- Catalyst-free synthesis of substituted pyridin-2-yl, quinolin-2-yl, and isoquinolin-1-yl carbamates from the corresponding hetaryl ureas and alcohols
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A novel catalyst-free synthesis ofN-pyridin-2-yl,N-quinolin-2-yl, andN-isoquinolin-1-yl carbamates utilizes easily accessibleN-hetaryl ureas and alcohols. The proposed environmentally friendly technique is suitable for the good-to-high yielding synthesis of a wide range ofN-pyridin-2-yl orN-quinolin-2-yl substituted carbamates featuring electron-donating and electron-withdrawing groups in the azine rings and containing various primary, secondary, and even tertiary alkyl substituents at the oxygen atom (48-94%; 31 examples). The DFT calculation and experimental study showed that the reaction proceeds through the intermediate formation of hetaryl isocyanates. The method can be applied to obtainN-isoquinolin-1-yl carbamates, although in lower yields, and ethyl benzo[h]quinolin-2-yl carbamate has also been successfully synthesized (68%).
- Baykov, Sergey V.,Boyarskaya, Irina A.,Boyarskiy, Vadim P.,Geyl, Kirill K.,Kasatkina, Svetlana O.
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p. 6059 - 6065
(2021/07/21)
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- Mesoionic insecticide
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The invention relates to a mesoionic compound. Specifically, the present invention relates to a mesoionic compound represented by formula (I) or a stereoisomer, a nitrogen oxide and a salt thereof ofthe mesoionic compound represented by formula (I), and a process for the preparation of mesoionic compounds, and their use as insecticides in agriculture, and their forms of insecticide compositions,as well as methods of controlling pests with these compounds or compositions; wherein R1, R2, R3, R4, R5, Ra, Rb, Rc, Rd, n, R6 and R7 have the meanings described in the invention.
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Paragraph 0161-0164
(2020/09/16)
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- 2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: Limitations and pitfalls of the photoswitchable inhibitor approach
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In photopharmacology, photoswitchable compounds including azobenzene or other diarylazo moieties exhibit bioactivity against a target protein typically in the slender E-configuration, whereas the rather bulky Z-configuration usually is pharmacologically less potent. Herein we report the design, synthesis and photochemical/inhibitory characterization of new photoswitchable kinase inhibitors targeting p38α MAPK and CK1δ. A well characterized inhibitor scaffold was used to attach arylazo- and diazocine moieties. When the isolated isomers, or the photostationary state (PSS) of isomers, were tested in commonly used in vitro kinase assays, however, only small differences in activity were observed. X-ray analyses of ligand-bound p38α MAPK and CK1δ complexes revealed dynamic conformational adaptations of the protein with respect to both isomers. More importantly, irreversible reduction of the azo group to the corresponding hydrazine was observed. Independent experiments revealed that reducing agents such as DTT (dithiothreitol) and GSH (glutathione) that are typically used for protein stabilization in biological assays were responsible. Two further sources of error are the concentration dependence of the E-Z-switching efficiency and artefacts due to incomplete exclusion of light during testing. Our findings may also apply to a number of previously investigated azobenzene-based photoswitchable inhibitors.
- Schehr, Miriam,Ianes, Chiara,Weisner, J?rn,Heintze, Linda,Müller, Matthias P.,Pichlo, Christian,Charl, Julia,Brunstein, Elena,Ewert, Julia,Lehr, Marc,Baumann, Ulrich,Rauh, Daniel,Knippschild, Uwe,Peifer, Christian,Herges, Rainer
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p. 1398 - 1407
(2019/06/19)
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- Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region
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Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative t
- Ngo, Van T.H.,Hoang, Van-Hai,Tran, Phuong-Thao,Ann, Jihyae,Cui, Minghua,Park, Gyungseo,Choi, Sun,Lee, Jiyoun,Kim, Hee,Ha, Hee-Jin,Choi, Kwanghyun,Kim, Young-Ho,Lee, Jeewoo
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supporting information
p. 1035 - 1049
(2018/02/12)
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- HETEROARYL RHEB INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same. Compositions comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in compositions of this invention is such that it is effective to measurably inhibit Rheb, in a biological sample or in a patient.
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Paragraph 00687
(2018/11/10)
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- Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer’s Agents Based on Rational Design
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Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of β-amyloid peptides (pGlu-Aβ) and thus may participate in the pathogenesis of Alzheimer’s disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aβ3E?42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aβ and total Aβ and restored cognitive functions. This potent Aβ-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.
- Hoang, Van-Hai,Tran, Phuong-Thao,Cui, Minghua,Ngo, Van T. H.,Ann, Jihyae,Park, Jongmi,Lee, Jiyoun,Choi, Kwanghyun,Cho, Hanyang,Kim, Hee,Ha, Hee-Jin,Hong, Hyun-Seok,Choi, Sun,Kim, Young-Ho,Lee, Jeewoo
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supporting information
p. 2573 - 2590
(2017/04/03)
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- KINASE MODULATORS FOR THE TREATMENT OF CANCER
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A method of treating cancer in which a compound that inhibits the expression, production or release of IL-10 by immune cells is combined with a compound that stimulates the production of IL-12 when given in combination with, or in the presence of TNFa. Sa
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Paragraph 0232; 0233
(2017/11/16)
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- Optimized 4,5-diarylimidazoles as potent/selective inhibitors of Protein Kinase CK1δ and their structural relation to P38α MAPK
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The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effecti
- Halekotte, Jakob,Witt, Lydia,Ianes, Chiara,Krüger, Marc,Bührmann, Mike,Rauh, Daniel,Pichlo, Christian,Brunstein, Elena,Luxenburger, Andreas,Baumann, Ulrich,Knippschild, Uwe,Bischof, Joachim,Peifer, Christian,Koch, Pierre,Laufer, Stefan
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supporting information
(2017/04/03)
-
- Design, synthesis, and evaluation of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives as Aurora kinase inhibitors
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A series of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives were designed, synthesized, and evaluated for the Aurora kinase inhibitory activities. The novel hinge-binder tethered 1,2,3-triazolylsalicylamide scaffold was effectively assembled by Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). A variety of alkynes with hinge binders were used to search proper structures-binding relationship to the hinge region. The synthesized 1,2,3-triazolylsalicylamide derivatives showed significant Aurora kinase inhibitory activity. In particular, 8a inhibited Aurora A kinase with an IC50 value of 0.284 μM, whereas 8m inhibited Aurora B kinase with an IC50 value of 0.364 μM.
- Jeong, Yunkyung,Lee, Jooyeon,Ryu, Jae-Sang
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supporting information
p. 2114 - 2124
(2016/04/20)
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- The discovery of new cytotoxic pyrazolopyridine derivatives
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A number of new 3,7-disubstituted pyrazolo[3,4-c]pyridines have been designed and synthesized from suitable 2-aminopyridines. The antiproliferative activity of the derivatives was determined against the pancreatic MIA PaCa-2 and ovarian SCOV3 cancer cell-lines. IC50values of the most promising analogue 46 lie in the submicromolar or low micromolar range. Furthermore, compound 46 shows similar inhibitory activities against DU145, A2058 and PC-3 cancer cells, blocks the cell cycle at the G0/G1phase and induce apoptosis, as determined by the appearance of apoptotic nuclei.
- Giannouli, Vassiliki,Lougiakis, Nikolaos,Kostakis, Ioannis K.,Pouli, Nicole,Marakos, Panagiotis,Skaltsounis, Alexios-Leandros,Nam, Sangkil,Jove, Richard,Horne, David,Tenta, Roxane,Pratsinis, Harris,Kletsas, Dimitris
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p. 5229 - 5233
(2016/11/02)
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- THERAPEUTIC COMPOUNDS AND COMPOSITIONS
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The present invention provides compounds and compositions that inhibit Factor XIa or kallikrein and methods of using these compounds and composition.
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Paragraph 0314
(2015/09/22)
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- Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel GABAA receptor agonists
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A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA A receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9-11, 14-16) display low to mid-micromolar GABAAR binding affinities to native GABAA receptors (Ki 1.1-24 μM). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (K i 0.044 μM) and equipotency as an agonist to GABA itself as well as the standard GABAA agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a α1β 2γ2 GABAA receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABAAR agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABAAR area.
- Petersen, Jette G.,S?rensen, Troels,Damgaard, Maria,Nielsen, Birgitte,Jensen, Anders A.,Balle, Thomas,Bergmann, Rikke,Fr?lund, Bente
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p. 404 - 416
(2014/08/05)
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- PYRIDYL UREAS AS MINERALOCORTICOID RECEPTOR ANTAGONISTS
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Mineralocorticoid receptor antagonists, of which formula (1) is exemplary.
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Page/Page column 60-61
(2012/05/31)
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- Zinc chloride promoted efficient and facile BOC protection of amines
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Amines are efficiently protected as their BOC derivatives under mild reaction conditions when reacted with BOC anhydride in presence of ZnCl2. The present method is applicable to a variety of amines including aliphatic, aromatic as well as heteroaromatic amines. This protocol appears to be competitive and in some cases superior to previously reported procedures that work under basic conditions.
- Arifuddin, M.,Lakshmikant, N.,Rajasekar, N.,Shinde, D. B.
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p. 1168 - 1172,5
(2020/08/31)
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- 2-SULFANYL-SUBSTITUTED IMIDAZOLE DERIVATIVES AND THEIR USE AS CYTOKINE INHIBITORS
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The invention relates to 2-thio-substituted imidazole derivatives of the Formula I, and to methods of use thereof.
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- Towards the improvement of the synthesis of novel 4(5)-aryl-5(4)- heteroaryl-2-thio-substituted imidazoles and their p38 MAP kinase inhibitory activity
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A series of 2-alkylsulfanyl-4-(4-fluorophenyl)-5-(2-aminopyridin-4-yl)- substituted imidazoles was prepared and interaction possibilities of the 2-thioether moiety with phosphate/ribose binding pockets of p38 MAP kinase were investigated. Introduction of the alkyl/benzyl amino function at the pyridine moiety was carried out via nucleophilic substitution or via palladium catalyzed aryl-C-N-bond formation. The Royal Society of Chemistry 2008.
- Laufer, Stefan,Koch, Pierre
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supporting information; experimental part
p. 437 - 439
(2008/10/09)
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- BENZIMIDAZOLE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to compounds of formula (I); compositions comprising the compounds, and methods of using the compounds to treat or prevent pain, diabetes, a diabetic complication, impaired glucose tolerance (IGT) or impaired fasting glucose
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Page/Page column 31
(2008/12/08)
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- PIPERIDINE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to Compounds of Formula (I), compositions comprising the compounds, and methods of using the compounds to treat or prevent pain, diabetes, a diabetic complication, impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) in a patient.
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Page/Page column 29
(2008/12/08)
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- COMPOUNDS FOR THE INHIBITION OF INTEGRINS AND USE THEREOF
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The present invention is related to a compound of formula (I), wherein A is a nonaromatic heterocyclic ring, Ar is either absent or phenylene; psi is a radical of formula (II), R2 is a hydrophobic moiety; and G is a radical containing one or more moieties selected from the group consisting of NH, OH and a basic moiety. The compounds are inhibitors of integrins, especially antagonists of the fibronectin receptor alpha5beta1, useful as anti-angiogenic agents.
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Page/Page column 123-124
(2008/06/13)
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- JNK INHIBITOR
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The present invention relates to a c-Jun N-terminal kinase inhibitor containing an azole compound (I) substituted by a nitrogen-containing aromatic group having substituent(s)(except a compound represented by the formula: ) or a salt thereof or a prodrug thereof.
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Page/Page column 80
(2010/02/07)
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- INDOLE DERIVATIVES USEFUL AS HISTAMINE H3 ANTAGONISTS
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Disclosed are novel compounds of the formula I wherein M1 is CH or N and M2 is C(R3) or N; R1 is optionally substituted indolyl or an aza derivative thereof; R2 is optionally substituted aryl or heteroaryl; and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of Formula I. Also disclosed are methods of treating various diseases or conditions, such as, for example, allergy, allergy-induced airway responses, and congestion (e.g., nasal congestion) using the compounds of formula I in combination with a H1 receptor antagonist.
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- 1-(4-PIPERIDINYL) BENZIMIDAZOLONES AS HISTAMINE H3 ANTAGONISTS
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Disclosed are histamine H3 antagonists of the formula (I) wherein R1 is benzimidazolone derivative, M1 and M2 are optionally substituted carbon or nitrogen, R2 includes optionally substituted aryl or heteroaryl, and the remaining variables are as defined
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- Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
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The invention relates to substituted polycyclic aryl and heteroaryl pyrazinone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.
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Page column 104; 105
(2012/01/30)
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- 5-PYRIDYL-1,3-AZOLE COMPOUNDS, PROCESS FOR PRODUCING THE SAME AND USE THEREOF
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An optionally N-oxidized compound represented by the formula: wherein R1 represents hydrogen, hydrocarbon, heterocycle, amino, acyl, R2 represents an aromatic group, R3 represents hydrogen, pyridyl, aromatic hydrocarbon, X represents oxygen, optionally oxidized sulfur, Y represents a bond, an oxygen, optionally oxidized sulfur, a group represented by the formula NR4 (R4 represents hydrogen, hydrocarbon or acyl) and Z represents a bond or a divalent acyclic hydrocarbon, or a salt thereof has an excellent adenosine A3 receptor antagonistic activity and is used as an agent for preventing or treating diseases related to an adenosine A3 receptor. Furthermore, the compound (I) or a salt thereof has p38 MAP kinase inhibitory activity and TNF-α inhibitory activity and is used as an agent for preventing or treating diseases related to p38 MAP kinase and diseases related to TNF-α.
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- Fibrinogen receptor antagonists
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Fibrinogen receptor antagonists having the structure, for example, of STR1 for example STR2
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