- OXIME COMPOUNDS USEFUL AS T CELL ACTIVATORS
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Disclosed herein are oxime compounds having the structure of Formula (I):or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1, R2, R3, a, L, X, and Y are as defined herein. Pharmaceutical compositions comprising them, processes for preparing them and uses of them to treat or prevent diseases, disorders and conditions are also provided. The compounds are inhibitors of one or both of diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ) and are useful in the treatment of diseases, disorders and conditions related to DGKα and / or DGKζ activity. In particular, the compounds are useful for treating viral infections and proliferative disorders, such as cancer.
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- Synthesis and anticancer evaluation of 6-azacyclonol-2,4,6-trimethylpyridin-3-ol derivatives: M3 muscarinic acetylcholine receptor-mediated anticancer activity of a cyclohexyl derivative in androgen-refractory prostate cancer
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We recently reported 2,4,5-trimethylpyridin-3-ol with C(6)-azacyclonol, whose code name is BJ-1207, showing a promising anticancer activity by inhibiting NOX-derived ROS in A549 human lung cancer cells. The present study was focused on structural modification of the azacyclonol moiety of BJ-1207 to find a compound with better anticancer activity. Ten new compounds (3A–3J) were prepared and evaluated their inhibitory actions against proliferation of eighteen cancer cell lines as a primary screening. Among the ten derivatives of BJ-1207, the effects of compounds 3A and 3J on DU145 and PC-3, androgen-refractory cancer cell lines (ARPC), were greater than the parent compound, and compound 3A showed better activity than 3J. Antitumor activity of compound 3A was also observed in DU145-xenografted chorioallantoic membrane (CAM) tumor model. In addition, the ligand-based target prediction and molecular docking study using DeepZema server showed compound 3A was a ligand to M3 muscarinic acetylcholine receptor (M3R) which is overexpressed in ARPC. Carbachol, a muscarinic receptor agonist, concentration dependently increased proliferation of DU145 in the absence of serum, and it also activated NADPH oxidase (NOX). The carbachol-induced proliferation and NOX activity was significantly blocked by compounds 3A in a concentration-dependent manner. This finding might become a new milestone in the development of pyridinol-based anti-cancer agents against ARPC.
- Karmacharya, Ujjwala,Chaudhary, Prakash,Lim, Dongchul,Dahal, Sadan,Awasthi, Bhuwan Prasad,Park, Hee Dong,Kim, Jung-Ae,Jeong, Byeong-Seon
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supporting information
(2021/03/16)
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- NOVEL ARYLOXYPIPERIDINE PYRAZOLE COMPOUNDS AS INDOLEAMINE 2,3-DIOXYGENASE INHIBITORS
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Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme: Also disclosed herein are uses of the compounds in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising these compounds. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder.
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Page/Page column 92; 93
(2020/03/15)
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- Nickel-Catalyzed Suzuki-Miyaura Coupling of Aliphatic Amides
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We report the Ni-catalyzed Suzuki-Miyaura coupling of aliphatic amide derivatives. Prior studies have shown that aliphatic amide derivatives can undergo Ni-catalyzed carbon-heteroatom bond formation but that Ni-mediated C-C bond formation using aliphatic amide derivatives has remained difficult. The coupling disclosed herein is tolerant of considerable variation with respect to both the amide-based substrate and the boronate coupling partner and proceeds in the presence of heterocycles and epimerizable stereocenters. Moreover, a gram-scale Suzuki-Miyaura coupling/Fischer indolization sequence demonstrates the ease with which unique polyheterocyclic scaffolds can be constructed, particularly by taking advantage of the enolizable ketone functionality present in the cross-coupled product. The methodology provides an efficient means to form C-C bonds from aliphatic amide derivatives using nonprecious-metal catalysis and offers a general platform for the heteroarylation of aliphatic acyl electrophiles.
- Boit, Timothy B.,Weires, Nicholas A.,Kim, Junyong,Garg, Neil K.
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p. 1003 - 1008
(2018/02/14)
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- ISOXAZOLE CARBOXAMIDE COMPOUNDS
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The present disclosure provides substituted isoxazole carboxamide compounds having Formula (I) and the pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, A, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer.
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Paragraph 0273
(2016/06/01)
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- Iodonium ylides for one-step, no-carrier-added radiofluorination of electron rich arenes, exemplified with 4-(([18F]fluorophenoxy)- phenylmethyl)piperidine NET and SERT ligands
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Iodonium ylide precursors of electron rich arenes, i.e. the NET and SERT ligands 4-((3- and 4-fluorophenoxy)phenylmethyl)piperidine, served as model compounds for the direct substitution with n.c.a. [18F]fluoride. Good radiochemical yields of a
- Cardinale, Jens,Ermert, Johannes,Humpert, Sven,Coenen, Heinz H.
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p. 17293 - 17299
(2014/05/06)
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- Preparation of unsymmetrical ketones from tosylhydrazones and aromatic aldehydes via formyl C-H bond insertion
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Preparation of ketones by insertion of diazo compounds into the formyl C-H bond of an aldehyde is an attractive procedure, but use of structurally diverse diazo compounds is hampered by preparation and safety issues. A convenient procedure for the synthesis of unsymmetrical ketones from bench-stable tosylhydrazones and aryl aldehydes is reported. The procedure can be performed in one pot from the parent carbonyl compound and needs only a base, with no additional promoters being required.
- Allwood, Daniel M.,Blakemore, David C.,Ley, Steven V.
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p. 3064 - 3067
(2014/06/23)
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- Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: Development of a [3.3.0]-based series and other piperidine bioisosteres
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This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this novel series and a number of other piperidine bioisosteric cores.
- Sheffler, Douglas J.,Nedelovych, Michael T.,Williams, Richard,Turner, Stephen C.,Duerk, Brittany B.,Robbins, Megan R.,Jadhav, Sataya B.,Niswender, Colleen M.,Jones, Carrie K.,Conn, P. Jeffrey,Daniels, R. Nathan,Lindsley, Craig W.
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p. 1062 - 1066
(2014/03/21)
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- PIPERIDINE AMIDE DERIVATIVES AS HIV ATTACHMENT INHIBITORS
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Compounds of Formula I, including pharmaceutically acceptable salts thereof: formule (I): wherein A is selected from the group consisting of:formule (II) and wherein Z is selected from the group consisting of: formule (III):,, and. are useful as HIV attac
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Page/Page column 63; 64
(2014/03/21)
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- Ketone formation via mild Nickel-catalyzed reductive coupling of alkyl halides with aryl acid chlorides
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The present work highlights unprecedented Ni-catalyzed reductive coupling of unactivated alkyl iodides with aryl acid chlorides to efficiently generate alkyl aryl ketones under mild conditions.
- Wu, Fan,Lu, Wenbin,Qian, Qun,Ren, Qinghua,Gong, Hegui
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supporting information; experimental part
p. 3044 - 3047
(2012/08/07)
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- FLUFENOXINE DERIVATIVES FOR THE TREATMENT AND PREVENTION OF AMILOYD PATHOLOGIES
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The present invention is directed to a compound of formula (I) for use in a method to treat or ameliorate amyloid or tau pathologies, such as Alzheimer's disease, or symptoms thereof. The invention is also directed to new compounds of formula (I), of subf
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Page/Page column 30
(2011/12/14)
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- KINASE INHIBITORS AND METHOD OF TREATING CANCER WITH SAME
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The present teachings provide a compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. Also described are a pharmaceutical composition and method of use thereof.
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Page/Page column 105
(2011/10/31)
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- GLYCINE TRANSPORTER-1 INHIBITORS
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The present invention provides compounds that are glycine transporter 1 (hereinafter referred to as GlyT-1) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of GlyT1 such as cognitive disorders associated with Schizophrenia, ADHD (attention deficit hyperactivity disorder), MCI (mild cognitive impairment), and the like. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 75-76
(2009/07/17)
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- AMIDE COMPOUNDS
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The present invention provides compounds represented by the formula (Ie) and the formula (If) wherein each symbol is as defined in the specification. According to the present invention, these compounds have a DGAT inhibitory activity and are useful for the prophylaxis, treatment or improvement of diseases or pathologies caused by high expression or high activation of DGAT
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Page/Page column 146-147
(2008/06/13)
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- Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration
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Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3-d]pyrimidine inhibitors of PKBβ with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.
- Caldwell, John J.,Davies, Thomas G.,Donald, Alastair,McHardy, Tatiana,Rowlands, Martin G.,Aherne, G. Wynne,Hunter, Lisa K.,Taylor, Kevin,Ruddle, Ruth,Raynaud, Florence I.,Verdonk, Marcel,Workman, Paul,Garrett, Michelle D.,Collins, Ian
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p. 2147 - 2157
(2008/12/22)
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- Chemical compounds
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Compounds of formula (I): compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
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Page/Page column 36
(2008/06/13)
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- The "reverse-tethered" ruthenium (II) catalyst for asymmetric transfer hydrogenation: Further applications
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The attachment of a tethering group from the basic nitrogen atom to the arene ligand of a ruthenium(II) catalyst greatly improves its ability to catalyze asymmetric transfer hydrogenation (ATH) reactions. In this paper, we describe further applications of this versatile system to an extended substrate range.
- Morris, David J.,Hayes, Aidan M.,Wills, Martin
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p. 7035 - 7044
(2007/10/03)
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- Syntheses and Binding Studies of New [(Aryl)(aryloxy)methyl]piperidine Derivatives and Related Compounds as Potential Antidepressant Drugs with High Affinity for Serotonin (5-HT) and Norepinephrine (NE) Transporters
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In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT1A and 5-HT2A receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT 1A and 5-HT2A receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and α2 receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K i i = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.
- Orjales, Aurelio,Mosquera, Ramón,Toledo, Antonio,Pumar, M. Carmen,García, Neftalí,Cortizo, Lourdes,Labeaga, Luis,Innerárity, Ana
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p. 5512 - 5532
(2007/10/03)
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- New diarylmethylpiperazines as potent and selective nonpeptidic δ opioid receptor agonists with increased in vitro metabolic stability
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Nonpeptide δ opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N,N-diethyl-4-[phenyl(1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human δ receptor (IC50 = 11 nM, μ/δ = 740, κ/δ > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for δ receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic nitrogen for δ binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)-methyl]benzamide (56) which had an improved in vitro binding profile (IC50 = 0.5 nM, μ/δ = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.
- Plobeck,Delorme,Wei,Yang,Zhou,Schwarz,Gawell,Gagnon,Pelcman,Schmidt,Yue,Walpole,Brown,Zhou,Labare,Payza,St-Ogne,Kamassah,Morin,Projean,Ducharme,Roberts
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p. 3878 - 3894
(2007/10/03)
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- N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: A novel, exceptionally selective, potent δ opioid receptor agonist with oral bioavailability and its analogues
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The design, synthesis, and pharmacological evaluation of a novel class of δ opioid receptor agonists, N,N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by repl
- Wei,Brown,Takasaki,Plobeck,Delorme,Zhou,Yang,Jones,Gawell,Gagnon,Schmidt,Yue,Walpole,Payza,St-Onge,Labarre,Godbout,Jakob,Butterworth,Kamassah,Morin,Projean,Ducharme,Roberts
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p. 3895 - 3905
(2007/10/03)
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- Compounds with analgesic effect
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PCT No. PCT/SE96/01635 Sec. 371 Date Apr. 24, 1997 Sec. 102(e) Date Apr. 24, 1997 PCT Filed Dec. 11, 1996 PCT Pub. No. WO97/23466 PCT Pub. Date Jul. 3, 1997Compounds of the formula (I) as well as their pharmaceutically acceptable salts, and pharmaceutical compositions comprising the novel compounds. The novel compounds of the formula (I) are useful in the management of pain.
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