- Optical control of muscular nicotinic channels with azocuroniums, photoswitchable azobenzenes bearing two N-methyl-N-carbocyclic quaternary ammonium groups
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By linking two N-methyl-N-carbocyclic quaternary ammonium groups to an azobenzene scaffold in meta- or para-positions we generated a series of photoswitchable neuromuscular ligands for which we coined the term “azocuroniums”. These compounds switched betw
- Herrera-Arozamena, Clara,Villalba-Galea, Carlos A.,de la Fuente Revenga, Mario,Estrada-Valencia, Martín,Martí-Marí, Olaia,Pérez, Concepción,Rodríguez-Franco, María Isabel
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Read Online
- Metal-Free Deoxygenation of Amine N-Oxides: Synthetic and Mechanistic Studies
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We report herein an unprecedented combination of light and P(III)/P(V) redox cycling for the efficient deoxygenation of aromatic amine N-oxides. Moreover, we discovered that a large variety of aliphatic amine N-oxides can easily be deoxygenated by using only phenylsilane. These practically simple approaches proceed well under metal-free conditions, tolerate many functionalities and are highly chemoselective. Combined experimental and computational studies enabled a deep understanding of factors controlling the reactivity of both aromatic and aliphatic amine N-oxides.
- Lecroq, William,Schleinitz, Jules,Billoue, Mallaury,Perfetto, Anna,Gaumont, Annie-Claude,Lalevée, Jacques,Ciofini, Ilaria,Grimaud, Laurence,Lakhdar, Sami
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p. 1237 - 1242
(2021/06/01)
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- A practical catalytic reductive amination of carboxylic acids
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We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.
- Andrews, Keith G.,Denton, Ross M.,Hirst, David J.,Stoll, Emma L.,Tongue, Thomas,Valette, Damien
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p. 9494 - 9500
(2020/10/02)
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- Ruthenium and Iron-Catalysed Decarboxylative N-alkylation of Cyclic Α-Amino Acids with Alcohols: Sustainable Routes to Pyrrolidine and Piperidine Derivatives
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A modular and waste-free strategy for constructing N-substituted cyclic amines via decarboxylative N-alkylation of α-amino acids employing ruthenium- and iron-based catalysts is presented. The reported method allows the synthesis of a wide range of five- and six-membered N-alkylated heterocycles in moderate-to-excellent yields starting from predominantly proline and a broad range of benzyl alcohols, and primary and secondary aliphatic alcohols. Examples using pipecolic acid for the construction of piperidine derivatives, as well as the one-pot synthesis of α-amino nitriles, are also shown.
- Afanasenko, Anastasiia,Hannah, Rachael,Yan, Tao,Elangovan, Saravanakumar,Barta, Katalin
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p. 3801 - 3807
(2019/07/31)
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- Synthesis, β-hematin inhibition studies and antimalarial evaluation of new dehydroxy isoquine derivatives against Plasmodium berghei: A promising antimalarial agent
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Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert-butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I
- Valverde, Edgar A.,Romero, Angel H.,Acosta, María E.,Gamboa, Neira,Henriques, Genesis,Rodrigues, Juan R.,Ciangherotti, Carlos,López, Simón E.
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supporting information
p. 498 - 506
(2017/11/13)
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- INHIBITORS OF LOW MOLECULAR WEIGHT PROTEIN TYROSINE PHOSPHATASE (LMPTP) AND USES THEREOF
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Protein tyrosine phosphatases (PTPs) are key regulators of metabolism and insulin signaling. As a negative regulator of insulin signaling, the low molecular weight protein tyrosine phosphatase (LMPTP) is a target for insulin resistance and related conditions. Described herein are compounds capable of modulating the level of activity of low molecular weight protein tyrosine phosphatase (LMPTP) and compositions, and methods of using these compounds and compositions.
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Paragraph 00233
(2018/11/26)
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- Dehydrogenative Aromatization and Sulfonylation of Pyrrolidines: Orthogonal Reactivity in Photoredox Catalysis
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Oxidative dehydrogenative aromatization and selective sulfonylation reactions of N-heterocycles under visible-light photoredox catalysis were established. The mild reaction conditions make this approach an appealing and versatile strategy to functionalize/oxidize pyrrolidines whereby arylsulfonyl chlorides were identified to be both catalyst regeneration and sulfonylation reagents.
- Muralirajan, Krishnamoorthy,Kancherla, Rajesh,Rueping, Magnus
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supporting information
p. 14787 - 14791
(2018/10/20)
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- Beta-carboline derivative targeted to CDK and DNA and preparation method and medical application thereof
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The invention discloses a beta-carboline derivative targeted to CDK and DNA and a preparation method and medical application thereof. The beta-carboline derivative has a structure shown in the general formula I in the description. The compound can be applied in combination with other antitumor drugs and can also be applied in combination with radiotherapy. The antitumor drugs or radiotherapy and the compound can be applied at the same time or at different times. The combined therapy can perform a synergistic effect, and thus the therapeutic effect can be easily improved.
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Paragraph 0104
(2017/06/02)
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- Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease
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A series of ebselen derivatives were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and glutathione peroxidase (GPx) mimics. Most of the compounds were found to be potent against AChEs and BuChE, compounds 5e and 5i, proved to be the most potent against AChE with IC50 values of 0.76 and 0.46 μM, respectively. Among these hybrids, most of the compounds were found to be good GPx mimics compare with ebselen. The selected compounds 5e and 5i were also used to determine the catalytic parameters and in vitro hydrogen peroxide scavenging activity. The results indicate that compounds 5e and 5i may be excellent multifunctional agents for the treatment of AD.
- Luo, Zonghua,Liang, Liang,Sheng, Jianfei,Pang, Yanqing,Li, Jianheng,Huang, Ling,Li, Xingshu
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supporting information
p. 1355 - 1361
(2014/03/21)
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- Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers
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A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized co
- Tang, Li,Zhao, Liying,Hong, Lingjuan,Yang, Fenyan,Sheng, Rong,Chen, Jianzhong,Shi, Ying,Zhou, Naimin,Hu, Yongzhou
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p. 5936 - 5944
(2013/09/23)
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- 3-SUBSTITUED IMIDAZO (4, 5-B) PYRIDINES AND ANALOGS AS SIRTUIN MODULATORS
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Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for e
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Page/Page column 86-87
(2011/10/10)
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- A fast and highly efficient method for the synthesis of tertiary amines in aqueous medium
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A facile and highly efficient method for the synthesis of tertiary amines by the reaction of secondary amines with benzylic bromides and 1,1'-dibromo p/o-xylenes in aqueous dioxane and NaOH is described. The reactions are dually promoted by the base in short time (15 min.) at ambient conditions in aqueous medium.
- Adimurthy, Subbarayappa,Joshi, Girdhar
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experimental part
p. 771 - 775
(2011/01/04)
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- Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment
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Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. This receptor is over-expressed or activated in tumor cells and is emerging as a novel target in cancer therapy. Efforts in our "Hit to Lead" group have generated a novel series of submicromolar IGF-1R inhibitors based on a isoquinolinedione template originating from a Lance enzyme HTS screen. Chemical triage and parallel synthesis incorporating focused library arrays were instrumental in moving these investigations through the Wyeth exploratory medicinal chemistry process. The strategies, synthesis, and SAR behind this interesting kinase scaffold will be described.
- Mayer, Scott C.,Banker, Annette L.,Boschelli, Frank,Di, Li,Johnson, Mark,Kenny, Cynthia Hess,Krishnamurthy, Girija,Kutterer, Kristina,Moy, Franklin,Petusky, Susan,Ravi, Malini,Tkach, Diane,Tsou, Hwei-Ru,Xu, Weixin
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scheme or table
p. 3641 - 3645
(2009/04/06)
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- INDOLINONE DERIVATIVES AND THEIR USE IN TREATING DISEASE-STATES SUCH AS CANCER
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The present invention encompasses compounds of general formula (1) wherein R1 to R4 are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use for preparing a pharmaceutical composition having the above-mentioned properties.
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Page/Page column 23
(2009/01/24)
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- 3- (AMINOMETHYLIDEN) 2-INDOLINONE DERIVATIVES AND THEIR USE AS CELL PROLIFERATION INHIBITORS
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The present invention encompasses compounds of general formula (1) wherein R1, R2, R3 and X are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a pharmaceutical composition having the above-mentioned properties.
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Page/Page column 17
(2008/06/13)
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- Thiazolopyridine kinase inhibitors
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The present invention is directed to novel thiazolopyridines, pharmaceutical compositions thereof, and the use thereof as inhibitors of ATP-protein kinase interactions. The thiazolopyridine compounds have the following Formula (I):
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Page/Page column 27-28
(2010/10/20)
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- QUINAZOLINE DERIVATIVES FOR USE AGAINST CANCER
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The invention concerns quinazoline derivatives of Formula (I) or a pharmaceutically-acceptable salt, solvate or pro-drug thereof, wherein each of p, R1, q, R2, R3, R4, R5, Ring A, X1, R6, r and R7 has any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders or in the treatment of disease states associated with angiogenesis and/or vascular permeability.
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Page/Page column 96
(2008/06/13)
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- QUINOLONE CARBOXYLIC ACID DERIVATIVES FOR TREATMENT OF HYPERPROLIFERATIVE CONDITIONS
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Quinolone carboxylic acid derivatives of formula (I) wherein Ar is an optionally substituted phenyl, pyridyl, or pyrimidinyl group and the substituent groups R1, R4, R10, R11, R19, and R20 are as defined in the specification, pharmaceutical compositions containing them, and methods of using them in treatment of hyperproliferative diseases such as cancer are disclosed and claimed.
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Page/Page column 18
(2010/02/14)
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- Substituted indolines which inhibit receptor tyrosine kinases
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Indolinones of the formula having an inhibitory effect on receptor tyrosine kinases and cyclin/CDK complexes, as well as on the proliferation of endothelial cells and various tumor cells. Exemplary are: (a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone, and (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-metboxycarbonyl-2-indolinone.
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Page column 42
(2008/06/13)
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- CHK-, PDK- AND AKT-INHIBITORY PYRIMIDINES, THEIR PRODUCTION AND USE AS PHARMACEUTICAL AGENTS
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This invention relates to pyrimidine derivatives of general formula (I) as inhibitors of kinases, their production as well as their use as medications for treating various diseases.
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- Efficient and chemoselective deoxygenation of amine N-oxides using polymethylhydrosiloxane
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Deoxygenation of aromatic and aliphatic amine N-oxides to the corresponding amines is achieved under mild conditions. The reagent combination employed for this transformation is polymethylhydrosiloxane (PMHS) in the presence of either tetrakis (triphenylphosphine) palladium (0) [Pd(PPh3)4], titanium (IV) isopropoxide [Ti(i-PrO)4] or palladium on carbon (Pd/C).
- Chandrasekhar,Reddy, Ch. Raji,Rao, R. Jagadeeshwar,Rao, J. Madhusudana
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p. 349 - 351
(2007/10/03)
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- Substituted indolinones with kinase inhibitory activity
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Substituted indolinones of general formula having effect on various kinases and cycline/CDK complexes and on the proliferation of various tumour cells. Exemplary compounds are: 3-Z-[1-(4-(N-Benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-a
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- Indolinones having kinase inhibitory activity
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The present invention relates to substituted indolinones of general formula [Figure] wherein R1 to R5, and X are defined as in claim 1, the isomers thereof and the salts thereof, particularly the physiologically acceptable salts thereof which have valuable pharmacological properties, particularly an inhibitory effect on various kinases and cycline/CDK complexes and on the proliferation of various tumour cells, pharmaceutical compositions containing these (compounds, their use and processes for preparing them.
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- Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety
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The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [125I]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium m
- Shiraishi, Mitsuru,Aramaki, Yoshio,Seto, Masaki,Imoto, Hiroshi,Nishikawa, Youichi,Kanzaki, Naoyuki,Okamoto, Mika,Sawada, Hidekazu,Nishimura, Osamu,Baba, Masanori,Fujino, Masahiko
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p. 2049 - 2063
(2007/10/03)
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- Anilide derivative, production and use thereof
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This invention is to provide a compound of the formula: wherein R1 is an optionally substituted 5- to 6-membered ring: C is a divalent group of the formula: wherein the ring A is an optionally substituted 5- to 6-membered aromatic ring, X is an optionally substituted C, N or O atom, and the ring B is an optionally substituted 5- to 7-membered ring; Z is a chemical bond or a divalent group; R2 is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, etc., or a salt thereof, which is useful for antagonizing MCP-1 receptor.
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- Structure-activity relationships for the antileishmanial and antitrypanosomal activities of 1'-substituted 9-anilinoacridines
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Members of the class of 9-anilinoacridine topoisomerase II inhibitors bearing lipophilic electron-donating 1'-aniline substituents are active against both the promastigote and amastigote forms of the parasite Leishmania major. A series of analogues of the known 1'-NHhexyl lead compound were prepared and evaluated against L. major in macrophage culture to further develop structure-activity relationships (SAR). Toxicity toward mammalian cells was measured in a human leukemia cell line, and the ratio of the two IC50 values (IC50(J)/IC50(L)) was used as a measure of the in vitro therapeutic index (IVTI). A 3,6-diNMe2 substitution pattern on the acridine greatly increased toxicity to L. major without altering mammalian toxicity, increasing IVTIs over that of the lead compound. The 2-OMe, 6-C1 acridine substitution pattern used in the antimalarial drug mepacrine also resulted in potent antileishmanial activity and high IVTIs. Earlier suggestions of the utility of 2'-OR groups in lowering mammalian cytotoxicity were not borne out in this wider study. A series of very lipophilic 1'-NRR (symmetric dialkylamino)-substituted analogues showed relatively high antileishmanial potency, but no clear trend was apparent across the series and none were superior to the 1'-NH(CH2)5Me subclass. Subsets of the most active 1'- N(R)(CH2)5Me- and 1'-N(alkyl)2-substituted compounds against L. major were also evaluated against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, but no consistent SAR could be discerned in these physiologically diverse test systems. The present study has confirmed earlier conclusions that lipophilic electron-donating groups at the 1'-position of 9- anilinoacridines provide high activity against L. major, but the SAR patterns observed do not carry over to the other parasites studied.
- Gamage, Swarna A.,Figgitt, David P.,Wojcik, Stanley J.,Ralph, Raymond K.,Ransijn, Adriana,Mauel, Jacques,Yardley, Vanessa,Snowdon, Diane,Croft, Simon L.,Denny, William A.
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p. 2634 - 2642
(2007/10/03)
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- Structure-activity studies on a 1,2,3-triazole derivative, a potent in vitro inhibitor of prostaglandin synthesis: The role of the heterocyclic ring
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This paper reports further structural modifications concerning the 1,2,3- triazole ring of the compound A, an effective in vitro inhibitor of prostaglandin synthesis. The introduction of different heterocyclic rings provided further information about of t
- Biagi,Dell'Omodarme,Ferretti,Giorgi,Livi,Scartoni
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p. 335 - 344
(2007/10/02)
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- Homolytic Alkylation of Enamines by Electrophilic Radicals
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The electrophilic radicals R* = p-O2NC6H4CH2* or Me2C(NO2)* add readily to CH2=C(NMe)2 to yield RCH2C(NMe2)2* which undergoes electron transfer with p-O2NC6H4CH2Cl or Me2C(NO2)2 to regenerate R*.Hydrolysis yields p-O2NC6H4CH2CONMe2 and Me2C=CHC(NMe2)2(1+), respectively. p-Nitrobenzyl radicals add readily to N-pyrrolidino- or N-morpholino-1-cycloalkenes to yield after hydrolysis the α-(p-nitrobenzyl)cycloalkanones.Photostimulated alkylation of N-pyrrolidino-1-cycloalkenes by Me2C(NO2)2 is not observed although in competitive reactions between the enamine and Me2C=NO2Li, the product from attack of Me2C(NO2)* upon the eneamine double bond is formed.The N-pyrrolidino-1-cycloalkenes are more reactive toward p-O2NC6H5CH2 than their morpholine analogues.
- Russell, Glen A.,Wang, Keyang
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p. 3475 - 3479
(2007/10/02)
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