- Discovery of Pyrazolopyridones as a Novel Class of Gyrase B Inhibitors Using Structure Guided Design
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The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.
- Cross, Jason B.,Zhang, Jing,Yang, Qingyi,Mesleh, Michael F.,Romero, Jan Antoinette C.,Wang, Bin,Bevan, Doug,Poutsiaka, Katherine M.,Epie, Felix,Moy, Terence,Daniel, Anu,Shotwell, Joseph,Chamberlain, Brian,Carter, Nicole,Andersen, Ole,Barker, John,Ryan, M. Dominic,Metcalf, Chester A.,Silverman, Jared,Nguyen, Kien,Lippa, Blaise,Dolle, Roland E.
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Read Online
- Photoassisted Charge Transfer Between DMF and Substrate: Facile and Selective N,N-Dimethylamination of Fluoroarenes
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A reversible Van der Waals complex formation between the electron-deficient fluorinated aromatic ring and N,N-dimethylformamide (DMF) molecules followed by light irradiation resulted in charge transfer (CT) process. The complex was stabilized by ammonium formate and further decomposed to form the C?N bond. Control experiments revealed that the simultaneous SNAr pathway also contributes to product formation. This methodology is mild, metal-free, and effective for the amination of a variety of substrates. The reproducibility of this methodology was also verified on gram-scale reactions. The CT states were supported by control UV/Vis spectroscopy and computational studies.
- Ansari, Tharique N.,Sharma, Sudripet,Bora, Pranjal P.,Ogulu, Deborah,Parmar, Saurav,Gallou, Fabrice,Kozlowski, Pawel M.,Handa, Sachin
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p. 2704 - 2709
(2021/06/09)
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- Directing Group Enables Electrochemical Selectively Meta-Bromination of Pyridines under Mild Conditions
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Without the use of catalysts and oxidants, a facile and sustainable electrochemical bromination protocol was developed. By introducing the directing groups, the regioselectivity of pyridine derivatives could be controlled at themeta-position utilizing the inexpensive and safe bromine salts at room temperature. A variety of brominated pyridine derivatives were obtained in 28-95% yields, and the reaction could be readily performed at a gram scale. By combining the installation and removing the directing group, the concept ofmeta-bromination of pyridines could be verified.
- Wu, Yanwei,Xu, Shanghui,Wang, Hong,Shao, Dongxu,Qi, Qiqi,Lu, Yi,Ma, Li,Zhou, Jianhua,Hu, Wei,Gao, Wei,Chen, Jianbin
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p. 16144 - 16150
(2021/07/19)
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- A Novel One-Pot Synthesis of N,N-Dimethylaminopyridines by Diazotization of Aminopyridines in Dimethylformamide in the Presence of Trifluoromethanesulfonic Acid
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Abstract: Diazotization of aminopyridines in the presence of trifluoromethanesulfonic acid gives the corresponding pyridinyl trifluoromethanesulfonates instead of expected diazonium salts. Pyridinyl trifluoromethanesulfonates can be converted to N,N-dimethylaminopyridines on heating in dimethylformamide via replacement of the trifluoromethanesulfonyloxy group. The reaction is accelerated under microwave irradiation. A novel one-pot procedure has been proposed for the synthesis of 2- and 4-(dimethylamino)pyridines from commercially available aminopyridines. The procedure provides high yields of the target products, and it can be regarded as an alternative to the known methods of synthesis of N,N-dimethylpyridin-4-amine (DMAP) widely used as base catalyst in organic synthesis.
- Filimonov, V. D.,Krasnokutskaya, E. A.,Potapova, M. I.,Sanzhiev, A. N.
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p. 1023 - 1028
(2020/07/25)
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- Aryl-Diadamantyl Phosphine Ligands in Palladium-Catalyzed Cross-Coupling Reactions: Synthesis, Structural Analysis, and Application
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Synthesis, temperature-dependent NMR structure investigation and utilization of a new, stable and easily accessible aryl-diadamantylphosphine ligand family is reported. The bulky and electron-rich phosphorus center of the ligand enhances the catalytic activity of palladium in cross-coupling reactions of sterically demanding ortho-substituted aryl halides. In our study, we demonstrated the synthetic applicability of the new phosphine ligands in Buchwald-Hartwig and tosyl hydrazone coupling reactions.
- Sinai, ádám,Simkó, Dániel Cs.,Szabó, Fruzsina,Paczal, Attila,Gáti, Tamás,Bényei, Attila,Novák, Zoltán,Kotschy, András
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supporting information
p. 1122 - 1128
(2020/03/03)
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- DUAL ATM AND DNA-PK INHIBITORS FOR USE IN ANTI-TUMOR THERAPY
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Provided herein are compounds of the Formula (I), (II), and (III), as well as pharmaceutically acceptable salts thereof, wherein the substituents are those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of oncologic diseases.
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Page/Page column 380
(2019/11/12)
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- Iron-catalyzed protodehalogenation of alkyl and aryl halides using hydrosilanes
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A simple and efficient iron-catalyzed protodehalogenation of alkyl and aryl halides using phenylhydrosilane is disclosed. The reaction utilizes FeCl3 without the requirement of ligands. Unactivated alkyl and aryl halides were successfully reduced in good yields; sterically hindered tertiary halides were also reduced including the less reactive chlorides. The scalability of this methodology was demonstrated by a gram-scale synthesis with a catalyst loading as low as 0.5 mol%. Notably, disproportionation of phenylsilane leads to diphenylsilane that further reduces the halides. Preliminary mechanistic studies revealed a non-radical pathway and the source of hydrogen is PhSiH3via deuterium labeling studies. Our methodology represents simplicity and provides a good alternative to typical tin, aluminum and boron hydride reagents.
- Pilli, Ramadevi,Balakrishnan, Venkadesh,Chandrasekaran, Revathi,Rasappan, Ramesh
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supporting information
p. 1749 - 1753
(2019/02/20)
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- Novel green and practical synthesis method of N,N-dimethyl pyridine compound
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The invention relates to a novel green and practical synthesis method of a N,N-dimethyl pyridine compound. The reaction method is characterized in that common inorganic alkaline and water are respectively used as an accelerant and a reaction solvent; under the mild condition and in air, 2-halogenated pyridine derivatives and N,N-dimethylformamide compounds can be smoothly promoted to selectively perform dehalogenation amination reaction to generate corresponding N,N-dimethyl pyridine derivatives. The direct amination reaction of cheap and easy-to-obtain inorganic alkaline promoted 2-halogenated pyridine compounds and N,N-disubstituted methylformamide compounds is innovatively realized for the first time; the limitation that a metallic catalyst needs to be used by a traditional method is overcome; a bran-new strategy is provided for laboratory preparation and industrial production of the N,N-dimethyl pyridine compound.
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Paragraph 0016-0029
(2018/11/04)
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- Environmentally benign indole-catalyzed position-selective halogenation of thioarenes and other aromatics
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Halogenated aromatic compounds are the cores of many pharmaceutical, agricultural and chemical products but they are commonly prepared using electrophilic halogenation reactions in non-green chlorinated solvents under harsh conditions. A separate problem happens in the aromatic halogenation of thioarenes because they readily undergo oxidative side-reactions. Herein we report an environmentally benign electrophilic bromination of aromatics using an indole-catalytic protocol, which is suitable for a wide range of substrates including thioarenes.
- Shi, Yao,Ke, Zhihai,Yeung, Ying-Yeung
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supporting information
p. 4448 - 4452
(2018/10/17)
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- SUBSTITUTED BENZAZINONES AS ANTIBACTERIAL COMPOUNDS
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The present invention relates to LpxC antibacterial compounds of Formula (1A), corresponding pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions:, compound preparation, treatment methods and uses for bacterial infections, especially those caused by gram-negative bacteria.
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Page/Page column 169
(2017/07/14)
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- ANTIOXIDANTS AND METHODS TO MAXIMIZE PERFORMANCE
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A method of preventing or reducing the level of degradation of an organic substrate is described, wherein a composition is formed that includes the organic substrate together with an effective amount of a sacrificial base and a diarylamine antioxidant.
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Page/Page column 28; 29
(2016/09/22)
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- PHOSPHOINOSITIDE 3-KINASE INHIBITORS WITH ZINC BINDING MOIETY
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PROBLEM TO BE SOLVED: To provide phosphoinositide 3-kinase inhibitors with a zinc binding moiety. SOLUTION: There is provided a compound represented by formula (I) in the figure. (X is S, O or the like; Y is CH, N or the like; G1 is optionally substituted N or the like; R1 and R2 are each independently H or the like; C is a substituted heterocycle or the like; B is a linear alkyl or the like; Ra and Rb together with the nitrogen atom coupled to them are morpholino or the like; G2 is an indazole ring or the like; q, r and s are independently from 0 to 1, provided that at least one of them is 1; t is from 0 to 1; n is from 0 to 4; and p is from 0 to 2.) COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0418
(2016/10/07)
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- ANTI-MALIGNANT TUMOR AGENT COMPOSITION
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To provide a satisfactory anticancer agent composition suppressing the growth of cancer (malignant tumor) reliably and hardly causing side effects, the present invention is directed to an anticancer agent composition including the following agents as active ingredient; a LAT1 inhibitor, and one or more agents selected from the group consisting of an alkylating agent, a platinum-based antineoplastic agent, an anti-metabolite, a topoisomerase inhibitor, an anti-microtubule polymerizing agent, a hormonal agent, an anti-microtubule depolymerizing agent, an anticancer antibiotic, and a molecular targeted agent.
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Paragraph 0109
(2016/01/25)
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- SUBSTITUTED PYRIDOPYRAZINES AS NOVEL SYK INHIBITORS
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Provided are pyridopyrazine compounds of formula (1), pharmaceutical compositions thereof and methods of use therefore, wherein R1, R2, R3, R4 and m are as defined in the specification.
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Paragraph 0168; 0169
(2014/05/08)
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- A mild method for the regioselective bromination of 2-aminopyridines
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An efficient and regioselective bromination of 2-aminopyridines was developed. The environmental friendly bromination occurs under mild and clean conditions using readily available 1-butylpyridinium bromide as the bromine source and hydrogen peroxide as the green oxidant.
- Xu, Tong,Zhou, Wen,Wang, Jing,Li, Xue,Guo, Jun-Wen,Wang, Bin
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supporting information
p. 5058 - 5061
(2015/01/08)
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- NOVEL ANTIPRION COMPOUNDS
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Described herein are novel compositions and methods of treatment addressing diseases such as neurodegenerative diseases, including prion diseases and Alzheimer's disease.
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Paragraph 0751
(2013/03/28)
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K-ras mutation in a subject in need thereof. The method comprises the steps of: (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) administering to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Paragraph 0485; 0486
(2013/05/08)
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- SUBSTITUTED PYRIDOPYRAZINES AS NOVEL SYK INHIBITORS
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Provided are certain pyridopyrazine compounds, pharmaceutical compositions thereof and methods of use therefor.
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Page/Page column 36
(2013/02/27)
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- SUBSTITUTED DIARYLAMINES AND USE OF SAME AS ANTIOXIDANTS
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The present invention relates to substituted heteroaromatic dianlamine compounds of Formula I and II, their pharmaceutically acceptable salts, and compositions thereof useful as antioxidants, wherein each of X, Y and Z are independently a carbon or nitrogen atom; R1 and R2 are each independently a hydrogen or an electron donating group, but are not both hydrogen, and wherein R1 and R2 are each bonded to a carbon atom in their own respective aryl ring.
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Page/Page column 44; 50
(2013/02/28)
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K- ras mutation in a subject in need thereof. The method comprises the steps of (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) adminsiterign to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Page/Page column 206
(2011/11/01)
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- 4-Amino-5-aryl-6-arylethynylpyrimidines: Structure-activity relationships of non-nucleoside adenosine kinase inhibitors
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A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.
- Matulenko, Mark A.,Paight, Ernest S.,Frey, Robin R.,Gomtsyan, Arthur,DiDomenico Jr., Stanley,Jiang, Meiqun,Lee, Chih-Hung,Stewart, Andrew O.,Yu, Haixia,Kohlhaas, Kathy L.,Alexander, Karen M.,McGaraughty, Steve,Mikusa, Joseph,Marsh, Kennan C.,Muchmore, Steven W.,Jakob, Clarissa L.,Kowaluk, Elizabeth A.,Jarvis, Michael F.,Bhagwat, Shripad S.
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p. 1586 - 1605
(2008/02/01)
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- 1H-IMIDAZO[4,5-C]QUINOLINE DERIVATIVES IN THE TREATMENT OF PROTEIN KINASE DEPENDENT DISEASES
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The invention relates to the use of imidazoquinolines and salts thereof in the treatment of protein kinase diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases, imidazoquinolines for use in the treatment of protein kinase dependent diseases, a method of treatment against said diseases, comprising administering the imidazoquinolines to a warm-blooded animal, especially a human, pharmaceutical preparations comprising an imidazoquinoline, especially for the treatment of a protein kinase dependent disease, novel imidazoquinolines, and a process for the preparation of the novel imidazoquinolines.
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Page/Page column 76
(2010/02/12)
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- FAB I INHIBITORS
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Compounds of the formula (I) are disclosed which are Fab I inhibitors and are useful in the treatment of bacterial infections.
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- AROMATIC AMINO ACID DERIVATIVES AND MEDICINAL COMPOSITIONS
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An aromatic amino acid derivative represented by the formula ( I ) or its pharmacologically acceptable salt: wherein,R1 is a hydrogen atom or an amino-protecting group,R2 is a halogen atom or an alkyl, aralkyl or aryl group,R3 is 1○ a hydrogen atom, 2○ an aroylamino group, 3○ a phenyl group substituted with lower alkyl, phenyl, phenoxy, etc. 4○ a naphthyl or tetrahydronaphthyl group optionally substituted with hydroxy, lower alkoxy or di(lower)alkylamino, 5○ an unsaturated mono-cyclic heterocyclic group containing N, O and/or S substituted with lower alkyl, phenyl, naphthyl or tetrahydroquinolyl, 6○ an unsaturated or partially saturated condensed heterocyclic group containing N, O and/or S, optionally substituted with oxo, carboxy, amino, lower alkyl, etc.; X is a halogen atom, an alkyl group or an alkoxy group; Y is oxygen atom or nitrogen atom; 1 is 0 or 1; m is 0, 1 or 2; n is an integer of 0-5. This compound can inhibit a transporter (LAT1) of essential amino acid which is one of main nutrition for cancer cells and accordingly cause drain of the essential amino acid on the cancer cells and finally can prohibit the multiplication of cancer cells.
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- SULFONYLAMINO-ACETIC ACID DERIVATIVES
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The invention relates to novel sulfonylamino-acetic acid derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of such compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as orexin receptor antagonists.
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- Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino- pyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure-activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists
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We previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo-[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF1 receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26h exhibited good binding affinity at the human CRF1 receptor with a Ki value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF1 receptor (IC50 = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC50 = 20 nM). 26h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26h was orally bioavailable and able to penetrate into the brain. 26h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF1 receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26h was developed into a clinical compound and exhibited efficacy in patients with major depression.
- Chen, Chen,Wilcoxen, Keith M.,Huang, Charles Q.,Xie, Yun-Feng,McCarthy, James R.,Webb, Thomas R.,Zhu, Yun-Fei,Saunders, John,Liu, Xin-Jun,Chen, Ta-Kung,Bozigian, Haig,Grigoriadis, Dimitri E.
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p. 4787 - 4798
(2007/10/03)
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- Compounds and methods for modulation of estrogen receptors
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Compounds that modulate the estrogen receptor (ER) are disclosed, as well as pharmaceutical compositions containing the same. In a specific embodiment, the compounds are selective for ER-β over ER-α. Methods are disclosed for modulating ER-β in cell and/o
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- Indoles
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A 1,4-substituted cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof: wherein A, B, C, D, T, Y, and Z each represent a methine or a nitrogen linkage; R1, R2, R3, R4, and R5 each represent a substituent; n represents 0 or an integer of 1 to 3; m represents 0 or an integer of 1 to 6; and p represents an integer of 1 to 3. The compounds have serotonin antagonism. They are therefore clinically useful as medicaments, in particular, for treating, ameliorating, and preventing spastic paralysis. They are also useful as central muscle relaxants for ameliorating myotonia.
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- Syntheses and properties of novel liquid crystals containing a trifluoromethylamino group
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Liquid crystals (LCs) containing a trifluoromethylamino group are prepared by the cross-coupling reaction of p-bromo-substituted- (hetero)aryl(trifluoromethyl)amines that are derived from the corresponding dithiocarbamates through oxidative desulfurizatio
- Kanie, Kiyoshi,Mizuno, Katsuya,Kuroboshi, Manabu,Takehara, Sadao,Hiyama, Tamejiro
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p. 2523 - 2535
(2007/10/03)
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- Bromination of Some Pyridine and Diazine N-Oxides
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Selected monosubstituted pyridines, pyrazines, pyrimidines, and their N-oxides, having an electron-donating substituent, were successfully brominated under very mild conditions.The N-oxide function itself is not sufficient to cause these ?-deficient systems to undergo electrophilic aromatic halogenation.Only strongly electron-donating substituents (amino groups) activate the heterocyclic nucleus toward bromination.These substituents direct the electrophilic substitution ortho/para to them with or without the N-oxide group present.Pyridine and diazines with moderately activating substituents such as alkoxy groups are brominated only when their ortho/para activation is augmented by the activation of the N-oxide funtion.Failure to brominate 5-methoxypyrimidine 1-oxide may well reflect the greater ? deficiency of the pyrimidine ring.
- Paudler, William W.,Jovanovic, Misa V.
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p. 1064 - 1069
(2007/10/02)
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