- Discovery of a novel series of guanidinebenzoates as gut-restricted enteropeptidase and trypsin dual inhibitors for the treatment of metabolic syndrome
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A novel series of guanidinebenzoate enteropeptidase and trypsin dual inhibitors has been discovered and SAR studies were conducted. Optimization was focused on improving properties for gut restriction, including increased aqueous solubility, lower cellular permeability, and reduced oral bioavailability. Lead compounds were identified with efficacy in a mouse fecal protein excretion study.
- Zhang, Xuqing,Zhu, Bin,Sun, Weimei,Wang, Mina,Albarazanji, Kamal,Ghosh, Brahma,Cummings, Maxwell,Lenhard, James,Leonard, James,Macielag, Mark,Lanter, James
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supporting information
(2021/03/22)
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- 5,8-DISUBSTITUTED-[1,2,4]TRIAZOLO[1,5-A]PYRIDINYL AND 5,8-DISUBSTITUTED-IMIDAZO[1,2-A]PYRIDINE DERIVATIVES USEFUL AS INHIBITORS OF ENTEROPEPTIDASE
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The present invention is directed to 5,8-disubstituted-[1,2,4]triazolo[1,5- a]pyridinyl and 5,8-disubstituted-imidazo[1,2-a]pyridine derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the enteropeptidase enzyme.
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Page/Page column 123
(2021/01/29)
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- CYANO-SUBSTITUTED IMIDAZO[1,2-A]PYRIDINECARBOXAMIDES AND THEIR USE
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The present application relates to novel substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for the treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prophylaxis of cardiovascular disorders.
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- IMIDAZO[1,2-A]PYRIDINES AS SOLUBLE GUANYLATE CYCLASE STIMULATORS FOR THE TREATMENT OF CARDIOVASCULAR DISEASES
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The present application relates to novel substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 0890; 0891; 0892; 0893; 0894
(2017/03/21)
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- SUBSTITUTED IMIDAZO[1,2-A]PYRIDINECARBOXAMIDES AND THEIR USE
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The present application relates to novel substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 0591; 0592; 0593; 0594; 0595
(2017/03/21)
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- IMIDAZO[1,2-A]PYRIDINES AS STIMULATORS OF SOLUBLE GUANYLATE CYCLASE FOR TREATING CARDIOVASCULAR DISEASES
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The present application relates to novel heterocyclyl- and heteroaryl-substituted imidazo[1,2-a]pyridines, to processes for preparation thereof, to the use thereof, alone or in combinations, for the treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 0588; 0591-0595
(2017/03/21)
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- HETEROARYL-SUBSTITUTED IMIDAZO[1,2-A]PYRIDINES AND THEIR USE
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The present application relates to novel heteroaryl-substituted imidazo[1,2-a]pyridines, to processes for preparation thereof, to the use thereof, alone or in combinations, for the treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 0567; 0573; 0574; 0575; 0576
(2017/11/14)
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- 3-ARYL-SUBSTITUTED IMIDAZO[1,2-A]PYRIDINES AND THEIR USE
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The present application relates to novel 3-aryl-substituted imidazo[1,2-a]pyridines, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 0594; 0600; 0601; 0602; 0603
(2016/12/26)
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- 3-(PYRIMIDINE-2-YL)IMIDAZO[1,2-A]PYRIDINES
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The present application relates to novel 3-(pyrimidin-2-yl)imidazo[1,2-a]pyridines, to processes for preparation thereof, to the use thereof, alone or in combinations, for the treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 0582; 0588; 0589; 0590; 0591; 0592
(2017/04/04)
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- ARYL- AND HETARYL-SUBSTITUTED IMIDAZO[1,2-A]PYRIDINE-3-CARBOXAMIDES AND USE THEREOF
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The present application relates to novel aryl- and hetaryl-substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 0532; 0533; 0534; 0535; 0536
(2017/01/02)
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- Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons
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Diacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective and reversible inhibitors are required to study the function of DAGLs in neuronal cells in an acute and temporal fashion, but they are currently lacking. Here, we describe the identification of a highly selective DAGL inhibitor using structure-guided and a chemoproteomics strategy to characterize the selectivity of the inhibitor in complex proteomes. Key to the success of this approach is the use of comparative and competitive activity-based proteome profiling (ABPP), in which broad-spectrum and tailor-made activity-based probes are combined to report on the inhibition of a protein family in its native environment. Competitive ABPP with broad-spectrum fluorophosphonate-based probes and specific β-lactone-based probes led to the discovery of α-ketoheterocycle LEI105 as a potent, highly selective, and reversible dual DAGL-α/DAGL-β inhibitor. LEI105 did not affect other enzymes involved in endocannabinoid metabolism including abhydrolase domain-containing protein 6, abhydrolase domain-containing protein 12, monoacylglycerol lipase, and fatty acid amide hydrolase and did not display affinity for the cannabinoid CB1 receptor. Targeted lipidomics revealed that LEI105 concentration-dependently reduced 2-AG levels, but not anandamide levels, in Neuro2A cells. We show that cannabinoid CB1-receptor-mediated short-term synaptic plasticity in a mouse hippocampal slice model can be reduced by LEI105. Thus, we have developed a highly selective DAGL inhibitor and provide new pharmacological evidence to support the hypothesis that "on demand biosynthesis" of 2-AG is responsible for retrograde signaling.
- Baggelaar, Marc P.,Chameau, Pascal J. P.,Kantae, Vasudev,Hummel, Jessica,Hsu, Ku-Lung,Janssen, Freek,Van Der Wel, Tom,Soethoudt, Marjolein,Deng, Hui,Den Dulk, Hans,Allarà, Marco,Florea, Bogdan I.,Di Marzo, Vincenzo,Wadman, Wytse J.,Kruse, Chris G.,Overkleeft, Herman S.,Hankemeier, Thomas,Werkman, Taco R.,Cravatt, Benjamin F.,Van Der Stelt, Mario
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p. 8851 - 8857
(2015/07/27)
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- Hydroxy-substituted imidazo[1,2-a]pyridinecarboxamides and their use
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The present application relates to novel substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for their preparation, to their use alone or in combinations for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 1273; 1274; 1275; 1276; 1277
(2014/05/20)
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- Carboxy-substituted imidazo[1,2-a]pyridinecarboxamides and their use
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The present application relates to novel substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for their preparation, to their use alone or in combinations for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 0426-0430
(2014/05/20)
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- Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
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The present application relates to novel substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for their preparation, to their use alone or in combinations for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.
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Paragraph 1076; 1077; 1078; 1079; 1080
(2014/05/20)
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- Identification of a new class of glucokinase activators through structure-based design
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Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate GK may serve as effective treatments for type 2 diabetes. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators (GKAs). We discovered an initial thiazolylamino pyridine-based hit that was optimized using a structure-based design strategy and identified 26 as an early lead. Compound 26 demonstrated a good balance of in vitro potency and enzyme kinetic parameters and demonstrated blood glucose reductions in oral glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker diabetic fatty rats.
- Hinklin, Ronald J.,Boyd, Steven A.,Chicarelli, Mark J.,Condroski, Kevin R.,Dewolf, Walter E.,Lee, Patrice A.,Lee, Waiman,Singh, Ajay,Thomas, Laurie,Voegtli, Walter C.,Williams, Lance,Aicher, Thomas D.
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supporting information
p. 7669 - 7678
(2013/11/06)
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- Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)
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Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.
- Cui, J. Jean,Tran-Dubé, Michelle,Shen, Hong,Nambu, Mitchell,Kung, Pei-Pei,Pairish, Mason,Jia, Lei,Meng, Jerry,Funk, Lee,Botrous, Iriny,McTigue, Michele,Grodsky, Neil,Ryan, Kevin,Padrique, Ellen,Alton, Gordon,Timofeevski, Sergei,Yamazaki, Shinji,Li, Qiuhua,Zou, Helen,Christensen, James,Mroczkowski, Barbara,Bender, Steve,Kania, Robert S.,Edwards, Martin P.
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scheme or table
p. 6342 - 6363
(2011/11/05)
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- Synthesis and in-vitro anti-hepatitis B virus activity of ethyl 6-Bromo-8-hydroxyimidazo[1,2-a]pyridine-3-carboxylates
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A series of ethyl 6-bromo-8-hydroxyimidazo[1,2-a]pyridine-3-carboxylate derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in HepG2.2.15 cells. Nearly half of the tested compounds were proved to be highly effective in inhibiting the replication of HBV DNA with IC50 values ranging from 1.3 to 9.1 μM. Among them, 10o and 10s were identified as the most promising compounds.
- Chen, Dong,Liu, Yajing,Zhang, Shulan,Guo, Dexiang,Liu, Chunhong,Li, Sai,Gong, Ping
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p. 158 - 164
(2011/10/05)
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- Straightforward and efficient synthesis of 3-benzyloxy-4-bromopicolinate ester and 3-benzyloxy-5-bromopicolinate ester, common building blocks for pharmaceuticals and agrochemicals
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A practical and rapid preparation of 3-benzyloxy-4-bromo and 3-benzyloxy-5-bromopicolinate esters 10 and 16 was developed in four steps, respectively, in 38% and 31% overall yield. Then their viability as partners for cross-coupling reactions has been evaluated in Suzuki-Miyaura, Hartwig-Buchwald, and Sonogashira reactions to synthesize biologically relevant targets. The preparation of these two highly functionalizable pyridines 10 and 16 has been never described to date in the literature and could be used as common building block for the preparation of several biologically active compounds or agrochemical products.
- Verdelet, Tristan,Mercey, Guillaume,Correa, Nobi,Jean, Ludovic,Renard, Pierre-Yves
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experimental part
p. 8757 - 8762
(2011/11/29)
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- GLUCOKINASE ACTIVATORS
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Provided are compounds of Formula I wherein R1, R2, Y, Z and G are as defined herein, that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase.
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Page/Page column 1
(2010/11/27)
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- Synthesis and evaluation of 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a] pyridines as potassium-competitive acid blockers
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7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines with excellent physicochemical and pharmacological properties were identified that represent interesting candidates for further development as potassium-competitive acid blockers (P-CABs). The title compounds were prepared following synthetic pathways that relied either on a Claisen rearrangement/cross-metathesis reaction or on the (asymmetric) reduction of prochiral ketones. The influence of the character of the substituents R3, R6, and Ar on the biological activity and the physicochemical properties of the target compounds was examined. In contrast to the parent system (R6 = H), compounds in which R6 represents a carboxamide residue generally show improved in vivo activity and favorable pKa/log D values. Whereas variation of R3 is useful to obtain target compounds with modified basicity and lipophilicity, strong inhibition of the H+/K+-ATPase and potent in vivo activity is observed for R3 = methyl only. Small modifications of the aryl group, e.g., replacement of hydrogen versus a fluoro atom or a methyl group, are allowed. The (9S)-enantiomers are responsible for the gastric acid secretion inhibiting action, whereas the (9R)-enantiomers are virtually inactive.
- Palmer, Andreas M.,Grobbel, Burkhard,Jecke, Cornelia,Brehm, Christof,Zimmermann, Peter J.,Buhr, Wilm,Feth, Martin P.,Simon, Wolfgang-Alexander,Kromer, Wolfgang
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p. 6240 - 6264
(2008/03/27)
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- THERAPEUTIC AGENTS, AND METHODS OF MAKING AND USING THE SAME
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In part, the present invention is directed towards compounds with FabI inhibiting properties. Such compounds may also inhibit other enzymes, including those similar to FabI either structurally or functionally, for example, Fab K. Kits and compositions that include the disclosed compounds are also provided. Methods of treating a subject with a bacterial illness is also disclosed.
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Page/Page column 58; 98-99
(2008/06/13)
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- AMINOHETEROARYL COMPOUNDS AS PROTEIN TYROSINE KINASE INHIBITORS
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Aminoheteroaryl compounds are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.
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Page/Page column 62
(2010/10/20)
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- TRICYCLIC IMIDAZOPYRIDINES FOR USE AS GASTRIC SECRETION INHIBITORS
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The invention provides compounds of the formula (1), in which the substituents and symbols are as defined in the description. The compounds inhibit the secretion of gastric acid.
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Page/Page column 39
(2010/02/12)
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- TRICYCLIC IMIDAZOPYRIDINES
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The invention provides compounds of the formula (1), in which the substituents and symbols are as defined in the description. The compounds inhibit the secretion of gastric acid.
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Page/Page column 74
(2010/02/14)
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- AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Aminopyridine and aminopyrazine compounds of formula (1), compositions including these compounds, and methods of their use are provided. Preferred compounds of formula 1 have activity as protein kinase inhibitors, including as inhibitors of c-MET.
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Page 91; 130
(2010/02/08)
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- NITROSATED IMIDAZOPYRIDINES
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The invention relates to nitrosated imidazopyridines of a certain formula (I), in which the substituents and symbols have the meanings indicated in the description. The compounds have gastric secretion-inhibiting, anti-inflammatory and antibacterial properties.
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Page/Page column 27
(2010/02/07)
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