- RHO-ASSOCIATED PROTEIN KINASE INHIBITOR, PHARMACEUTICAL COMPOSITION COMPRISING SAME, AND USE THEREOF
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A Rho-associated protein kinase (ROCK) inhibitor represented by formula (I), a pharmaceutical composition comprising same, and a use thereof for preventing or treating ROCK-mediated diseases.
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Paragraph 0228-0232
(2022/01/12)
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- Synthetic method of drug intermediate nitrogen-containing heterocycle-containing brominated compound
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The invention relates to a method for synthesizing a pharmaceutical intermediate nitrogen heterocyclic bromo-compound. The method comprises that 6-bromoisoquinoline, dichloromethane and m-chloroperoxybenzoic acid as raw materials undergo a reaction to produce a mixture 6-bromoisoquine oxynitride, phosphorus oxychloride is added into the mixture so that solid and water phase products are obtained,the solid products are dried, the water phase products are repeatedly washed and are extracted multiple times, the organic phase is spin-dried, the solid and water phases are treated so that 6-bromo-1-chloroisoquinoline is obtained, the solid crude product and the water crude product are mixed, the mixture is treated through a silica gel column of 100-200 meshes, the mixture is eluted through a petroleum ether PE: ethyl acetate EA eluent A to form a pure product 6-bromo-1-chloroisoquinoline, trimethylbromosilane, acetonitrile and 6-bromo-1-chloroisoquinoline undergo a reaction, pH of the reaction product is adjusted to 7 so that 1, 6-dibromoisoquinoline is obtained, and the 1, 6-dibromoisoquinoline is added into dichloroditriphenyl phosphine and a homemade Grignard reagent so that a finalproduct 6-bromo-1-methylisoquinoline is obtained. The method has the advantages of clear processes, less waste, high yield, raw material saving and operation easiness.
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- The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate
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This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled a
- Panarese, Joseph D.,Engers, Darren W.,Wu, Yong-Jin,Guernon, Jason M.,Chun, Aspen,Gregro, Alison R.,Bender, Aaron M.,Capstick, Rory A.,Wieting, Joshua M.,Bronson, Joanne J.,Macor, John E.,Westphal, Ryan,Soars, Matthew,Engers, Julie E.,Felts, Andrew S.,Rodriguez, Alice L.,Emmitte, Kyle A.,Jones, Carrie K.,Blobaum, Anna L.,Jeffrey Conn,Niswender, Colleen M.,Hopkins, Corey R.,Lindsley, Craig W.
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p. 342 - 346
(2018/12/05)
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- Wnt SIGNALING INHIBITOR, COMPOSITION, AND COMPOUND AS USE THEREFOR
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PROBLEM TO BE SOLVED: To provide an inhibitor for Wnt signaling route. SOLUTION: The present invention provides a compound represented by formula I, and a composition comprising the compound (X1-X8 independently represent CR4 or N; Y1 is H or C (R4)3; Y2 and Y3 independently represent H, halogen or C (R3)3; R1 and R2 independently represent H, halogen, C1-6 alkyl, quinolinyl or the like; R3s independently represent H, halogen, cyano, C1-6 alkyl or the like; R4s independently represent H, halogen, cyano, C1-6 alkoxy or the like). SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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- Method for preparing 2-methyl-1-oxo-1, 2-dihydroisoquinolines-6-formic acid
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The invention relates to a method for synthesizing 2-methyl-1-oxo-1, 2-dihydroisoquinolines-6-formic acid. The 2-methyl-1-oxo-1, 2-dihydroisoquinolines-6-formic acid is made of 6-bromoisoquinoline. The method includes adding meta-chloroperoxybenzoic acid into the 6-bromoisoquinoline and carrying out reaction on the 6-bromoisoquinoline and the meta-chloroperoxybenzoic acid under room-temperature conditions overnight to obtain a mixture which is bromoisoquinoline nitrogen oxide; adding the mixture into phosphoryl chloride in batches, carrying out temperature reaction on the mixture and the phosphoryl chloride to obtain reaction products, cooling the reaction products to precipitate a large quantity of solid and washing and drying the solid to obtain 6-bromine-1-chloroisoquinoline; extracting aqueous phases and directly carrying out spin dry on organic phases to obtain 6-bromine-1-chloroisoquinoline with the purity higher than 95%; placing the 6-bromine-1-chloroisoquinoline into THF (tetrahydrofuran) and adding n-butyl lithium and carbon dioxide gas into the 6-bromine-1-chloroisoquinoline and the THF to obtain 1-chloroisoquinoline-6-formic acid; placing the 1-chloroisoquinoline-6-formic acid into concentrated hydrochloric acid to obtain white solid which is 1-oxo-1, 2-dihydroisoquinolines-6-formic acid; placing the 1-oxo-1, 2-dihydroisoquinolines-6-formic acid into solvents, adding cesium carbonate into the 1-oxo-1, 2-dihydroisoquinolines-6-formic acid and the solvents and dropwise adding methyl iodide into the 1-oxo-1, 2-dihydroisoquinolines-6-formic acid and the solvents to obtain 2-methyl-1-oxo-1, 2-dihydroisoquinolines-6-methyl formate; adding the 2-methyl-1-oxo-1, 2-dihydroisoquinolines-6-methyl formate into methyl alcohol, adding NaOH solution into the 2-methyl-1-oxo-1, 2-dihydroisoquinolines-6-methyl formate and the methyl alcohol, removing the methyl alcohol by means of reduced-pressure distillation to obtain mixtures, regulating the PH (potential of hydrogen) of the mixtures until the PH of the mixtures is equal to 2, precipitating solid, carrying out suction filtration and washing and drying the solid to obtain a product which is the 2-methyl-1-oxo-1, 2-dihydroisoquinolines-6-formic acid. The method has the advantages of reasonable route, little wastage, high yield, easiness in operation and capability of saving raw materials.
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- Inhibiting WNT signal conduction of compound, composition and use thereof (by machine translation)
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The invention relates to a having the general formula (1) compounds and compositions thereof, and the use of the compound or composition thereof to inhibit WNT signal transmission method. The compounds of this invention and its composition can effectively inhibit the secretion of WNT protein, inhibit WNT signal conduction, so the WNT-mediated disease with a very good therapeutic effect. . (by machine translation)
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- IMIDAZOISOQUINOLINE COMPOUNDS, COMPOSITIONS COMPRISING THE COMPOUNDS AND THEIR USE FOR CONTROLLING INVERTEBRATE PESTS
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The present invention relates to novel imidazoisoquinoline compounds of the formula I and the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof wherein A1 is N or C(R2), A2 is N or C(R3); A3 is N or C(R4); A4 is N or C(R5); A5 is N or C(R6); and where Ar, R, R1, R2, R3, R4,R5 and R6 are as defined in the claims. The compounds of formula (I), as well as the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof, are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.
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Page/Page column 140; 141
(2016/08/10)
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- Regioselective Chlorination of Quinoline N-Oxides and Isoquinoline N-Oxides Using PPh3/Cl3CCN
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A novel method for the regioselective C2-chlorination of heterocyclic N-oxides has been developed. PPh3/Cl3CCN were used as chlorinating reagents and the desired N-heterocyclic chlorides were obtained smoothly in satisfactory yields. The reactions proceeded in a highly efficient and selective manner across a broad range of substrates demonstrating excellent functional group tolerance. In addition, this chlorination reaction can be used for the modification of N-heterocyclic scaffolds of appealing ligands and pharmaceuticals.
- Qiao, Kai,Wan, Li,Sun, Xiaoning,Zhang, Kai,Zhu, Ning,Li, Xin,Guo, Kai
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p. 1606 - 1611
(2016/04/05)
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- TUMOR BIOMARKERS AND USE THEREOF
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Disclosed herein are biomarkers related to WNT signal transduction pathway, as well as methods and kits comprising the same. Further, the present disclosure relates to the use of the biomarkers in patient selection, companion diagnostics, and treatment of cancer.
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- Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery
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Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.
- Devine, William,Woodring, Jennifer L.,Swaminathan, Uma,Amata, Emanuele,Patel, Gautam,Erath, Jessey,Roncal, Norma E.,Lee, Patricia J.,Leed, Susan E.,Rodriguez, Ana,Mensa-Wilmot, Kojo,Sciotti, Richard J.,Pollastri, Michael P.
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supporting information
p. 5522 - 5537
(2015/08/03)
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- Compound as WNT Signaling Inhibitor, Composition, and Use Thereof
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The present invention relates to a compound having the structure of Formula I as inhibitor of WNT signal transduction pathways, as well as a composition comprising the compound. Further, the present invention relates to the use of the compound and the method of inhibiting the WNT signal transduction pathways.
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- COMPOUNDS FOR TREATMENT OF FIBROSIS DISEASES
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The present invention relates to compounds as inhibitor of WNT signal transduction pathway, as well as a composition comprising the same. Further, the present invention relates to the use of the compounds in the treatment of fibrosis. Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury.
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- COMPOUNDS FOR TREATMENT OF CANCER
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The present invention relates to compounds as inhibitor of WNT signal transduction pathway, as well as a composition comprising the same. Further, the present invention relates to the use of the compounds in the treatment of cancer.
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- A practical and mild chlorination of fused heterocyclic N-oxides
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Fused azine N-oxides were selectively chlorinated at C2 in moderate to excellent yields, employing Vilsmeier reagent as both the activating agent and the nucleophilic chloride source. Remarkable features of the method include simple operation, mild reaction conditions, a wide substrate scope, and the use of only stoichiometric amount of POCl3. The potential extension of this method to a one-pot oxidation/chlorination sequence that obviates the need for isolation of the N-oxide intermediates is also validated.
- Wang, Dong,Jia, Hailing,Wang, Wuchang,Wang, Zhe
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supporting information
p. 7130 - 7132
(2015/02/02)
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- COMPOUND AS WNT SIGNALING INHIBITOR, COMPOSITION, AND USE THEREOF
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The present invention relates to a compound having the structure of Formula I as inhibitor of WNT signal transduction pathways, as well as a composition comprising the compound. Further, the present invention relates to the use of the compound and the method of inhibiting the WNT signal transduction pathways.
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- Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors
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Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
- Ray, Peter,Wright, Jane,Adam, Julia,Bennett, Johnathan,Boucharens, Sylviane,Black, Darcey,Cook, Andrew,Brown, Angus R.,Epemolu, Ola,Fletcher, Dan,Haunso, Anders,Huggett, Margaret,Jones, Phil,Laats, Steven,Lyons, Amanda,Mestres, Jordi,De Man, Jos,Morphy, Richard,Rankovic, Zoran,Sherborne, Brad,Sherry, Lorcan,Van Straten, Nicole,Westwood, Paul,Zaman, Guido Z.R.
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supporting information; scheme or table
p. 97 - 101
(2011/02/28)
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- SUBSTITUTED ISOQUINOLINE AND ISOQUINOLINONE DERIVATIVES
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The invention relates to 6-substituted isoquinoline and isochinolone derivatives of the formula (I) useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.
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Page/Page column 54
(2008/12/06)
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- CYCLOALKYLAMINE SUBSTITUTED ISOQUINOLONE AND ISOQUINOLINONE DERIVATIVES
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The invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of the formula 1 useful for the treatment and prevention of diseases associated with Rho-kinase and Rho- kinase mediated phosphorylation of myosin light chain phosphatase, and composition containing such compound
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Page/Page column 42-43
(2008/12/06)
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- Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity
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The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse iv t1/2 = 0.3 h, po F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t1/2 = 5.0 h, po F = 51%) but resulted in >500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity.
- Zhu, Gui-Dong,Gong, Jianchun,Claiborne, Akiyo,Woods, Keith W.,Gandhi, Viraj B.,Thomas, Sheela,Luo, Yan,Liu, Xuesong,Shi, Yan,Guan, Ran,Magnone, Shayna R.,Klinghofer, Vered,Johnson, Eric F.,Bouska, Jennifer,Shoemaker, Alexander,Oleksijew, Anatol,Stoll, Vincent S.,Jong, Ron De,Oltersdorf, Tilman,Li, Qun,Rosenberg, Saul H.,Giranda, Vincent L.
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p. 3150 - 3155
(2007/10/03)
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- Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors
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A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (Ki = 0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other kinases. It is least selective for other members of the AGC family of kinases but is nonetheless 40-fold selective for Akt over PKA. The compound shows cellular activity and significantly slows tumor growth in vivo.
- Woods, Keith W.,Fischer, John P.,Claiborne, Akiyo,Li, Tongmei,Thomas, Sheela A.,Zhu, Gui-Dong,Diebold, Robert B.,Liu, Xuesong,Shi, Yan,Klinghofer, Vered,Han, Edward K.,Guan, Ran,Magnone, Shayna R.,Johnson, Eric F.,Bouska, Jennifer J.,Olson, Amanda M.,Jong, Ron de,Oltersdorf, Tilman,Luo, Yan,Rosenberg, Saul H.,Giranda, Vincent L.,Li, Qun
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p. 6832 - 6846
(2007/10/03)
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- Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-Isoquinolinylguanidines
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A series of 1-isoquinolinylguanidines are shown to be potent inhibitors of uPA with selectivity over tPA and plasmin. Potency is enhanced by the presence of a 4-halo and a 7-aryl substituent, particularly when substituted by a 3-carboxylic acid group. Compound 13j (UK-356,202) combines excellent potency and selectivity, and has been selected as a candidate for clinical evaluation.
- Barber, Christopher G.,Dickinson, Roger P.,Fish, Paul V.
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p. 3227 - 3230
(2007/10/03)
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors are disclosed having the general formula:(I) wherein R1, R2, R3, R', B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds toinhibit HCV are also disclosed.
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- Kinase inhibitors
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Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
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- Kinase inhibitors
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Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
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Page/Page column 36
(2010/01/31)
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- Heterocyclic derivatives and their use as antithrombotic agents
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The present invention relates to antithrombotic compounds comprising the group Q, Q having formula (I), wherein the substructure (i) is a structure selected from (a, b and c), wherein X is O or S; X′ being independently CH or N; and m is 0, 1, 2 or 3; wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom, or a pharmaceutically acceptable salt thereof or a prodrug thereof. The compounds of the invention are therapeutically active and in particular are antithrombotic agents.
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- Isoquinolines as urokinase inhibitors
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Compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein one of R1 and R2 is H and the other is N=C(NH2)2 or NHC(=NH)NH2, and the other substituents are as defined herein, are urokinase (uPA) inhibitors.
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- Substituted sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
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The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, which are for treating a patient suffering from, or subject to, physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.
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- Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors
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Thienopyridine sulfonamide pyrrolidinones were found to be potent and selective inhibitors of the coagulation cascade enzyme factor Xa. SAR studies led to several compounds that were selected for further in vivo investigation. These novel aryl binding pocket moieties represent a structural modification to a series of fXa inhibitors. Several compounds proved to be efficacious iv antithrombotic agents.
- Becker, Michael R.,Ewing, William R.,Davis, Roderick S.,Pauls, Henry W.,Ly, Cuong,Li, Aiwen,Mason, Helen J.,Choi-Sledeski, Yong Mi,Spada, Alfred P.,Chu, Valeria,Brown, Karen D.,Colussi, Dennis J.,Leadley, Robert J.,Bentley, Ross,Bostwick, Jeff,Kasiewski, Charles,Morgan, Suzanne
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p. 2753 - 2758
(2007/10/03)
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- 1-Aminoisoquinoline as benzamidine isoster in the design and synthesis of orally active thrombin inhibitors
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Replacement of the highly basic benzamidine moiety of NAPAP by the moderately basic 1-aminoisoquinoline moiety resulted in thrombin inhibitors with improved selectivity towards trypsin and enhanced Caco-2 cell permeability.
- Rewinkel,Lucas,Van Galen,Noach,Van Dinther,Rood,Jenneboer,Van Boeckel
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p. 685 - 690
(2007/10/03)
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- SUBSTITUTED SULFONIC ACID N-[(AMINOIMINOMETHYL)PHENYLALKYL]-AZAHETEROCYCLAMIDE COMPOUNDS
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The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, which are for treating a patient suffering from, or subject to, physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.
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