cas 7584-05-6, 4-Cyano-3-methylpyridine | Articles data

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2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes
The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes δ, η, θ (in particular PKC/η, and display a 10-100-fold sele
p. 7367 - 7372
(2011)
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Nickel/Photoredox-Catalyzed Methylation of (Hetero)aryl Chlorides Using Trimethyl Orthoformate as a Methyl Radical Source
Methylation of organohalides represents a valuable transformation, but typically requires harsh reaction conditions or reagents. We report a radical approach for the methylation of (hetero)aryl chlorides using nickel/photoredox catalysis wherein trimethyl orthoformate, a common laboratory solvent, serves as a methyl source. This method permits methylation of (hetero)aryl chlorides and acyl chlorides at an early and late stage with broad functional group compatibility. Mechanistic investigations indicate that trimethyl orthoformate serves as a source of methyl radical via β-scission from a tertiary radical generated upon chlorine-mediated hydrogen atom transfer.
Kariofillis, Stavros K.,Shields, Benjamin J.,Tekle-Smith, Makeda A.,Zacuto, Michael J.,Doyle, Abigail G.
supporting information
p. 7683 - 7689
(2020/04/22)

Macrocyclic MCL-1 inhibitors and methods of use
The present disclosure provides for compounds of Formula (I) wherein A2, A3, A4, A6, A7, A8, A15, RA, R5, R9, R10A, R10B, R11, R12, R13, R14, R16, W, X, and Y have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents for the treatment of diseases and conditions, including cancer. Also provided are pharmaceutical compositions comprising compounds of Formula (I).
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Paragraph 0793

(2019/02/28)

Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy
The chemokine CC receptor subtype 2 (CCR2) has attracted intensive interest for drug development in diverse therapeutic areas, including chronic inflammatory diseases, diabetes, neuropathic pain, atherogenesis and cancer. By employing a cut-and-sew scaffold hopping strategy, we identified an active scaffold of 3,4-dihydro-2,6-naphthyridin-1(2H)-one as the central pharmacophore to derive novel CCR2 antagonists. Systematic structure–activity relationship study with respect to the ring size and the substitution on the naphthyridinone ring gave birth to 1-arylamino-6-alkylheterocycle-6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-ones as a brand new chemotype of CCR2 antagonists with nanomolar inhibitory activity. The best antagonism activity in this series was exemplified by compound 13a, which combined the optimal substitutions of 3,4-dichlorophenylamino at C-1 and 3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl at N-6 position, leading to an IC50 value of 61 nM and 10-fold selectivity for CCR2 over CCR5. Efficient and general synthesis was established to construct the innovative core structure and derive the compound collections. This is the first report on our designed 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one as novel CCR2 antagonist scaffold and its synthesis.
Qin, Li-Huai,Wang, Zhi-Long,Xie, Xin,Long, Ya-Qiu
p. 3559 - 3572
(2018/05/28)

C?H Cyanation of 6-Ring N-Containing Heteroaromatics
Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far-reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C?H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one-pot protocol is simple to perform, is applicable to a broad range of decorated 6-ring N-containing heterocycles, and has been shown to be suitable for late-stage functionalization of complex drug-like architectures.
Elbert, Bryony L.,Farley, Alistair J. M.,Gorman, Timothy W.,Johnson, Tarn C.,Genicot, Christophe,Lallemand, Bénédicte,Pasau, Patrick,Flasz, Jakub,Castro, José L.,MacCoss, Malcolm,Paton, Robert S.,Schofield, Christopher J.,Smith, Martin D.,Willis, Michael C.,Dixon, Darren J.
supporting information
p. 14733 - 14737
(2017/10/07)

Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.
Okawa, Tomohiro,Aramaki, Yoshio,Yamamoto, Mitsuo,Kobayashi, Toshitake,Fukumoto, Shoji,Toyoda, Yukio,Henta, Tsutomu,Hata, Akito,Ikeda, Shota,Kaneko, Manami,Hoffman, Isaac D.,Sang, Bi-Ching,Zou, Hua,Kawamoto, Tetsuji
p. 6942 - 6990
(2017/09/07)

One-Step Synthetic Access to Isosteric and Potent Anticancer Nitrogen Heterocycles with the Benzo[c]phenanthridine Scaffold
A versatile one-step two-component cyclization to build new tetracyclic nitrogen heterocycles is described. Ortho-methylhetarenecarbonitrile components were condensed with aldehydes to access a large library of differently substituted ring systems. The heterocyclic core can be easily modified by variation of the position of the endocyclic nitrogen atom in the o-methylhetarenecarbonitrile substrate. The manner of the nucleophilic attack that leads to the condensation can be triggered by different electron-density distribution in the molecule induced by the position of the nitrogen atom. Taking this into account, there is an electronic preference that leads to either pyridophenanthrolines or the corresponding pyridoazacarbazoles as the main products. We demonstrate the high antitumor potential of some of our synthesized heterocycles, which is strongly dependent on the substitution pattern introduced through the aldehyde component. The position and number of endocyclic nitrogen atoms play an important role regarding cytotoxicity of the studied compounds. Isosteric nitrogen heterocycles: A large library of heterocycles, some possessing promising anticancer properties, with different substitution patterns is accessible by a facile one-step cyclization method through application of different aldehydes and distinct o-methylhetarenecarbonitrile components with diverse numbers of nitrogen atoms at various positions in the ring (see scheme).
Steinhauer, Tamara N.,Girreser, Ulrich,Meier, Christopher,Cushman, Mark,Clement, Bernd
supporting information
p. 8301 - 8308
(2016/06/13)

AZAINDENOISOQUINOLINE TOPOISOMERASE I INHIBITORS
The invention described herein pertains to substituted azaindenoisoquinoline compounds, in particular 7-, 8-, 9-, and 10-azaindenoisoquinoline compounds, which are inhibitors of topoisomerase I, processes and intermediates for their syntheses, pharmaceutical compositions of the compounds, and methods of using them in the treatment of cancer.
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Paragraph 0154

(2014/02/16)

Oxidative ammonolysis of 3(4)-methyl- and 3,4-dimethylpyridines using vanadium oxide catalysts
Oxidative ammonolysis of 3(4)-methyl- and 3,4-dimethylpyridines using vanadium oxide catalyst doped with Cr2O3, SnO2, and ZrO2 was studied. The yields of nitriles and conversion of the starting compounds were found to depend on the CH-acidity of the latter in the gas phase. The possible mechanisms of the formation of pyridine-3,4-dicarboxylic acid imide at the oxidative ammonolysis of 3,4-dimethylpyridine was discussed. The relation between the activity of the modified catalysts and the proton affinity of the vanadyl oxygen calculated by the extended Hueckel method was established.
Vorobyev,Serebryanskaya
p. 1987 - 1993
(2013/06/05)

Azaindenoisoquinolines as topoisomerase i inhibitors and potential anticancer agents: A systematic study of structure-activity relationships
A comprehensive study of a series of azaindenoisoquinoline topoisomerase I (Top1) inhibitors is reported. The synthetic pathways have been developed to prepare 7-, 8-, 9-, and 10-azaindenoisoquinolines. The present study shows that 7-azaindenoisoquinolines possess the greatest Top1 inhibitory activity and cytotoxicity. Additionally, the introduction of a methoxy group into the D-ring of 7-azaindenoisoquinolines improved their biological activities, leading to new lead molecules for further development. A series of QM calculations were performed on the model "sandwich" complexes of azaindenoisoquinolines with flanking DNA base pairs from the Drug-Top1-DNA ternary complex. The results of these calculations demonstrate how changes in two forces contributing to the π-π stacking (dispersion and charge-transfer interactions) affect the binding of the drug to the Top1-DNA cleavage complex and thus modulate the drug's Top1 inhibitory activity.
Kiselev, Evgeny,Agama, Keli,Pommier, Yves,Cushman, Mark
experimental part
p. 1682 - 1697
(2012/05/04)

1,2,4-oxadiazole derivatives and their therapeutic use
New derivatives of general formula (I), or pharmaceutically acceptable salts or N-oxides thereof wherein, A is selected from the group consisting of -N-, -O- and -S-; B and C are independently selected from the group consisting of-N- and -O-, with the proviso that at least two of A, B and C are nitrogen atoms; G1 is selected from the group consisting of -CH2-, -NH- and -O-; G2 is selected from the group consisting of -NR4- and -O-; R1 represents: ? a 8 to 10 membered bicyclic N-containing heteroaryl group optionally substituted with a C1-4 carboxyalkyl group or a C1-4 aminoalkyl group, ? a pyridyl group optionally substituted with one or more substituents selected from hydroxy groups, C1-4 alkyl groups, C1-4 carboxyalkyl groups, C1-4 haloalkyl groups, C1-4 alkoxy groups, amino groups, C1-4 aminoalkyl groups and C1-4 aminoalkoxy groups, ? a pyridone group substituted with one or more C1-4 alkyl groups; C1-4 haloalkyl groups or C1-4 aminoalkyl groups, or ? a group of formula: wherein: ? Ra represents a hydrogen atom, a halogen atom, a C1-4 alkyl group, C3-4 cycloalkyl group or a -CF3 group; ? Rb represents a hydrogen atom, a halogen atom, a C14 alkyl group, a -CF3 group or a C1-4 alkoxy group; ? Rd represents a hydrogen atom, a C1-4 alkyl group or a C1-4 alkoxy group; ? Rc represents: ○ a hydrogen atom, a C1-4 hydroxyalkyl group, a C1-4 aminoalkyl group which is optionally substituted with one or more substituents selected from halogen atoms, hydroxy groups and -CF3 groups; ○ a 4 to 6-membered saturated N-containing heterocyclic ring optionally substituted with a C1-2 carboxyalkyl group; ○ -(CH2)(0-4)-C(O)OR', -(CH2)(0-4)-C(O)NR'R", -(CH2)(0-4)-NHC(O)R", -S(O)2NR'R", -O-(CH2)(2-4)NR'R", -O-(CH2)(1-4)C(O)OR", -O-(CH2)(1-4)-C(O)NR'R", -(CH2)(0-4)-NR'R", -(CH2)(0-4)-CONHS(O)2R', -(CH2)(0-4)-NHS(O)2R' or -(CH2)(0-3)-N H-(CH2)(1-3)-(NH)(0-1)S(O)2R' wherein, ■ R' represents a hydrogen atom or a C1-4 alkyl group, ■ R" represents a hydrogen atom, a C1-4 alkyl group, a C3-4 cycloalkyl group, a C1-4 carboxyalkyl group, a C1-4 haloalkyl group, a C1-4 hydroxyalkyl group or a 6 membered, saturated N-containing heterocyclic ring, or ■ R' and R" together with the nitrogen atom to which they are attached from a 4 to 6 membered heterocyclic group which contains, as heteroatoms, one N atom and, optionally, one further atom selected from N and O, and which is optionally substituted with a carboxy or a C1-4 carboxyalkyl group, or Rc together with Rd form a C5-6 cycloalkyl group optionally substituted by a -NHRf group, wherein Rf is selected from the group consisting of a hydrogen atom and a carboxymethyl group; R2 and R3 are independently selected from the group consisting of hydrogen atoms, halogen atoms and C1-4 alkyl groups; and R4 is selected from the group consisting of a hydrogen atom, a phenyl group, a C3-4 cycloalkyl-C1-4 alkyl group, C1-4 aminoalkyl group, C1-4 haloalkyl group and a linear or branched C1-4 alkyl group which is optionally substituted by a phenyl or a pyridyl group.
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Page/Page column 50

(2010/07/08)

Identification of orally available naphthyridine protein kinase D inhibitors
A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.
Meredith, Erik L.,Ardayfio, Ophelia,Beattie, Kimberly,Dobler, Markus R.,Enyedy, Istvan,Gaul, Christoph,Hosagrahara, Vinayak,Jewell, Charles,Koch, Keith,Lee, Wendy,Lehmann, HansJoerg,Mckinsey, Timothy A.,Miranda, Karl,Pagratis, Nikos,Pancost, Margaret,Patnaik, Anup,Phan, Dillon,Plato, Craig,Qian, Ming,Rajaraman, Vasumathy,Rao, Chang,Rozhitskaya, Olga,Ruppen, Thomas,Shi, Jie,Siska, Sarah J.,Springer, Clayton,Van Eis, Maurice,Vega, Richard B.,Von Matt, Anette,Yang, Lihua,Yoon, Taeyoung,Zhang, Ji-Hu,Zhu, Na,Monovich, Lauren G.
experimental part
p. 5400 - 5421
(2010/11/18)

COMPOUNDS AND COMPOSITIONS AS MODULATORS OF GPR119 ACTIVITY
The invention provides compounds of Formula (I): pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of GPR119.
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Page/Page column 29

(2009/10/18)

COMPOUNDS USEFUL AS FAAH MODULATORS AND USES THEREOF
Compounds are disclosed that have formula (I): where A, B, L1, X, W, Y, R1, R3, and nlare as defined herein. The compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, anxiety, depression, inflammation, cognitive disorders, weight and eating disorders, Parkinson's disease, Alzheimer's disease, spasticity, addiction, glaucoma, and others.
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Page/Page column 56-57

(2009/03/07)

[2, 6] NAPHTHYRIDINES USEFUL AS PROTEIN KINASE INHIBITORS
The present invention provides a compound of formula I: (formula I) said compound is inhibitor of selective subset of kinases belonging to the AGC or calmodulin kinase family, such as for example MARK1/2/3, PKD-1/2/3, PKN-1/2, CDK-9, CaMKII, ROCK-I/II, inhibitors of histone deacetylase (HDAC) phosphorylation, or inhibitors of other kinases. Finally, the present invention also provides a pharmaceutical composition.
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Page/Page column 49

(2008/12/04)

2, 6-NAPHTHYRIDINE DERIVATIVES AS PROTEIN KINASE MODULATORS
The present invention relates to novel organic compounds comprising a naphthyridine which may be mediators of a selective subset of kinases belonging to the AGC kinase family, such as for example PKC, PKD, PKN-1/2, CDK-9, MRCK-beat, PASK, PRKX, ROCK-I/II or mediators of other kinases, the selectivity of which would be depending on the structural variation thereof.
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Page/Page column 19

(2008/12/04)

4-Piperidinecarboxamide modulators of vanilloid VR1 receptor
This invention is directed to vanilloid receptor VR1 ligands. More particularly, this invention relates to hetero isonipecotic amides that are potent modulators of VR1 which are useful for the treatment and prevention of disease conditions in mammals.
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Page/Page column 55

(2010/11/08)

ARYL SULFONAMIDES
Compounds are provided that act as potent antagonists of the CCR9 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR9-mediated diseases, and as controls in assays for the identification of CCR9 antagonists.
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Page 46-47

(2008/06/13)

The selenium dioxide oxidation of 2,3- and 3,4-dimethylpyridines
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Dunn
p. 120 - 123
(2007/10/03)

Synthesis of ellipticine and olivacine by the thermal electrocyclic reaction via pyridine 3,4-quinodimethane intermediates
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Hibino,Sugino
p. 1751 - 1755
(2007/10/02)

1-ACYLOXYPYRIDINIUM ION: THE REACTIVE INTERMEDIATE IN A MODIFIED REISSERT-HENZE REACTION
Cyanation of 3-X-1-dimethylaminocarbonyloxypyridinium ions with trimethylsilanecarbonitrile or cyanide ion gives 3-methyl-2-pyridinecarbonitrile (ca.90percent) contaminated with 5-methyl-2-pyridinecarbonitrile (ca.10percent) when X = -CH3, and approximately equal amounts of the 3- and 5-X derivatives when X = -COOCH3.These product mixtures are identical to those obtained with the corresponding pyridine 1-oxides and dimethylcarbamoyl chloride in a modified Reissert-Henze reaction.
Fife, Wilmer K.,Boyer, Brett D.
p. 1121 - 1124
(2007/10/02)

Amination of 2,6- and 2,7-Naphtyridine. An NMR Study on ?-Adducts of Heterocyclic Systems with Amide Ions
A facile synthesis of 2,6-naphtyridine is described.Both 2,6- and 2,7-naphtyridine undergo with potassium amide under kinetically and thermodynamically controlled conditions ?-adduct formation at position 1.Chichibabin amination of 2,6-naphtyridine yields 1-amino-2,6-naphtyridine in 54percent yield.
Haak, Henk J. W. van den,Plas, Henk C. van der,Veldhuizen, Beb van
p. 1349 - 1352
(2007/10/02)

Process for substituting and dequaternizing pyridylethyl quaternary salts of pyridine and bypyridine bases
A process for dequaternizing a 2-(2-pyridyl)ethyl or 2-(4-pyridyl)ethyl quaternary salt of a pyridine or bipyridine base comprising the step of heating or reacting the pyridylethyl quaternary salt with a caustic material such as sodium hydroxide. Also included is a process for preparing a second pyridine base (or a bipyridine base) in which a first pyridine base is initially selected and its 2-(2-pyridyl)ethyl or 2-(4-pyridyl)ethyl quaternary salt or its acid salt prepared. An electrophilic, nucleophilic or coupling reaction can then be performed on the quaternary salt to change the substituent or to form the bipyridyl coupling and the resultant salt dequaternized with a caustic material, such as sodium hydroxide, to produce a second pyridine or a bipyridine base.
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(2008/06/13)

Studies on the ammoxidation of N heterocyclic compounds. IV. Vapor phase ammoxidation of lutidine isomers
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Okada,Morita,Miwa
p. 2402 - 2406
(2007/10/04)