- Methods for treating neisseria gonorrhoeae infection with substituted 1,2-dihydro-2A,5,8A-triazaacenaphthylene-3,8-diones
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The present invention relates to methods for treating Neisseria Gonorrhoeae infection which comprises administering to a subject in need thereof novel 1,2-dihydro-2a,5,8a-triazaacenaphthylene-3,8-dione compounds: or pharmaceutically acceptable salts thereof and/or corresponding pharmaceutical compositions.
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Page/Page column 50
(2020/07/21)
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- Design, synthesis and anti-HBV activity evaluation of new substituted imidazo[4,5-b]pyridines
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The design and synthesis of a number of new imidazo[4,5-b]pyridines is described. The heterocyclic scaffold possesses 6-chloro- or 5,6-dichloro-substitution and bears various 2-alkylamino-methyl or ethyl groups. The corresponding N1 and N3-tosylates are also presented. The anti-HBV activity of the compounds was evaluated in HBV infectious system at the level of HBV rcDNA secretion and CC50, EC50 and selectivity index values were determined. The tosylates showed low antiviral potency and relatively high cytotoxicity, on the contrary, a number of 2,5 and/or-6-substituted imidazopyridines, mainly those belonging to the 6-chloroimidazo[4,5-b]pyridine series, were endowed with a very interesting profile and were further investigated. The most promising among them, along with the reduction of the secreted HBV rcDNA, also caused a reduction in HBV cccDNA and pgRNA levels, with a concomitant accumulation of the intracellular encapsidated rcDNA. Surprisingly, the most active 2-diethylaminoethyl-substituted derivative (21d), was highly competitive to interferon.
- Gerasi, Maria,Frakolaki, Efseveia,Papadakis, Georgios,Chalari, Anna,Lougiakis, Nikolaos,Marakos, Panagiotis,Pouli, Nicole,Vassilaki, Niki
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- Synthesis of new imidazopyridine nucleoside derivatives designed as maribavir analogues
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The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure-activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scafflold. We have thus synthesized a number of novel amino substituted imidazopyridine nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir and have evaluated their potential antiviral activity. The target compounds were synthesized upon glycosylation of suitably substituted 2-aminoimidazopyridines, which were prepared in six steps starting from 2-amino-6-chloropyridine. Even if the new compounds possessed only a slight structural modification when compared to the original drug, they were not endowed with interesting antiviral activity. Even so, three derivatives showed promising cytotoxic potential.
- Papadakis, Georgios,Gerasi, Maria,Snoeck, Robert,Marakos, Panagiotis,Andrei, Graciela,Lougiakis, Nikolaos,Pouli, Nicole
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- NEW ANTIBACTERIAL COMPOUNDS
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The present invention relates to novel antibacterial compounds, pharmaceutical compositions containing them and their use as antimicrobials.
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Page/Page column 92
(2018/01/19)
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- TYK2 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
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Paragraph 0431; 0432; 0433
(2016/09/26)
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- 6-chlorine-N-(substituted benzyl)-1H-pyrrolo[2,3-b]pyridine-2-amide compound and preparation method as well as application thereof
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The invention discloses a 6-chlorine-N-(substituted benzyl)-1H-pyrrolo[2,3-b]pyridine-2-amide compound and a preparation method as well as application thereof, belonging to the field of HIV-1 integrase inhibitors. The compound is represented by a general formula (I), wherein R1 represents -F, -Me, -OMe and -H; R2 represents -H, -F, -Me, -OMe and -Cl; R3 represents -H, -F, -Me, -OMe, -Cl, -Br, -CF3 and -SO2Me. The preparation method of the compound comprises the steps of synthetising N-(6-chloropyridine-2-tertiary butyl) amide by using 6-chloropyridine-2-amine as a raw material and pivaloyl chloride, performing pyridine ring iodination, then hydrolyzing to obtain 6-chlorine-3-iodine pyridine-2-amine, cyclizing to obtain a compound with a carboxylic acid structure, and finally reacting with various substituted benzyls to obtain the compound disclosed by the invention.
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Paragraph 0031-0033
(2016/10/10)
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- FUNCTIONALLY SELECTIVE LIGANDS OF DOPAMINE D2 RECEPTORS
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The present invention relates to novel functionally selective ligands of dopamine D2 receptors, including agonists, antagonists, and inverse agonists. The invention further relates to the use of these compounds for treating central nervous system disorders related to D2 receptors.
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Page/Page column 47
(2012/01/15)
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- BICYCLIC HETEROARYLS AS KINASE INHIBITORS
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The invention is directed to heteroaryl compounds useful as inhibitors of various kinase enzymes. In various embodiments, the invention provides a heteroaryl compound having inhibitory bioactivity with respect to a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Flt kinase, an Aurora kinase, or a Src kinase, or any combination thereof. Compounds of the invention include bicyclic heteroaryl compounds of formula (I), which can contain a bridging nitrogen atom at a ring junction. The invention further provides methods of synthesis of compounds of the invention, pharmaceutical compositions, pharmaceutical combinations, and methods of treatment of malconditions using compounds of the invention.
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Page/Page column 118
(2011/05/06)
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- HETEROCYCLIC COMPOUNDS CONTAINING A PYRROLOPYRIDINE OR BENZIMIDAZOLE CORE
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The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5 and n are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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Page/Page column 49
(2011/06/26)
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- Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)
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Rho kinase (ROCK) inhibitors are potential therapeutic agents to treat disorders such as hypertension, multiple sclerosis, cancers, and glaucoma. Here, we disclose the synthesis, optimization, biological evaluation of potent indole and 7-azaindole based ROCK inhibitors that have high potency on ROCK (IC 50 = 1 nM) with 740-fold selectivity over PKA (47). Moreover, 47 showed very good DMPK properties making it a good candidate for further development. Finally, docking studies with a homology model of ROCK-II were performed to rationalize the binding mode of these compounds and showed the compounds bound in both orientations to take advantage to H-bonds with Lys-121 of ROCK-II.
- Chowdhury, Sarwat,Sessions, E. Hampton,Pocas, Jennifer R.,Grant, Wayne,Schr?ter, Thomas,Lin, Li,Ruiz, Claudia,Cameron, Michael D.,Schürer, Stephan,Lograsso, Philip,Bannister, Thomas D.,Feng, Yangbo
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scheme or table
p. 7107 - 7112
(2012/01/05)
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- The synthesis of a dopamine D2 partial agonist for the treatment of schizophrenia
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The synthesis of the phosphoric acid salt of dopamine D2 partial agonist 2-{4-[4-(7-fluoro-naphthalen-1-yl)-piperazin-1-yl]- butoxy}-5,6,7,9-tetrahydro- 1,7,9-triaza-benzocyclohepten-8- one (1) is reported. The most prominent feature of the molecule is a seven-membered ring urea functionality that has been prepared via an efficient one-pot, three-step transformation. The original synthesis from the Medicinal Chemistry group provided precursor 13 in 10 steps and 2% overall yield, required four chromatographies and employed unsafe reagents such as 2-iodoxybenzoic acid (IBX) and HClO4. The optimized synthetic route for the preparation of phosphate salt 1 consists of 12 linear steps with a 10% overall yield. Safer and more robust reaction conditions have been developed with only one required chromatography. Another key step in the synthesis is the coupling of iodide 25 with naphthalenopiperazine 12 to provide 13. Due to the difficulty to purify this intermediate, a protocol had to be developed to obtain crude material with the required purity, suitable for use in the subsequent salt formation step. Finally, considerable work was carried out to determine the most stable polymorph of the API. As a result, a robust set of conditions has been developed for the formation of phosphoric acid salt 1, providing the desired polymorph in excellent yield and purity.
- Magano, Javier,Acciacca, Alison,Akin, Anne,Collman, Benjamin M.,Conway, Brian,Waldo, Michael,Chen, Michael H.,Mennen, Kenneth E.
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experimental part
p. 555 - 566
(2010/04/22)
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- TRICYCLIC NITROGEN CONTAINING COMPOUNDS AS ANTIBACTERIAL AGENTS
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Tricyclic nitrogen containing compounds and their use as antibacterials. Z1and Z2 are independently selected from CH and N.
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Page/Page column 33
(2008/12/08)
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- PYRROLOPYRIDINE-2-CARBOXYLIC ACID AMIDES
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Compounds represented by Formula (I) or pharmaceutically acceptable salts thereof, are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, and as cardioprotectants.
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Page/Page column 22
(2008/06/13)
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- Practical asymmetric synthesis of a non-peptidic αvβ 3 antagonist
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(Chemical Equation Presented) The development of a practical and highly convergent synthesis of an αvβ3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite β-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.
- Keen, Stephen P.,Cowden, Cameron J.,Bishop, Brian C.,Brands, Karel M. J.,Davies, Antony J.,Dolling, Ulf H.,Lieberman, David R.,Stewart, Gavin W.
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p. 1771 - 1779
(2007/10/03)
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- PYRROLOPYRIDINE-2-CARBOXYLIC ACID AMIDE INHIBITORS OF GLYCOGEN PHOSHORYLASE
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Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are inhibitors of glycogen phosphorylase and are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, and as cardioprotectants.
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- Synthesis and structure-activity relationships of 7-substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones as selective inhibitors of pp60(c-src)
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7-Substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones are potent inhibitors of protein tyrosine kinases, with some selectivity for c-Src. The compounds were prepared by condensing 4,6-diaminonicotinaldehyde with 2,6-dichlorophenylacetonitrile and selectively converting the 2- and 7-amino groups of the product to hydroxy and fluoro groups, respectively, by prolonged diazotization in 50% aqueous fluoboric acid. N-Methylation, followed by treatment with aliphatic diamines, aromatic amines, or their derived lithium anions, gave the desired compounds. Selected isomeric 1,8-naphthyridin-2(1H)-ones were also prepared in order to evaluate the relative contributions of both ring A aza atoms of the related pyrido[2,3-d]pyrimidin-7(8H)-ones to the inhibitory activity. The compounds were evaluated for their ability to prevent phosphorylation of a model substrate by c-Src, FGF-1 receptor, and PDGF-β receptor enzymes. Overall, there was a high degree of correlation of the activities against the different kinases, with c-Src being generally the most sensitive to structural changes. 1,6-Naphthyridin-2(1H)-one analogues bearing basic aliphatic side chains [7-NH(CH2)(n)NRR, 7-NHPhO(CH2)(n)NRR, or 7-NHPhN(CH2)4NMe] were the most potent against c-Src (IC50s of 10-80 nM), showing good selectivity with respect to PDGFR (10-300-fold) but less with respect to FGFR. The 1,6-naphthyridin-2(1H)-ones showed broadly similar activity to the analogous pyrido[2,3-d]-pyrimidin-7(8H)-ones, whereas the 1,8-naphthyridin-2(1H)-ones were at least 103-fold less potent. These results, indicating that the 3-aza atom in the pyrido[2,3-d]pyrimidin-7(8H)-ones is mandatory, whereas the 1-aza atom is not, support the published binding model for these compounds to c-Src (J. Med. Chem. 1998, 41, 1752), where the 3-aza and 2-NH atoms form a bidentate H-bond donor - acceptor motif that interacts with Met341 and the 1-aza atom is not involved in specific binding interactions.
- Thompson,Rewcastle,Boushelle,Hartl,Kraker,Lu,Batley,Panek,Hollis Showalter,Denny
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p. 3134 - 3147
(2007/10/03)
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- Regiospecific Electrophilic Substitution of Aminopyridines: Ortho Lithiation of 2-, 3-, and 4-(Pivaloylamino)pyridines
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2- and 4-(pivaloylamino)pyridines have been shown to undergo metalation exclusively at C-3 and these smoothly react with a variety of electrophiles to produce 2,3- and 3,4-disubstituted pyridines, respectively.Removal of the pivaloyl protecting group results in overall electrophilic substitution of an aminopyridine.Utilization of this method is exemplified by efficient syntheses of 2- and 4-aminonicotinaldehydes.Minor modifications of the reaction conditions permitted exclusive ortho metalation of 2-(pivaloylamino)pyridines additionally functionalized by chloro, fluoro, or methyl groups.Although the major product from reaction of 3-(pivaloylamino)pyridine by this method was metalation at C-4, the reaction was complicated by substantial quantities of product derived from nucleophilic attack by n-butyllithium on the pyridine nucleus.
- Turner, James A.
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p. 3401 - 3408
(2007/10/02)
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