- Synthesis method for 4-Aaminotetrahydropyran synthesis
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The invention discloses a synthesis method for 4-aminotetrahydropyran. The method comprises the steps that tetrahydro-2H-pyran-4-carboxylic acid is dissolved in water, the temperature is increased to60-70 DEC G by heating, ammonia water is added dropwisely under the condition of stirring, stirring reaction is conducted for 1-2 hours after dropwise adding is completed, the temperature is decreasedto the room temperature after the reaction is completed to obtain tetrahydro-2H-pyran-4-carboxamide mixed solution; cooling is conducted on the prepared tetrahydro-2H-pyran-4-carboxamide mixed solution to reduce the temperature to 5-10 DEC G, NaOH solution is added, NaBrO solution is added dropwisely in the mixed solution after the mixed solution is stirred uniformly, after the dropwise adding iscompleted, the reaction is performed constantly for 1-2 hours under the temperature of 5-10 DEC G, the temperature is decreased to the room temperature after the temperature is increased to 50-60 DECG to perform the reaction constantly for 1 hour, extraction is conducted by using dichloromethane, an organic phase is combined, and after the dichloromethane is removed by distillation through reducing pressure, recrystallization is conducted to obtain the 4-aminotetrahydropyran. The method has the advantages of being simple to operate, mild in condition, less in byproducts, high in product purity, and higher in product yield.
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Paragraph 0020; 0028; 0034; 0035; 0036; 0044; 0052
(2018/06/23)
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- 4-Aminotetrahydropyrans process for one-pot synthesis
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The invention discloses a one-kettle method synthesis process of 4-aminotetrahydropyran. The synthesis process comprises the following steps: synthesizing 4-carboxamide tetrahydropyran by taking 4-cyano-tetrahydropyran and a sodium hydroxide solution (or a potassium hydroxide solution) as raw materials, further slowly adding a sodium hypochlorite solution (or a sodium hypobromite solution) into 4-carboxamide tetrahydropyran, then heating till reflux, and performing decarboxylation to generate a product, namely 4-aminotetrahydropyran. All the reaction raw materials are placed into one kettle for reaction, the appropriate reaction conditions are selected for synthesizing 4-aminotetrahydropyran, and the synthesis process has the advantages of high selectivity, few impurities, no need of separating intermediate products, high yield and high practical value.
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Paragraph 0014; 0015
(2017/02/02)
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- Optimization of diarylthiazole B-Raf inhibitors: Identification of a compound endowed with high oral antitumor activity, mitigated hERG inhibition, and low paradoxical effect
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Aberrant activation of the mitogen-activated protein kinase (MAPK)-mediated pathway components, RAF-MEK-ERK, is frequently observed in human cancers and clearly contributes to oncogenesis. As part of a project aimed at finding inhibitors of B-Raf, a key player in the MAPK cascade, we originally identified a thiazole derivative endowed with high potency and selectivity, optimal in vitro ADME properties, and good pharmacokinetic profiles in rodents, but that suffers from elevated hERG inhibitory activity. An optimization program was thus undertaken, focused mainly on the elaboration of the R1 and R2 groups of the scaffold. This effort ultimately led to N-(4-{2-(1-cyclopropylpiperidin-4-yl)-4-[3-(2,5-difluorobenzenesulfonylamino)-2-fluorophenyl]thiazol-5-yl}-pyridin-2-yl)acetamide (20), which maintains favorable in vitro and in vivo properties, but lacks hERG liability. Besides exhibiting potent antiproliferative activity against only cell lines bearing B-Raf V600E or V600D mutations, compound 20 also intriguingly shows a weaker "paradoxical" activation of MEK in non-mutant B-Raf cells than other known B-Raf inhibitors. It also demonstrates very good efficacy in vivo against the A375 xenograft melanoma model (tumor volume inhibition >90% at 10 mg kg-1); it is therefore a suitable candidate for preclinical development.
- Pulici,Traquandi,Marchionni,Modugno,Lupi,Amboldi,Casale,Colombo,Corti,Fasolini,Gasparri,Pastori,Scolaro,Donati,Felder,Galvani,Isacchi,Pesenti,Ciomei
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p. 276 - 295
(2015/02/05)
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- BIPHENYL COMPOUNDS AND USES THEREOF
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The present invention relates to biphenyl compounds and uses thereof in medicine. Specifically, the present invention relates to a compound of Formula (I), or a stereoisomer, a geometric isomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer, an N-oxide, a hydrate, a solvate, a metabolite, a hydrolysate, a pharmaceutically acceptable salt or a prodrug thereof. The compound disclosed herein is used as a therapeutic agent particularly a GPR40 agonist for treating diabetes and metabolic disease in a patient.
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Paragraph 00325
(2015/05/19)
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- Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries
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The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.
- Craven, Philip,Aimon, Anthony,Dow, Mark,Fleury-Bregeot, Nicolas,Guilleux, Rachel,Morgentin, Remy,Roche, Didier,Kalliokoski, Tuomo,Foster, Richard,Marsden, Stephen P.,Nelson, Adam
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supporting information
p. 2629 - 2635
(2015/01/30)
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- NOVEL COMPOUNDS USEFUL AS S100-INHIBITORS
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A compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising the compound. The compound is an inhibitor of interactions between S100A9 and interaction partners such as RAGE, TLR4 and EMMPRIN and as such is useful in the treatment of disorders such as cancer, autoimmune disorders, inflammatory disorders and neurodegenerative disorders.
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Page/Page column 71; 72
(2015/12/08)
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- N-Acyl-N'-(pyridin-2-yl) Ureas and Analogs Exhibiting Anti-Cancer and Anti-Proliferative Activities
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Described are compounds of Formula 1 which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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Paragraph 0254
(2014/09/29)
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- N-Acyl-N'-(pyridin-2-yl) Ureas and Analogs Exhibiting Anti-Cancer and Anti-Proliferative Activities
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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Paragraph 0358
(2014/09/30)
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- THIAZOLYLPHENYL-BENZENESULFONAMIDO DERIVATIVES AS KINASE INHIBITORS
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Thiazolylphenyl-benzenesulfonamido derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.
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Paragraph 0326; 0327
(2014/01/07)
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- THIAZOLYLPHENYL-BENZENESULFONAMIDO DERIVATIVES AS KINASE INHIBITORS
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Thiazolylphenyl-benzenesulfonamido derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.
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Page/Page column 41-42
(2012/09/11)
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- NEW IMIDAZOLONE DERIVATIVES, PREPARATION THEREOF AS DRUGS, PHARMACEUTICAL COMPOSITIONS, AND USE THEREOF AS PROTEIN KINASE INHIBITORS, IN PARTICULAR CDC7
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The present invention relates to imidazolone derivatives of formula (I) to methods of preparing such derivatives, intermediates thereto, pharmaceutical compositions comprising such derivatives, and methods of inhibiting protein kinase, and methods of treatment comprising administration of such derivatives.
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Page/Page column 55
(2009/10/17)
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- Process for Preparing Tetrahydropyran-4-Carboxylic Acid Compound
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The present invention is to provide a process for preparing tetrahydropyran-4-carboxylic acid represented by the formula (1): which comprises hydrolyzing a 4-cyanotetrahydropyran-4-carboxylic acid compound represented by the formula (2): wherein R represents a hydrogen atom or a hydrocarbon group, in the presence of an acid; a process for preparing a tetrahydropyran-4-carboxylic acid ester which comprises reacting the tetrahydropyran-4-carboxylic acid represented by the above-mentioned formula (1) with an alcohol in the presence of an acid; and a process for preparing tetrahydropyran-4-carboxylic acid amide which comprises reacting the tetrahydropyran-4-carboxylic acid represented by the above-mentioned formula (1) with a halogenating agent to prepare tetrahydropyran-4-carboxylic acid halide, and then, reacting an amine compound to the resulting compound.
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Page/Page column 6
(2009/01/20)
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- HIV integrase inhibitors
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The invention encompasses a series bicyclic pyrimidinone compounds of Formula I which inhibit HIV integrase and prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.
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Page/Page column 45
(2010/11/27)
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- Process for production of pyrazole-fused ring derivatives
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An object of the invention is to find out intermediates usful for the synthesis of pyrazol-fused ring derivatives (such as 7-phenylpyrazolo[1,5-a]pyridine derivatives) and a method for producing the same. A method for producing compound represented by the general formula (II), wherein Z1 and Z2 each independently represents a methine group or a nitrogen atom; R1 represents an ethyl group or the like; R5 represents a hydrogen atom or the like; R2 and R3 each independently represents a C1-6 alkyl group or the like, salts thereof, or solvates of both, comprising the step of: reacting a compound represented by the general formula (I), wherein Z1, Z2, R5, R1, R2 and R3 each has the same definition as described above, with an organometallic reagent; and then reacting the resulting product with pentafluoroiodobenzene. [image]
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Page/Page column 9
(2010/11/28)
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- SUBSTITUTED IMIDAZOQUINOLINES, IMIDAZONAPHTHYRIDINES, AND IMIDAZOPYRIDINES, COMPOSITIONS, AND METHODS
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Certain 1H-imidazo[4,5-c]quinolines, 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolines, 1H-imidazo[4,5-c][1,5]naphthyridines, 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridines, and 1H-imidazo[4,5-c]pyridines substituted at the 1- and 2-positions, pharmaceutical compositions containing these compounds, methods of making the compounds, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases, are disclosed.
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Page/Page column 111
(2010/11/27)
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- NITROGEN-CONTAINING HETEROCYCLIC COMPOUND AND PHARMACEUTICAL APPLICATION THEREOF
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It is intended to provide a compound represented by the general formula (I): (I) (wherein all the symbols are as defined in the description) which has a p38 MAP kinase inhibitory activity, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. The compound of the invention is useful for preventing or treating a disease in which the abnormal production of a cytokine such as an inflammatory cytokine or a chemokine or overreaction to them is considered to be involved in the cause and aggravation of pathological conditions, in other words, an inflammatory disease, a respiratory disease, a cardiovascular disease, a central nervous system disease or the like, which is a cytokine-mediated disease.
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Page/Page column 79
(2010/11/26)
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- ARYLOXY AND ARYLALKYLENEOXY SUBSTITUTED IMIDAZOQUINOLINES
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Imidazoquinoline compounds with an aryloxy or arylalkyleneoxy or hydroxy substituent at the 6, 7, 8, or 9-position, pharmaceutical compositions containing the compounds, intermediates, and methods of use of these compounds as immunomodulators, for modulating cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases, are disclosed.
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Page/Page column 248
(2008/06/13)
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- CB1 MODULATOR COMPOUNDS
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Novel compounds of structural formula (I) are disclosed. As modulators of the Cannabinoid-1 (CB1) receptor, these compounds are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. As such, compounds of the present invention are useful as in the treatment, prevention and suppression of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders (e.g., multiple sclerosis, Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis), cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, and nicotine. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith.
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Page/Page column 88
(2008/06/13)
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- 7-phenylpyrazolopyridine compounds
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A compound represented by the formula: [wherein R1 is methoxy, methylthio, ethyl, etc.; R5 and R6 are each independently cyclopropylmethyl, (4-tetrahydropyranyl)methyl, etc.; and two of R40, R41 and R42 are C1-6 alkoxy while the remaining one is methoxymethyl, etc.], a salt thereof, or a hydrate of the foregoing. This compound has excellent antagonism against corticotropin-releasing factor receptor.
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- ARYL / HETARYL SUBSTITUTED IMIDAZOQUINOLINES
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Aryl substituted imidazoquinoline compounds, according to formula I, pharmaceutical compositions containing the compounds, intermediates, and methods of use of these compounds as immunomodulators, for inducing w or inhibiting cytokine biosynthesis in animals and in the treatment of diseases including viral., and neoplastic, are disclosed. formula (I): wherein: R is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl;. N is 0 or 1; R3 is selected from the group consisting of: -Z-Ar,-Z-Ar’-Y-R4, -Z-Ar’-X-Y-R4, Z-Ar’-R5, and-Z-Ar'-X-R5; Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy; heterocyctyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino.
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Page 283-284
(2008/06/13)
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