- Synthesis route and preparation method of 3-fluorine-4-nitrobenzaldehyde
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The invention discloses a new synthetic route of 3-fluorine-4-nitrobenzaldehyde and a preparation method thereof. The preparation method comprises the following steps: adding 3-fluorine-4-nitrobenzoicacid and an acidic catalyst into an organic solvent methanol, stirring at 60 to 80 DEG C for 5 to 12 hours, and carrying out after-treatment to obtain a solid intermediate product 2; adding the intermediate product 2 into an organic solvent II, adding sodium borohydride while uniformly stirring at 0 DEG C, stirring for 0.5 to 1h at 0 DEG C, slowly heating to 60 DEG C, stirring for 2 to 6h, stopping stirring, and carrying out post-treatment to obtain an intermediate product 3; and adding the intermediate product 3 and an oxidant III into an organic solvent IV, heating and refluxing for 3 to 10hours, cooling to 20 to 30 DEG C after the reaction is finished, and carrying out post-treatment on the reaction solution to obtain the product 3-fluorine-4-nitrobenzaldehyde. According to the methoddisclosed by the invention, sodium borohydride which is safe and easy to treat is adopted to replace high-activity ultralow-temperature anhydrous oxygen diisobutyl aluminum hydride for reduction reaction, so that a relatively good effect is achieved, and the compound 3-fluorine-4-nitrobenzaldehyde is safely and efficiently synthesized. The method is simple, the requirements of production equipment are reduced, the cost is controlled, and the method is suitable for industrial production.
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Paragraph 0004; 0011-0012; 0016-0017
(2021/01/28)
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- DIHYDROQUINOXALINE BROMODOMAIN RECOGNITION PROTEIN INHIBITOR, PREPARATION METHOD AND USE THEREOF
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The present invention relates to dihydroquinoxaline bromodomain recognition protein inhibitor, preparation method and use thereof. The inhibitor of the present invention is compound represented by general formula (I), or stereoisomer, pharmaceutically acceptable salt, prodrug, solvate, hydrate and crystal form thereof. The definition of each substituent is as described in the description and claims. The compound represented by general formula (I) of the present invention may inhibit bromodomain recognition protein and may be used for preparing medicament which regulates the apparent state of cells and treats series of diseases and symptoms which are mediated by the bromodomain recognition protein.
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Paragraph 0152; 0153; 0154; 0246; 0247
(2020/02/14)
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- TRACELESS REDUCTIVELY CLEAVABLE LINKER MOLECULES FOR PEPTIDE PURIFICATION
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The present invention relates to linker molecules of formula (1), X-Tb-Va-U-Y-Z (1) and a method for purifying peptides using said linker molecules. The linker molecule can be coupled to a purification resin via the moiety X and to a
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Page/Page column 71
(2020/03/23)
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- NEW CLASS OF DNA GYRASE AND/OR TOPOISOMERASE IV INHIBITORS WITH ACTIVITY AGAINST GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA
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The present invention relates to compounds having a structure of general formula (I), processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in humans and warm-blooded animals.
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Page/Page column 56-57
(2020/03/29)
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- Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors
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BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure. Among them, compound 19 was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound 19 is a potential BET protein drug candidate for the treatment of cancer.
- Cao, Danyan,Chen, Danqi,Chen, Lin,Damaneh, Mohammadali Soleimani,Hu, Jianping,Huan, Xia-Juan,Li, Jian,Li, Yanlian,Lv, Kaikai,Meng, Tao,Miao, Ze-Hong,Qin, Lihuai,Shen, Jingkang,Song, Shan-Shan,Tian, Chang-Qing,Wang, Xin,Wang, Ying-Qing,Xiong, Bing,Yu, Ting
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- Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups
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Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays. Throughout the study, compounds 9, 28 and 37 showed significant inhibitory activity for c-Myc or PD-L1 protein expression and mRNA transcription both at concentration of 0.2 and 1 μM. Compound 9 was found possessing the best balance of binding affinity, in vitro metabolic stability and in vivo pharmacokinetic properties. Therefore, it was selected for in vivo pharmacological study. By using MM.1S cell derived xenograft model, we confirmed compound 9 showed comparable in vivo tumor inhibition to phase II investigation drug I-BET762, which, together with the novel WPF binder, further indicated the utility of this series of BRD4 inhibitors.
- Hu, Jianping,Wang, Yingqing,Li, Yanlian,Cao, Danyan,Xu, Lin,Song, ShanShan,Damaneh, Mohammadali Soleimani,Li, Jian,Chen, Yuelei,Wang, Xin,Chen, Lin,Shen, Jingkang,Miao, Zehong,Xiong, Bing
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p. 156 - 175
(2018/03/21)
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- Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists
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Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor.
- Morin, Matthew D.,Wang, Ying,Jones, Brian T.,Su, Lijing,Surakattula, Murali M. R. P.,Berger, Michael,Huang, Hua,Beutler, Elliot K.,Zhang, Hong,Beutler, Bruce,Boger, Dale L.
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supporting information
p. 4812 - 4830
(2016/06/13)
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- QUINOXALINE COMPOUNDS AND USES THEREOF
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This invention provides compounds of formula I and subsets thereof: wherein T, J, R, R4, Rq, o, RA, and RB and subsets thereof are as described in the specification. The compounds are inhibitors of NAMPT and are thus useful for treating cancer, inflammatory conditions, or T-cell mediated autoimmune disease.
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Paragraph 00254
(2015/11/09)
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- NEOSEPTINS: SMALL MOLECULE ADJUVANTS
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A MD-2:TLR4 complex agonist compound is disclosed whose structure corresponds to Formula (I), as defined within. Also disclosed are a method of its preparation and use, as well as a pharmaceutical composition containing the same.
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Page/Page column 147
(2014/09/03)
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- COMPOSITIONS AND METHODS FOR MODULATING FXR
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The present invention relates to compounds of Formula (I), a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesiod X receptors (FXR).
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Page/Page column 84; 85
(2012/07/13)
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- COMPOSITIONS AND METHODS FOR MODULATING FARNESOID X RECEPTORS
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The present invention relates to compounds of Formula (I), a stereoisomer, enantiomer, a pharmaceutically acceptable salt or an amino acid conjugate thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful
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Page/Page column 43
(2012/07/13)
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- BENZIMIDAZOLES AS FATTY ACID SYNTHASE INHIBITORS
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This invention relates to the use of benzimidazole derivatives for the modulation, notably the inhibition of the activity or function of fatty acid synthase (FAS). Suitably, the present invention relates to the use of benzimidazoles in the treatment of cancer.
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Page/Page column 105
(2011/06/11)
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- Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3β
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Glycogen synthase kinase-3β (GSK-3β) is implicated in abnormal hyperphosphorylation of tau protein and its inhibitors are expected to be a promising therapeutic agents for the treatment of Alzheimer's disease. Here we report design, synthesis and structure-activity relationships of a novel series of oxadiazole derivatives as GSK-3β inhibitors. Among these inhibitors, compound 20x showed highly selective and potent GSK-3β inhibitory activity in vitro and its binding mode was determined by obtaining the X-ray co-crystal structure of 20x and GSK-3β.
- Saitoh, Morihisa,Kunitomo, Jun,Kimura, Eiji,Hayase, Yoji,Kobayashi, Hiromi,Uchiyama, Noriko,Kawamoto, Tomohiro,Tanaka, Toshimasa,Mol, Clifford D.,Dougan, Douglas R.,Textor, Garret S.,Snell, Gyorgy P.,Itoh, Fumio
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experimental part
p. 2017 - 2029
(2009/05/26)
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- Design, synthesis, and biological evaluation of 1,5-benzothiazepine-4-one derivatives targeting factor VIIa/tissue factor
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The 1,5-benzothiazepine-4-one scaffold was earlier shown to provide efficient protease inhibitors. In this contribution, we describe its use in the design of factor VIIa/tissue factor inhibitors. A series containing a scaffold non-substituted on its aryl part led to compound 20 with an IC50 of 2.16 μM. Following molecular modelling studies of this compound, a second series was prepared, which necessitated the synthesis of protected 7- or 8-substituted 1,5-benzothiazepine-4-one derivatives.
- Ayral, Erwan,Gloanec, Philippe,Berge, Gilbert,de Nanteuil, Guillaume,Mennecier, Philippe,Rupin, Alain,Verbeuren, Tony J.,Fulcrand, Pierre,Martinez, Jean,Hernandez, Jean-Francois
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supporting information; experimental part
p. 1386 - 1391
(2009/10/15)
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- Retinoid receptor subtype-selective modulators through synthetic modifications of RARγ agonists
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A series of retinoids designed to interfere with the repositioning of H12 have been synthesized to identify novel RARγ antagonists based on the structure of known RARγ agonists. The transcriptional activities of the novel ligands were revealed by cell-based reporting assays, using engineered cells containg RAR subtype-selective fusions of the RAR ligand-binding domains with the yeast GAL4 activator DNA-binding domain and the cognate luciferase reporter gene. Whereas none of the ligands exhibited features of a selective RARγ antagonist, some of them are endowed with interesting activities. In particular 24a acts as a pan-RAR agonist that induces at high concentration a higher transactivation potential on RARα than TTNPB and synergizes at low concentration with TTNPB-bound RARα but not RARβ or RARγ. Similarly, 24c synergizes with TTNPB-bound RARγ and exhibits RARα,β antagonist activity. Compounds 24b and 25b are strong RARα,β-selective antagonists without agonist or antagonist activities for RARγ. Compounds 24b and 24c display weak RXR antagonist activity. In addition several pan-antagonists and partial agonist/antagonists have been defined.
- Alvarez, Susana,Alvarez, Rosana,Khanwalkar, Harshal,Germain, Pierre,Lemaire, Geraldine,Rodriguez-Barrios, Fatima,Gronemeyer, Hinrich,de Lera, Angel R.
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scheme or table
p. 4345 - 4359
(2009/10/17)
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- 4-OXO-4,5-DIHYDROPYRROLO[1,2-A] QUINOXALINE DERIVATIVES AS INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE(PARP)
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The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of poly(ADP- ribose)polymerase (PARP) and thus useful for the treatment of cancer, inflammatory diseases, reperfusio
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Page/Page column 46-47
(2008/06/13)
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- INHIBITORS OF SERINE PALMITOYLTRANSFERASE
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This invention provides compounds of the formula (I) useful in the inhibition or modulation of serine palmitoyl transferase and their use in methods of treatment or amelioration of type 2 diabetes, type 1 diabetes, insulin resistance, the effects of obesity, metabolic syndrome (sometimes referred to as Syndrome X), impaired glucose tolerance, Cushing's disease, cardiovascular disease, prothrombotic conditions, myocardial infarction, hypertension, congestive heart failure, cardiomyopathy, atherosclerosis, dyslipidemia, sepsis, liver damage, retinal degenerative disorders, cachexia, emphysema, hepatitis C infections, HIV infections and inflammatory disorders and useful in methods for raising HDL plasma levels in a mammal. The compounds of this invention can also be used to prevent damage or loss of pancreatic islet beta cells (such as in the case of pancreatic beta cell apoptosis, including those related to insulin-dependent diabetes mellitus).
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Page/Page column 52-53
(2008/12/07)
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- Identification of a novel series of benzimidazoles as potent and selective antagonists of the human melanocortin-4 receptor
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A novel series of benzimidazoles was identified and optimized, leading to the discovery of potent and selective antagonists of the human melanocortin-4 receptor. In addition, compound 5i was shown to cross the blood-brain barrier after intravenous dosing
- Poitout, Lydie,Brault, Valerie,Sackur, Carole,Bernetiere, Sonia,Camara, Jose,Plas, Pascale,Roubert, Pierre
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p. 4464 - 4470
(2008/03/11)
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- Novel carbazole derivatives as NPY Y1 antagonists
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The synthesis of a series of carbazole derivatives and their SAR at the NPY Y1 receptor is described. Modulation of physicochemical properties by appropriate decoration led to the identification of a high-affinity NPY Y1 antagonist that shows high brain penetration and modest oral bioavailability.
- Leslie, Colin P.,Fabio, Romano Di,Bonetti, Francesca,Borriello, Manuela,Braggio, Simone,Forno, Giovanna Dal,Donati, Daniele,Falchi, Alessandro,Ghirlanda, Damiano,Giovannini, Riccardo,Pavone, Francesca,Pecunioso, Angelo,Pentassuglia, Giorgio,Pizzi, Domenica A.,Rumboldt, Giovanna,Stasi, Luigi
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p. 1043 - 1046
(2007/10/03)
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- BENZOTHIAZOLE AND AZABENZOTHIAZOLE COMPOUNDS USEFUL AS KINASE INHIBITORS
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A compound of Formula (I), or an enantiomer, diastereomer or a pharmaceutically-acceptable salt thereof, wherein A is independently selected from: (a); (b); (c); or (d), further wherein R1, R2, R3, R4, R5, R6, R7, and W are as described herein. Also discl
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Page/Page column 47
(2008/06/13)
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- Small-molecule modulators of TRP-P8 activity
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Provided are small-molecule Trp-p8 modulators, including Trp-p8 agonists and Trp-p8 antagonists, and compositions comprising small-molecule Trp-p8 agonists as well as methods for identifying and characterizing novel small-molecule Trp-p8 modulators and methods for decreasing viability and/or inhibiting growth of Trp-p8 expressing cells, methods for activating Trp-p8-mediated cation influx, methods for stimulating apoptosis and/or necrosis, and related methods for the treatment of diseases, including cancers such as lung, breast, colon, and/or prostate cancers as well as other diseases, such as benign prostatic hyperplasia, that are associated with Trp-p8 expression.
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Page/Page column 19
(2008/06/13)
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- THIENOPYRIMIDINES FOR PHARMACEUTICAL COMPOSITIONS
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The present invention relates to novel pharmaceutical compositions of general formula (I) comprising thienopyrimidine compounds. Moreover, the present invention relates to the use of the thienopyrimidine compounds of the invention for the production of pharmaceutical compositions for the prophylaxis and/or treatment of diseases which can be influenced by the inhibition of the kinase activity of Mnk1 and/or Mnk2 (Mnk2a or Mnk2b) and/or variants thereof.
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Page/Page column 119
(2010/11/25)
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- Novel derivatives of benzimidazole and imidazo-pyridine and their use as medicaments
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A compound of the formula wherein the substituents are as defined in the specification and pharmaceutical salts thereof having a good affinity for sub-types of melanocortin receptors making them useful for treating diseases in which such receptors are included such as pain, inflammatory conditions, etc.
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Page/Page column 18
(2008/06/13)
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- VIRAL POLYMERASE INHIBITORS
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An enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I): wherein either A or B is nitrogen and the other B or A is C, and the radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined herein, or a salt or ester thereof as viral polymerase inhibitors. The compound is used as an inhibitor of RNA dependent RNA polymerases, particularly those viral polymerases within the Flaviviridae family, more particularly to HCV polymerase.
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Page/Page column 88-89
(2008/06/13)
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- 4-PHENYL-PYRIMIDO [4,5-B] INDOLE DERIVATIVES
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The present invention relates to 4-phenyl-pyrimido[4,5-b]indoles which are useful as an active ingredient of pharmaceutical preparations. The 4-phenyl-pyrimido[4,5-b]indoles of the present invention have MKK7 and MKK4 inhibitory activity, and can be used for the prophylaxis and treatment of diseases associated with MKK7 and MKK4 activity.Such diseases include, inflammatory and immunoregulatory disorders and diseases such as asthma, atopic dermatitis, rhinitis, allergic rhinitis, allergic diseases, COPD, septic shock, arthritis, joint diseases and myocardial injuries, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis as well as cancer.The compounds of the present invention are also useful for treatment of ischemia, myocardial injury, pulmonary hypertension, renal failure, Huntington's chorea and cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and focal ischemia.
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- Benzimidazole compounds and antiviral uses thereof
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The present invention relates to novel benzimidazole compounds that have useful antiviral activity. More specifically, the invention encompasses benzimidazole compounds that inhibit membrane fusion associated events such as viral transmission, reduce vira
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- RARY-SPECIFIC RETINOBENZOIC ACID DERIVATIVES
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Retinoid-like activity is exhibited by compounds of the formula STR1 wherein X is F, Cl, OH or CH 3, Y is H or F, R 1-R 6 are each independently hydrogen or C 1-C 6 alkyl, n is an integer of 1 to 4 and R 7 is hydrogen or a carboxyl-protecting group, and pharmaceutically acceptable salts thereof. The compounds of formula I selectively interact with the retinoic acid subtype RARγ and have been found to lack the liver toxicity associated with systemic administration of non-selective retinoids.
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