- Ion complexation-controlled columnar mesophase of calix[4]arene-cholesterol derivatives with Schiff-base bridges
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Two novel calix[4]arene-cholesterol derivatives 7a and 7b with Schiff-base bridges were synthesized in yields of 70-80%. Their structural and conformational characterization had been achieved by NMR, MS, and elemental analysis. Their mesomorphic behaviors were studied by polarizing optical microscopy, differential scanning calorimetry, and X-ray diffraction. They possess mesomorphic properties with the molecular arrangement of the calixarene bowlic column and Schiff-based cholesterol unit as ancillary lateral column. The complexes of 7a and 7b with AgClO4 showed no mesophase. These results suggested that the mesophase of compounds 7a and 7b could be tuned by the ion-complexation behavior.
- Zhang, Xiaoyi,Guo, Hongyu,Yang, Fafu,Yuan, Jin
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Read Online
- Synthesis and biological activity of thieno[3,2-d]pyrimidines as potent JAK3 inhibitors for the treatment of idiopathic pulmonary fibrosis
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Idiopathic pulmonary fibrosis (IPF) is a serious and fatal lung disease, with a median survival of only 3–5 years from diagnosis. Janus kinase 3 (JAK3) has a well-established role in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA) and autoimmune-related pulmonary fibrosis. In this study, through the use of a conformationally-constrained design strategy, a series of thieno[3,2-d]pyrimidines were synthesized as potent JAK3 inhibitors for the treatment of IPF. Among them, the most potent JAK3 inhibitor, namely 8e (IC50 = 1.38 nM), significantly reduced the degree of airsacculitis and fibrosis according to hematoxylin-eosin (HE) staining assay for the lung tissue in the bleomycin (BLM)-induced pulmonary fibrosis mouse model. The clear reduction of the lung collagen deposition by the determination of Masson and hydroxyproline (HYP) content also demonstrated its efficacy in the treatment of fibrosis. In addition, 8e also reduced the expression of the inflammatory markers IL-6, IL-17A, TNF-α and malondialdehyde (MDA) in lung tissue, which indicated its higher anti-inflammatory activity compared with that of the reference agents (nintedanib and gefitinib). Furthermore, it possessed low cytotoxicity against normal human bronchial epithelia (HBE) cells (IC50 > 39.0 μM) and C57BL mice. All these evaluated biological properties suggest that 8e may be a potential JAK3 inhibitor for the treatment of IPF.
- Zhu, Yanming,Zheng, Xu,Wang, Changyuan,Sun, Xiuli,Sun, Huijun,Ma, Tengyue,Li, Yanxia,Liu, Kexin,Chen, Lixue,Ma, Xiaodong
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- Dithiocarbamate type compound used as BTK (Bruton Tyrosine Kinase) inhibitor
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The invention aims at providing a dithiocarbamate type compound used as a BTK (Bruton Tyrosine Kinase) inhibitor and a pharmaceutical composition thereof, a preparation method and application. The compound provided by the invention has a structure shown as a general formula (I). The formula (I) is shown in the description.
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Paragraph 0089; 0090; 0091
(2019/04/27)
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- Design, synthesis and biological evaluation of novel dithiocarbamate-substituted diphenylaminopyrimidine derivatives as BTK inhibitors
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Bruton's tyrosine kinase (BTK) has emerged as an attractive target related to B-lymphocytes dysfunctions, especially hematologic malignancies and autoimmune diseases. In our study, a series of diphenylaminopyrimidine derivatives bearing dithiocarbamate moieties were designed and synthesized as novel BTK inhibitors for treatment of B-cell lymphoma. Among all these compounds, 30ab (IC50 = 1.15 ± 0.19 nM) displays similar or more potent inhibitory activity against BTK than spebrutinib (IC50 = 2.12 ± 0.32 nM) and FDA approved drug ibrutinib (IC50 = 3.89 ± 0.57 nM), which is attributed to close binding of 30ab with BTK predicted by molecular docking. In particular, 30ab exhibits enhanced anti-proliferative activity against B-lymphoma cell lines at the IC50 concentration of 0.357 ± 0.02 μM (Ramos) and 0.706 ± 0.05 μM (Raji), respectively, almost 10-fold better than ibrutinib and spebrutinib. In addition, 30ab displays stronger selectivity on B-cell lymphoma over other cancer cell lines than spebrutinib. Furthermore, 30ab efficiently blocks BTK downstream pathways and results in apoptosis of cancer cells. In vivo xenograft model evaluation demonstrates the significant efficacy and broad safety margin of 30ab in treatment of B-cell lymphoma. We propose that compound 30ab is a candidate for further study and development based on our current findings.
- Zhai, Zheng,Li, Ridong,Bai, Xinyu,Ning, Xianling,Lin, Zhiqiang,Zhao, Xuyang,Jin, Yan,Yin, Yuxin
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p. 4124 - 4142
(2019/08/07)
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- Palladium catalyzed chloroethoxylation of aromatic and heteroaromatic chlorides: An orthogonal functionalization of a chloroethoxy linker
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A novel disconnection based on cross-coupling chemistry was designed to access pharmaceutically relevant aryl-aminoethyl ethers. The developed palladium-catalyzed functionalization of aryl- and heteroaryl chlorides with a sodium tetrakis-(2-chloroethoxy) borate salt is orthogonal to the simple nucleophilic replacement of the chloro function of the ethylene linker. The transformation enables efficient 2-chloroethoxylation in the absence of an additional external base. Subsequent amine substitution of the alkyl halide affords 2-aminoethoxy arenes. The applicability of this method was demonstrated through the synthesis of various aryl- and heteroaryl-alkyl ethers, including the intermediates of marketed drug molecules.
- Petho, Bálint,Vangel, Dóra,Csenki, János T.,Zwillinger, Márton,Novák, Zoltán
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supporting information
p. 4895 - 4899
(2018/07/15)
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- Design, synthesis, biological evaluation and molecular docking studies of novel 3-aryl-4-anilino-2H-chromen-2-one derivatives targeting ERα as anti-breast cancer agents
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The estrogen receptor (ER) has played an important role in breast cancer development and progression and is a central target for anticancer drug discovery. In order to develop novel selective ERα modulators (SERMs), we designed and synthesized 18 novel 3-aryl-4-anilino-2H-chromen-2-one derivatives based on previously reported lead compounds. The biological results indicated that most of the compounds presented potent ERα binding affinity and possessed better anti-proliferative activities against MCF-7 and Ishikawa cell lines than the positive control tamoxifen. The piperidyl substituted compounds such as 16d and 18d demonstrated strong ERα binding affinities and excellent anti-proliferative activities respectively. Compound 18d displayed the most potent ERα binding affinity with RBA value of 2.83%, while 16d exhibited the best anti-proliferative activity against MCF-7 cells with IC50 value of 4.52?±?2.47?μM. Further molecular docking studies were also carried out to investigate binding pattern of the newly synthesized compounds with ERα. All these results together with the structure–activity relationships (SARs) indicated that these 3-aryl-4-anilino-2H-chromen-2-one derivatives with basic side chain could serve as promising leads for further optimization as novel SERMs.
- Luo, Guoshun,Chen, Mingqi,Lyu, Weiting,Zhao, Ruheng,Xu, Qian,You, Qidong,Xiang, Hua
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supporting information
p. 2668 - 2673
(2017/05/29)
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- Structure-based design of novel 2-amino-6-phenyl-pyrimido[5′, 4′:5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as potent and orally active inhibitors of lymphocyte specific kinase (Lck): Synthesis, SAR, and in vivo anti-inflammatory activity
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Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5′,4′:5,6]pyrimido[1,2- a]benzimidazol-5(6H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2- ((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5′,4′:5,6] pyrimido-[1,2-a]benzimidazol-5(6H)-one (25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.
- Martin, Matthew W.,Newcomb, John,Nunes, Joseph J.,Boucher, Christina,Chai, Lilly,Epstein, Linda F.,Faust, Theodore,Flores, Sylvia,Gallant, Paul,Gore, Anu,Gu, Yan,Hsieh, Faye,Huang, Xin,Kim, Joseph L.,Middleton, Scot,Morgenstern, Kurt,Oliveira-dos-Santos, Antonio,Patel, Vinod F.,Powers, David,Rose, Paul,Tudor, Yanyan,Turci, Susan M.,Welcher, Andrew A.,Zack, Debra,Zhao, Huilin,Zhu, Li,Zhu, Xiaotian,Ghiron, Chiara,Ermann, Monika,Johnston, David,Saluste, Carl-Gustaf Pierre
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p. 1637 - 1648
(2008/12/22)
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- DIARYLAMINE-CONTAINING COMPOUNDS AND COMPOSITIONS, AND THEIR USE AS MODULATORS OF C-KIT RECEPTORS
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Described herein are compounds that include a diarylamine structural feature. Also described herein are methods for making such compounds, methods for using such compounds to modulate the activity of c-kit receptors, and pharmaceutical compositions and medicaments comprising such compounds. Also described herein are methods of using such compounds, pharmaceutical compositions and medicaments to treat and/or prevent and/or inhibit and/or ameliorate the pathology and/or symptomology diseases or conditions associated with the activity of c-kit receptors.
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Page/Page column 170
(2008/06/13)
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- Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: Synthesis, SAR, and in vivo antiinflammatory activity
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The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)- oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.
- Martin, Matthew W.,Newcomb, John,Nunes, Joseph J.,McGowan, David C.,Armistead, David M.,Boucher, Christina,Buchanan, John L.,Buckner, William,Chai, Lilly,Elbaum, Daniel,Epstein, Linda F.,Faust, Theodore,Flynn, Shaun,Gallant, Paul,Gore, Anu,Gu, Yan,Hsieh, Faye,Huang, Xin,Lee, Josie H.,Metz, Daniela,Middleton, Scot,Mohn, Deanna,Morgenstern, Kurt,Morrison, Michael J.,Novak, Perry M.,Oliveira-Dos-Santos, Antonio,Powers, David,Rose, Paul,Schneider, Stephen,Sell, Stephanie,Tudor, Yanyan,Turci, Susan M.,Welcher, Andrew A.,White, Ryan D.,Zack, Debra,Zhao, Huilin,Zhu, Li,Zhu, Xiaotian,Ghiron, Chiara,Amouzegh, Patricia,Ermann, Monika,Jenkins, James,Johnston, David,Napier, Spencer,Power, Eoin
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p. 4981 - 4991
(2007/10/03)
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- Fused pyrrolecarboxamides: GABA brain receptor ligands
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Substituted pyrrolecarboxamide compounds are disclosed. These compounds are highly selective agonists, antagonists or inverse agonists for GABAA brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAA brain receptors and are therefore useful in the diagnosis and treatment of anxiety, depression, Alzheimer's dementia, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. Pharmaceutical compositions, including packaged pharmaceutical compositions, are further provided. Compounds of the invention are also useful as probes for the localization of GABAA receptors in tissue samples.
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- PHENYL-[4-(3-PHENYL-1H-PYRAZOL-4-YL)-PYRIMIDIN-2-YL]-AMINE DERIVATIVES AS IGF-IR INHIBITORS
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The present invention relates to a compound of formula (I) and derivatives thereof. Furthermore, the invention relates to the use of such compounds as medicaments. In addition, the invention relates to the use of such compounds for manufacturing a medicament useful for treating proliferative diseases.
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Page/Page column 41
(2008/06/13)
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- Synthesis, dopamine D2 receptor binding studies and docking analysis of 5-[3-(4-arylpiperazin-1-yl)propyl]-1H-benzimidazole, 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazole and their analogs
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5-[3-(4-Arylpiperazin-1-yl)propyl]-1H-benzimidazoles and 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazoles were synthesized and their affinity for the D1, D2 and 5-HT1A receptors examined. They expressed a rather high affinity for the D2 dopamine receptor. The main features of ligand-D2 receptor interactions revealed by docking analyses were: salt bridge between piperazine ring protonated N1 and Asp 86, hydrogen bonds of ligand bezimidazole part with Ser 141, Ser 122 and His 189, edge-to-face interactions of arylpiperazine aromatic ring with Phe 178, Tyr 216 and Trp 182 and hydrogen bond between ethereal oxygen in ethylenoxy ligands and hydrogen of Phe 185 or Trp 115. The most active 5-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethoxy}-1,3-dihydro-2H- benzimidazole-2-thione (27) has a maximal number of attractive interactions. A satisfactory correlation between docking of the compounds into the D2 receptor and competition binding results was observed.
- ?ukalovi?,Andri?, Deana,Rogli?,Kosti?-Raja?i?, Sladjana,Schrattenholz,?o?ki?
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p. 481 - 493
(2007/10/03)
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- PHENYL-[4-(3-PHENYL-1H-PYRAZOL-4-YL)-PYRIMIDIN-2-Yl)-AMINE DERIVATIVES
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The invention relates to phenyl-[4-(3-phenyl-1H-pyrazol-4-yl)-pyrimidin-2-yl)-amine derivatives and to processes for the preparation thereof, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives - alone or in combination with one or more other pharmaceutically active compounds - for the preparation of pharmaceutical compositions for the treatment especially of a proliferative disease, such as a tumour.
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- NOVEL COMPOUNDS HAVING A DOPAMINERGIC AND/OR SEROTONINERGIC ACTIVITY
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The invention relates to novel compounds of 4-[2-(4-arylpiperazin-1-yl)-ethoxy]benzo-1,2-diamine I, to the derivatives thereof in the form of benzoimidazole-2-thiones, benzoimidazoles and benzotriazoles, to the use of the pharmacologically acceptable salts thereof as dopaminergic and serotoninergic agents, and to a method for producing said compounds.
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Page/Page column 10
(2008/06/13)
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- HETEROCYCLIC BETA-3 ADRENERGIC RECEPTOR AGONISTS
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This invention provides compounds of Formula I having the structure U, V, W, X, and Y are as defined hereinbefore, or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
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- Novel aryl substituted tetrahydroindazoles as ligands of the GABA receptor
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Disclosed are compounds of the formula 1 and the pharmaceutically acceptable salts thereof wherein the variables R1, R2, R3, n, and Ar are defined herein. These compounds are highly selective agonists, antagonists or inverse agonists for GABAA brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAA brain receptors and are therefore useful in the diagnosis and treatment of anxiety, depression, Down Syndrome, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.
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- Substituted fused pyrroleoximes and fused pyrazoleoximes
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Disclosed are compounds of the formula and the pharmaceutically acceptable salts thereof wherein R, Ar, A, n, R1 and R2 are defined herein. These compounds are highly selective agonists, antagonists or inverse agonists for GABAA brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAA brain receptors and are therefore useful in the diagnosis and treatment of anxiety, depression, Down Syndrome, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. Pharmaceutical compositions, including packaged pharmaceutical compositions, are also disclosed.
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- Fused pyrrolecarboxamides; a new class of GABA brain receptor ligands
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Disclosed are compounds of the formula: or the pharmaceutically acceptable non-toxic salts thereof wherein: G, X, T, n, and R3-R6are as defined herein, which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.
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- FUSED PYRROLECARBOXAMIDES; A NEW CLASS OF GABA BRAIN RECEPTOR LIGANDS
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The present invention encompasses structures of the formula I: STR1 or the pharmaceutically acceptable non-toxic salts thereof wherein: G represents STR2 where Q is aryl substituents optionally mono or disubstituted with hydroxy or halogen;T is halogen, hydrogen, hydroxyl, amino or alkoxy having 1-6 carbon atoms;W is oxygen, nitrogen, sulfur, or optionally substituted methylene;X is hydrogen, hydroxyl, or alkyl; Z is an organic or inorganic substituent optionally forming a ring with subtituents on Q; STR3 independently represent optionally substituted carbon chains; wherein k, m, and n are independently 0, or an integer of from 1-3 R 3, R 4, R 5, and R 6 are the same or different and represent organic or inorganic substituents.These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.
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- Substituted phenyl sulfonamides as selective β 3 agonists for the treatment of diabetes and obesity
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Substituted phenylsulfonamides are selective β 3 adrenergic receptor agonists with very little β 1 and β 2 adrenergic receptor activity and as such the compounds are capable of increasing lipolysis and energy expenditure in cells. The compounds thus have potent activity in the treatment of Type II diabetes and obesity. The compounds can also be used to lower triglyceride levels and cholesterol levels or raise high density lipoprotein levels or to decrease gut motility. In addition, the compounds can be used to reduced neurogenic inflammation or as antidepressant agents. The compounds are prepared by coupling an aminoalkylphenyl-sulfonamide with an appropriately substituted alkyl epoxide. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for increasing gut motility are also disclosed.
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- Reactive dyestuffs
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Triphendioxazine reactive dyestuffs of the general formula STR1 with the substituent definition given in the description, are outstandingly suitable for dyeing and printing materials containing hydroxyl groups or amide groups. They give red dyeings with high wet- and light-fastnesses.
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- Antiarrhythmic agents, compositions and method of use thereas
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An antiarrhythmic agent of the formula STR1 or a pharmaceutically acceptable salt thereof; wherein R1 is H, C1 -C4 alkyl or C1 -C4 alkoxy; X is O, STR2 or a direct link; and R2 and R3, which are the same or different, are each C1 -C4 alkyl, with the proviso that when X is STR3 R2 and R3 are the same.
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- Sulphonamide antiarrhythmic agents
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The invention provides sulphonamide antiarrythmic agents of the formula: wherein each R, which is the same, is a C1-C4 alkyl group; X is CH2 or O; and Y is O or a direct link; or a pharmaceutically acceptable salt thereof.
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- Urea derivatives and their use as herbicides
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Compounds, useful as herbicides, of the formula SPC1 Wherein R1 is haloalkyl, halocycloalkyl, haloalkenyl, or halocycloalkenyl; n1 is 1 or 2; R4 is halogen, trifluoromethyl, alkyl, or alkoxy; n2 is 0, 1, 2, or 3; R2 is hydrogen or alkyl; and R3 is alkyl or alkoxy. Methods for making these compounds.
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