonucleosides related to AZT and AZU
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Approaches to 1,4-anhydro-3-azido-2,3-dideoxy-2-[3,4-dihydro-2,4-dioxo-5- methyl-1(2H)-pyrimidinyl]-D-arabinitol, and the related uracil derivative, have been developed. These conceptually new, optically active analogs of AZT, derived from 1,4-anhydro-D-ribitol, are among the first examples of regioisomeric analogs of AZT.
- Purdy,Zintek,Nair
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p. 109 - 126
(2007/10/02)
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- Electroorganic Synthesis, 56. Synthesis of Advanced Prostaglandin Precursors by Kolbe Electrolysis, I. - Preparation of (1'R,4'S,3R/S)-3-(cis-4-Acetoxycyclopent-2-enyloxy)-3-ethoxypropionic Acid
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The key intermediate of a novel synthesis of prostaglandin precursors, (1'R,4'S,3R/S)-3-(cis-4-acetoxycyclopent-2-enyloxy)-3-ethoxypropionic acid (3), is prepared by two different synthetic sequences: In a first strategy transacetalization of ethyl 3,3-diethoxypropionate (6) with (1R,4S)-4-acetoxy-1-hydroxy-2-cyclopentene (7) leads to the formation of the mixed acetal 8.By subsequent hydrolysis and acylation 8 could be converted into acid 3 in six steps in 6percent overall yield.However, the generation of acid 3 by bromoalkoxidation of 3-ethoxyacrylates 13d, e and subsequent electrochemical reduction proved to be more efficient.In this reduction it is possible to debrominate the α-bromo esters 14d, e and to remove the 2-haloethyl ester group in one step.Using this reaction sequence, we could synthesize acid 3 in five steps in 38percent overall yield. - Key Words: Kolbe electrolysis / Radical cyclization / Electrochemical dehalogenation / Prostaglandins
- Weiguny, Jens,Schaefer, Hans J.
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p. 225 - 234
(2007/10/02)
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- Improved synthesis of (E)-3-alkoxy- and (E)-3-phenoxyacryloyl chlorides
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A one-step preparation of (E)-3-alkoxy- and (E)-3-phenoxyacryloyl chlorides by reaction of vinyl ethers and oxalyl chloride with subsequent decarbonylation is presented.
- Tietze,Schneider,Pretor
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p. 1079 - 1080
(2007/10/02)
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