- BET INHIBITORS FOR MODULATING DUX4 EXPRESSION IN FSHD
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The present disclosure provides BET inhibitors of the formula: wherein the variables are defined herein, as well as pharmaceutical compositions thereof. The present disclosure also provides methods of treating a patient comprising administering a bromo- and extra-terminal (BET) domain inhibitor for the treatment of FSHD which modulates DUX4 expression. In some embodiments, the present methods comprise using one or more BET inhibitors as a therapeutic agent for the treatment of FSHD patients including patients who are being treated with one or more palliative treatments such as therapy and/or agents which lead to increased muscle mass.
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Page/Page column 309
(2020/07/14)
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- INHIBITORS OF FATTY ACID AMIDE HYDROLASE
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The present invention provides compounds, and pharmaceutically acceptable compositions thereof, encompassed by any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera thereof. The present invention also provides methods for treating an FAAH mediated disease, disorder or condition by administering a therapeutically effective amount of a compound or composition comprising a compound of any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera thereof, to a patient in need thereof. Additionally, the present invention provides methods for inhibiting FAAH by administering a therapeutically effective amount of a compound or composition comprising a compound of any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera thereof, to a patient in need thereof.
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Paragraph 1019
(2016/01/15)
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- Synthesis and biological evaluation of 2-substituted quinoline 6-carboxamides as potential mGluR1 antagonists for the treatment of neuropathic pain
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A series of 2-amino and 2-methoxy quinoline-6-carboxamide derivatives have been synthesized and their metabotropic glutamate receptor type 1 (mGluR1) antagonistic activities were evaluated in a functional cell-based assay. The compound 13c showed the highest potency with IC50 value of 2.16μM against mGluR1. Finally, in vivo evaluation of 13c in the rat spinal nerve ligation (SNL) model exhibited weak analgesic effects with regard to both mechanical allodynia and cold allodynia.
- Kim, Younghee,Son, Jiwon,Kim, Juhyeon,Baek, Du-Jong,Lee, Yong Sup,Lim, Eun Jeong,Lee, Jae Kyun,Pae, Ae Nim,Min, Sun-Joon,Cho, Yong Seo
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p. 508 - 518
(2014/07/08)
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- PHOSPHATIDYLINOSITOL 3 KINASE INHIBITORS
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Provided are compounds according to Formula (I), or stereoisomer, prodrug, polymorph, or pharmaceutically acceptable salt forms thereof, wherein X, Y, R1, R6 , R7, and R8 are as defined, which compounds are effective inhibitors of PI3-kinase and/or other medically and clinically relevant kinases. Also provided are pharmaceutical compositions and methods of using the compounds and compositions as PB -kinase and kinase inhibitors. More particularly, the compounds of the invention provide treatments and therapeutics for human diseases regulated by, or associated with, the activity of, PI3-kinases and/or protein kinases, or mutant or variant forms thereof.
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Page/Page column 132
(2010/01/12)
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- 6-1H-IMIDAZO-QUINAZOLINE AND QUINOLINES DERIVATIVES, NEW MAO INHIBITORS AND IMIDAZOLINE RECEPTOR LIGANDS
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The present invention is directed to 6-(1H-imidazo-1-yl)-2-aryl and 2-heteroaryl quinazoline and quinolines derivatives, compounds of formula (I), their pharmaceutical acceptable salts and solvates and corresponding pharmaceutical compositions, that acts
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Page/Page column 42
(2010/01/12)
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- Sequential and selective Buchwald-Hartwig amination reactions for the controlled functionalization of 6-bromo-2-chloroquinoline: Synthesis of ligands for the Tec Src homology 3 domain
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(Chemical Equation Presented) Src homology 3 (SH3) domains are highly conserved protein-protein interaction domains that mediate important biological processes and are considered valuable targets for the development of therapeutic agents. In this paper, we report the preparation of a range of new 6-heterocyclic substituted 2-aminoquinolines using Buchwald-Hartwig chemistry. 6-Heterocyclic substitution of the 2-amino-quinoline has provided ligands with increased binding affinity for the SH3 domain relative to the lead compound, 2-aminoquinoline, that are the highest affinity ligands prepared to date. The key step in the synthesis of these compounds required a selective Buchwald-Hartwig amination of an aryl bromide in the presence of an activated heteroaryl chloride. The optimization of reaction conditions to achieve the selective amination is discussed and has allowed for cross-coupling with a range of cyclic amines. Introduction of the amino functionality of the 6-heterocyclic 2-aminoquinolines involved additional Buchwald-Hartwig chemistry utilizing lithium bis(trimethylsilyl)amide as an ammonia equivalent.
- Smith, Jessica A.,Jones, Rhiannon K.,Booker, Grant W.,Pyke, Simon M.
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experimental part
p. 8880 - 8892
(2009/04/11)
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- ANTIBACTERIAL QUINOLINE DERIVATIVES
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The present invention relates to novel substituted quinoline derivatives according to the general formula (Ia) or formula (Ib), including any stereochemically isomeric form thereof, a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvat
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Page/Page column 43
(2008/12/06)
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- ANTIBACTERIAL QUINOLINE DERIVATIVES
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The present invention relates to novel substituted quinoline derivatives according to the general Formula (Ia) or Formula (Ib): the pharmaceutically acceptable acid or base addition salts thereof, the quaternary amines thereof, the stereochemically isomer
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Page/Page column 32-33
(2010/11/25)
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- NOVEL CHEMICAL COMPOUNDS
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This invention relates to newly identified compounds for inhibiting hYAK3 proteins and methods for treating diseases associated with hYAK3 activity.
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Page/Page column 43-44
(2010/11/25)
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- 6-Substituted 1H-quinolin-2-ones and 2-methoxy-quinolines: Synthesis and evaluation as inhibitors of steroid 5α reductases types 1 and 2
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A Negishi-type coupling reaction between 6-bromo-2-methoxyquinoline. (1a) and various 4-bromo-N,N'dialkyl-benzamides gave access to 6-substituted 2-methoxy-quinolines 1-3 and 1H-quinolin-2-ones 4-12. Most of these compound proved to be inhibitors of steroid 5α reductases with activity arid selectivity both being strongly dependent on the features of the heterocycle and the size of the N,N-dialkylamide substituent. The most active inhibitor for the human type 2 isozyme was 6-[4-(N,N-diisopropylcarbamoyl)phenyl]-1H-quinolin-2-one 4 (K(i) 800 ± 85 nM), showing mostly competitive inhibitory patterns. A type 1 selective inhibitor could be identified with 6-[4-(N,N-diisopropylcarbamoyl)phenyl]-N-methyl-quinolin-2-one (5, IC50 510 nM). (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Baston, Eckhard,Palusczak, Anja,Hartmann, Rolf W.
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p. 931 - 940
(2007/10/03)
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- Regioselective Alkoxydehalogenation of 2,4-Dihalogenoquinolines and a Reinvestigation of the Bromination of 2-Methoxyquinoline
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Regioselective alkoxydehalogenation of 2,4-dichloro- and 2,4-dibromo-quinoline with solid sodium alkoxide in toluene gives the 2-alkoxy-4-halogenoquinolines 7-10, identified by 1H and 13C NMR spectroscopy.Bromination of 2-methoxyquinoline occurs at the 6- and 8-positions and does not give the 4-bromo derivative as originally reported.
- Osborne, Alan G.,Miller, Luke A. D.
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p. 181 - 184
(2007/10/02)
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- Quinolone inotropic agents
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A series of novel phenyl-substituted 2-(1H)-quinolone compounds have been prepared, including the 3,4-dihydro derivatives thereof, wherein the phenyl ring moiety is a mono-or di-substituted phenyl group attached to the 5-, 6-, 7- or 8-positions of the qui
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- 2(1H)-Quinolinones with cardiac stimulant activity. 1. Synthesis and biological activities of (six-membered heteroaryl)-substituted derivatives
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A series of (six-membered heteroaryl)-substituted 2(1H)-quinolinones was synthesized, and structure-activity relationships for cardiac stimulant activity were determined. Most compounds were prepared by acidic hydrolyisis of a heteroaryl-2-methoxyquinoline obtained by palladium-catalyzed cross-coupling methodology. Direct reaction of a pyridinylzinc reagent with a 6-haloquinolinone also proved successful. In anesthetized dogs, 6-pyridin-3-yl-2(1H)-quinolinone (3; 50 μg/kg) displayed greater inotropic activity (percentage increase in dP/dt max) than positional isomers, and potency was maintained with either mono- or di- alkylpyridinyl substituents. Introduction of a 4- or 7- methyl group into 3 reduced inotropic activity, whereas the 8-isomer proved to be the most potent member of the series. Compound 26 and the 2,6-dimethylpyridinyl analogue (27 were approximately 6 and 3 times more potent than milrinone. Several quinolinones displayed positive inotropic activity (decrease in QA interval) in conscious dogs after oral administration (1 mg/kg), and 26, 27 were again the most potent members of the series. Compound 27 (0.25, 0.5, 1.0 mg/kg po) demonstrated dose-related cardiac stimulant activity, which was maintained for at least 4 h. No changes in heart rate were observed. Compounds 3, 4, 26, and 27 also selectively stimulated the force of contraction, rather than heart rate, in the dog heart-lung preparation. For a 50% increase in dP/dt max with 27, heart rate changed by less than 10 beats/min. In norepinephrine contracted rabbit femoral artery and saphenous vein, 27 produced dose related (5 x 10-7 to 5 x 10-4 M) vasorelaxant activity. The combined cardiac stimulant and vasodilator properties displayed by 27, coupled with a lack of effect on heart rate, should be beneficial for the treatment of congestive heart failure.
- Alabaster,Bell,Campbell,Ellis,Henderson,Roberts,Ruddock,Samuels,Stefaniak
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p. 2048 - 2056
(2007/10/02)
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- Quinolone inotropic agents
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A heterocyclic-substituted 2-quinolone compound of the formula: STR1 or a pharmaceutically-acceptable salt thereof, wherein "Het" is an optionally substituted 5-or 6-membered monocyclid aromatic heterocyclic group attached by a carbon atom to the 5-, 6-, 7- or 8- position of the quinolone nucleus; R, which is attached to the 5-, 6-, 7- or 8- position, is hydrogen, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 alkylthio, C1 -C4 alkylsulphinyl, C1 -C4 alkylsulphonyl, halo, CF3, hydroxy, hydroxymethyl, or cyano; R1 is hydrogen, cyano (C1 -C4 alkoxy)carbonyl, C1 -C4 alkyl, nitro, halo, --NR3 R4 or --CONR3 R4 where each of R3 and R4 is hydrogen or C1 -C4 alkyl or R3 and R4 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic group optionally containing a further heteroatom or group selected from O, S and N--R5 where R5 is hydrogen or C 1 -C4 alkyl; R2 is hydrogen, C1 -C4 alkyl, or 2-hydroxyethyl; Y is hydrogen or C1 -C4 alkyl; and the dotted line between the 3- and 4- positions represents an optional bond. The compounds are inotropic agents useful as cardiac stimulants in the treatment of congestive heart failure.
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