- Continuous synthesis method for substituted benzoic acid organic matter
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The invention provides a continuous synthesis method for a substituted benzoic acid organic matter. The continuous synthesis method comprises the following steps: in the presence of a catalyst and anorganic solvent, continuously putting an organic matter of a formula (I) shown in the specification, and oxygen into a continuous reaction device, carrying out a continuous oxidation reaction so as toobtain the substituted benzoic acid organic matter, and continuously discharging the substituted benzoic acid organic matter, wherein the substituted benzoic acid organic matter is of a structure ofa formula (II) shown in the specification. Oxygen is a green reagent and is cheap and easy to obtain, a great amount of wastes are not generated after reactions are completed, and the system is easy to treat. Due to continuous reaction operation, the risk that the solvent has flash evaporation explosion because of high-concentration oxygen in in-batch reactions can be reduced. Under same oxidationconditions, due to a continuous preparation process, escape of oxygen can be reduced, the utilization rate of oxygen can be greatly increased, operation can be also simplified, the security of reactions can be improved, and the yield of the substituted benzoic acid organic matter can be increased.
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Paragraph 0135-0137; 0138
(2019/10/01)
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- INHIBITORS OF STEAROYL-COA DESATURASE
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity.
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- PYRROLE ANTIFUNGAL AGENTS
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The invention provides compounds of formula (I), and pharmaceutically and agriculturally acceptable salts thereof; wherein: R1, R2, R3, R4, R5, R6, A1, L1 and n are as defined herein. These compounds and their pharmaceutically acceptable salts are useful in prevention or treatment of a fungal disease. Compounds of formula (I), and agriculturally acceptable salts thereof, may also be used as agricultural fungicides.
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Page/Page column 145
(2009/12/05)
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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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- Pyrimido-Benzimidazole Derivatives and the Use Thereof in the Form of Agonists and Antagonists of Melanocortin Receptors
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The invention relates to novel pyrimido-benzimidazole derivatives. Said products exhibit a good affinity for certain melanocortin receptor sub-types, in particular MC4 receptors. Said products represent a particular interest for treating pathological disorders and diseases associated with one or several melanocortin receptors. Pharmaceutical compositions containing said products and the use thereof for a drug preparation are also disclosed.
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Page/Page column 5
(2009/09/05)
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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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- 2,3,4,5-TETRAHYDRO-1H-1,5-BENZODIAZEPINE DERIVATIVE AND MEDICINAL COMPOSITION
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The present invention has its object to provide a 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine derivative represented with the Formula (1) , or the pharmaceutically acceptable salt, which is effective as a therapeutic and prophylactic agent for diabetes, diabetic nephropathy, or glomerulosclerosis.
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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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- Neuroprotective small organic molecules, compositions and uses related thereto
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The present application is directed to therapeutic compounds, compositions, and methods for culturing neuronal cells and for preventing and the treatment of neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis (ALS).
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Page/Page column sheet 2; 44-45
(2008/06/13)
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- 2,3,4,5-TETRAHYDRO-1H-1,5-BENZODIAZEPINE DERIVATIVE AND MEDICINAL COMPOSITION
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A 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine derivative represented by the generalformula (1): [Chemical formula 1] (1) or a pharmaceutically acceptable saltthereof. They are useful as a therapeutic/preventive agent for diabetes, diabeticnephropathy, or glomerulosclerosis.
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Page/Page column 60-61
(2010/11/30)
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- Novel benzimidazole and imidazopyridine derivatives and use thereof as a medicament
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The invention relates to novel benzimidazole and imidazopyridine derivatives having general formula (I), which have a good affinity with certain sub-types of melanocortin receptors, particularly MC4 receptors. Said derivatives are particularly suitable for the treatment of pathological states and diseases involving one or more melanocortin receptors. The invention also relates to pharmaceutical compositions containing said products.
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Page/Page column 8
(2010/11/25)
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- Discovery of 1-(3′-aminobenzisoxazol-5′-yl)-3-trifluoromethyl- N-[2-fluoro-4-[(2′-dimethylaminomethyl)imidazol-1-yl]phenyl] -1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor
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Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P1 ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P4 moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3′-aminobenzisoxazol-5′-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2′-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).
- Quan, Mimi L.,Lam, Patrick Y. S.,Han, Qi,Pinto, Donald J. P.,He, Ming Y.,Li, Renhua,Ellis, Christopher D.,Clark, Charles G.,Teleha, Christopher A.,Sun, Jung-Hui,Alexander, Richard S.,Bai, Steve,Luettgen, Joseph M.,Knabb, Robert M.,Wong, Pancras C.,Wexler, Ruth R.
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p. 1729 - 1744
(2007/10/03)
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- BENZAMIDE DERIVATIVES
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A compound represented by formula (1): wherein X is a single bond or a substituted or unsubstituted lower alkylene group; Z is a saturated or unsaturated monocyclic hydrocarbon ring group or the like; and each of R1, R2, R3 and R4, which may be the same or different, is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug has inhibitory effect on Rho kinase and hence is useful for treating diseases which are such that morbidity due to them is expected to be improved by inhibition of Rho kinase and secondary effects such as inhibition of the Na+/H+ exchange transport system caused by the Rho kinase inhibition, for example, hypertension.
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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 9
(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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- SUBSTITUTED BENZIMIDAZOLE COMPOUNDS
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Disclosed are substituted benzimidazole compounds of formula (I) wherein R1, R2, R3, R4 and Xa are defined herein. The compounds of the invention inhibit Itk kinase and are therefore useful for treating diseases and pathological conditions involving inflammation, immunological disorders and allergic disorders. Also disclosed are processes for preparing these compounds and the pharmaceutical compositions comprising these compounds.
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Page 157; 157
(2008/06/13)
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- Alkyl urea retinoid agonists
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The current invention provide novel compounds, methods of treating or preventing emphysema, cancer and dermatological disorders, pharmaceutical compositions suitable for the treatment or prevention of emphysema, cancer and dermatological disorders and methods for delivering formulations into the lung of a mammal suffering from emphysema, cancer and dermatological disorders.
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- Elucidation of the vicarious nucleophilic substitution of hydrogen mechanism via studies of competition between substitution of hydrogen, deuterium, and fluorine
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Relations of rates of the vicarious nucleophilic substitution of hydrogen (VNS) and SNAr substitution of fluorine in 2-fluoronitrobenzenes with chloroalkyl aryl sulfone carbanions were determined from competitive experiments carried out at various concentrations of base. The observed dependence of the VNS/SNAr rate ratio on the base concentration confirmed the two-step mechanism of the VNS, which consists of reversible formation of σH adducts of the α-chlorocarbanion to nitroarene, followed by base-induced β-elimination of HCl. It was also evidenced that both of these processes can be the rate-limiting steps: the β-elimination at low base concentration and the nucleophilic addition at high base concentration. Consistent with that conclusion is the finding that the kinetic isotope effect in the VNS reaction decreases from 4.2 (a value typical of a primary KIE) to 0.8 (a value typical of a secondary KIE) with increasing base concentration. Also reported is our discovery that the SNAr substitution of the 2-fluoronitrobenzenes studied in this work was subject to base catalysis under some of the experimental conditions employed in our competitive experiments.
- Makosza, Mieczyslaw,Lemek, Tadeusz,Kwast, Andrzej,Terrier, Francois
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p. 394 - 400
(2007/10/03)
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- Synthesis of selectively deuterated nitrobenzene derivatives
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Selectively ortho-deuterated nitroarenes of high isotopic purity are prepared via acid catalysed H→D exchange in para-substituted anilines followed by oxidation of the amino groups.
- Lemek, Tadeusz,Ma?kosza, Mieczys?aw,Goliński, Jerzy
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p. 4753 - 4757
(2007/10/03)
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- 4-Acetylamino-3-(imidazol-1-yl)-benzoic acids as novel inhibitors of influenza sialidase
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Two methods for the synthesis of 4-acetylamino benzoic acids substituted at the 3-position with imidazoles are described. Many of the compounds are inhibitors of influenza virus sialidases with levels of activity similar to the recently described 4-acetylamino-3-guanidino-benzoic acid (BANA 113).
- Howes, Peter D.,Cleasby, Anne,Evans, Derek N.,Feilden, Helen,Smith, Paul W.,Sollis, Steven L.,Taylor, Neil,Wonacott, Alan J.
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p. 225 - 234
(2007/10/03)
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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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- 4-Nitrobenzophenone compounds
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A compound of the formula I STR1 and other compounds and process for preparing, which compounds are useful as intermediates.
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- Novel Fluorinated Antifolates. Enzyme Inhibition and Cytotoxicity Studies on 2'- and 3'-Fluoroaminopterin
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Two novel analogues of aminopterin with a single fluorine substitution in the 2' (compound 8) or in the 3' (compound 9) position of the p-aminobenzoyl group were synthesized and evaluated as inhibitors of dihydrofolate reductase from two bacterial species and from human HeLa cells.The 2'fluoro compound was bound essentially the same as aminopterin itself, while the 3'-fluoro derivative bound two- to threefold more tightly in all cases.UV spectral shifts indicated normal binding of the pteridine.Cytotoxicity studies against mouse leukemia L1210 cells and the human stomach cancer line HuTu80 indicated equivalent toxicity of the parent drug with the 2'-fluoro analogue. 3'-Fluoroaminopterin was, however, twice as toxic as aminopterin to both cell lines.
- Henkin, Jack,Washtien, Wendy L.
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p. 1193 - 1196
(2007/10/02)
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