- Palladium-Catalyzed Migratory Insertion of Carbenes and C-C Cleavage of Cycloalkanecarboxamides
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A palladium catalyzed reaction of cycloalkanecarboxamides and diazomalonates or bis(phenylsulfonyl)diazomethane has been developed. The reaction proceeds via carbene migratory insertion and cascade C-C cleavage pathways. Cycloalkanecarboxamides with four to seven membered rings are applicable in the transformation. A series of ring opening products were prepared with moderate yields. The finding provides valuable clues for the development of new reactions involving carbene migratory insertion and the cleavage of unstrained C(sp3)-C(sp3) bonds.
- Zhang, Peng,Zeng, Jia,Pan, Ping,Zhang, Xue-Jing,Yan, Ming
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supporting information
p. 536 - 541
(2022/01/20)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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-
Paragraph 00803; 0088-0089
(2021/06/26)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00512; 00709-00710
(2021/06/26)
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- SMALL MOLECULE INHIBITORS OF ULK1
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The present technology is directed to compounds, compositions, and methods related to inhibition of ULK1 and treatment of cancers therefrom.
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Paragraph 0252; 0292
(2021/07/10)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same. The compounds include an IRAK binding moiety capable of binding to IRAK4 and a degradation inducing moiety (DIM). The DIM could be DTM a ligase binding moiety (LBM) or lysine mimetic. The compounds could be useful as IRAK protein kinase inhibitors and applied to IRAK mediated disorders.
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Paragraph 00920; 001982-001983; 002921-002923
(2021/01/23)
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- ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model
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Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.
- Hiramatsu, Atsushi,Hirooka, Yasuo,Hisaichi, Katsuya,Imagawa, Akira,Iwaki, Yuzo,Katoh, Makoto,Kobayashi, Juta,Komichi, Yuka,Maeda, Tatsuo,Matsumura, Naoya,Moriguchi, Hideki,Nakatani, Shingo,Nishiyama, Taihei,Ohhata, Akira,Okabe, Yasuyuki,Okada, Masahiro,Ota, Hiroto,Saga, Hiroshi,Sugiyama, Tetsuya,Watanabe, Toshihide,Yamamoto, Shingo
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supporting information
p. 1335 - 1341
(2020/07/06)
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- Design, synthesis and biological evaluation of novel indazole-based derivatives as potent HDAC inhibitors via fragment-based virtual screening
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Based on fragment-based virtual screening and bioisoterism strategies, novel indazole and pyrazolo[3,4-b] pyridine derivatives as HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDACs, especially compounds 15k and 15m were identified as potent inhibitors of HDAC1 (IC50 = 2.7 nM and IC50 = 3.1 nM), HDAC2 (IC50 = 4.2 nM and IC50 = 3.6 nM) and HDAC8 (IC50 = 3.6 nM and IC50 = 3.3 nM). Further anti-proliferation assays revealed that compounds 15k and 15m showed better anti-proliferative activities against HCT-116 and HeLa cells than positive control SAHA. The western blot analysis results indicated that compounds 15k and 15m noticeably up-regulated the level of acetylated α-tubulin and histone H3. In addition, the two compounds 15k and 15m could arrest cell cycle in G2/M phase and promote cell apoptosis, which was similar as the reference compound SAHA. Through the molecular docking and dynamic studies, the potent HDAC inhibitory activities mainly caused by van der Waals and electrostatic interactions with the HDACs.
- Gao, Liang,Gao, Lina,He, Fengjun,Hu, Lihong,Kang, Di,Liu, Jian,Wang, Ping,Wen, Yu,Zhou, Jingxian
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- COMPOUNDS USEFUL AS IMMUNOMODULATORS
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The present disclosure generally relates to compounds useful as immunomodulators. Provided herein are compounds, compositions comprising such compounds, and methods of their use. The disclosure further pertains to pharmaceutical compositions comprising at least one compound according to the disclosure that are useful for the treatment of various diseases, including cancer and infectious diseases.
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Page/Page column 75-76
(2018/07/29)
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- PYRAN DERVATIVES AS CYP11A1 (CYTOCHROME P450 MONOOXYGENASE 11A1) INHIBITORS
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Compounds of formula (I) wherein R1, R2,R3,R4,R5,R23,R24,L, A and Bare as defined in claim 1, or pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as cytochrome P450 monooxygenase 11A1(CYP11A1) inhibitors. The compounds are useful as medicaments in the treatment of steroidreceptor, particularly androgen receptor,dependent diseases and conditions, such asprostate cancer.
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Page/Page column 62; 63; 79; 80
(2018/07/29)
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- Imidazole alcohol derivative containing bridged ring
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The present invention relates to the field of drugs, particularly to an imidazole alcohol derivative containing a bridged ring structure, wherein the imidazole alcohol derivative can be used for preparing drugs for treatment of diseases having pathologica
- -
-
Paragraph 0311; 0312; 0313; 0314; 0315
(2018/04/02)
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- 1-(CYCLOALKYL-CARBONYL)PROLINE DERIVATIVE
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A compound represented by formula (1) (in the formula: ring-D represents a three- to eight-membered hydrocarbon ring; Ra represents an optionally substituted amino C1-6 alkyl group or the like; Rb1 and Rb2 each independently represent a hydrogen atom, a halogen atom, or the like; Rc represents an optionally substituted C6-10 aryl group or the like; Rd represents a hydrogen atom or the like; and ring-Q represents a (hetero)aryl group or the like which may be substituted with a carboxyl group or the like) or a pharmaceutically acceptable salt thereof exhibits an excellent FXIa inhibitory activity, and is useful as a therapeutic agent against thrombosis or the like.
- -
-
Paragraph 0466
(2015/06/03)
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- Cyclohexyl-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulenes as V1a antagonists
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The present invention provides 4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulenes, which act as V1a receptor modulators, and in particular as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The active compounds of the present invention are useful as therapeutics acting peripherally and centrally in the conditions of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior.
- -
-
Paragraph 0155
(2014/08/19)
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- PRODRUG BIPYRIDYLAMINOPYRIDINES AS SYK INHIBITORS
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The present invention provides compounds of Formula (I), which are prodrugs of trans-4-[(1R)-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3'-bipyridin-6'-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid, a potent inhibitor of Syk. The compounds are useful in the treatment and prevention of diseases mediated by the enzyme, such as asthma, COPD, rheumatoid arthritis and cancer.
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Page/Page column 46; 47
(2014/05/24)
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- Counterion effects in the preparation of aldehyde-bisulfite adducts
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The identification and development of an aldehyde-bisulfite adduct as an isolable starting material in the synthesis of the CETP inhibitor Evacetrapib are described. The physical properties of the sodium and potassium analogs are compared, and the extension of the scope of this study to include an investigation into the solid state properties of a range of sodium and potassium bisulfite adducts of commonly encountered aldehydes is discussed.
- Kissane, Marie G.,Frank, Scott A.,Rener, Gregory A.,Ley, Christopher P.,Alt, Charles A.,Stroud, Paul A.,Vaid, Radhe K.,Boini, Sathish K.,McKee, Laura A.,Vicenzi, Jeffrey T.,Stephenson, Gregory A.
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supporting information
p. 6587 - 6591
(2013/11/19)
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- Chloroform as a hydrogen atom donor in barton reductive decarboxylation reactions
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The utility of chloroform as both a solvent and a hydrogen atom donor in Barton reductive decarboxylation of a range of carboxylic acids was recently demonstrated (Ko, E. J. et al. Org. Lett. 2011, 13, 1944). In the present work, a combination of electronic structure calculations, direct dynamics calculations, and experimental studies was carried out to investigate how chloroform acts as a hydrogen atom donor in Barton reductive decarboxylations and to determine the scope of this process. The results from this study show that hydrogen atom transfer from chloroform occurs directly under kinetic control and is aided by a combination of polar effects and quantum mechanical tunneling. Chloroform acts as an effective hydrogen atom donor for primary, secondary, and tertiary alkyl radicals, although significant chlorination was also observed with unstrained tertiary carboxylic acids.
- Ho, Junming,Zheng, Jingjing,Meana-Paneda, Ruben,Truhlar, Donald G.,Ko, Eun Jung,Savage, G. Paul,Williams, Craig M.,Coote, Michelle L.,Tsanaktsidis, John
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p. 6677 - 6687
(2013/07/26)
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- Discovery of LFF571: An investigational agent for Clostridium difficile infection
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Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.
- Lamarche, Matthew J.,Leeds, Jennifer A.,Amaral, Adam,Brewer, Jason T.,Bushell, Simon M.,Deng, Gejing,Dewhurst, Janetta M.,Ding, Jian,Dzink-Fox, Joanne,Gamber, Gabriel,Jain, Akash,Lee, Kwangho,Lee, Lac,Lister, Troy,McKenney, David,Mullin, Steve,Osborne, Colin,Palestrant, Deborah,Patane, Michael A.,Rann, Elin M.,Sachdeva, Meena,Shao, Jian,Tiamfook, Stacey,Trzasko, Anna,Whitehead, Lewis,Yifru, Aregahegn,Yu, Donghui,Yan, Wanlin,Zhu, Qingming
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supporting information; experimental part
p. 2376 - 2387
(2012/06/01)
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- EFFICIENT SYNTHETIC METHOD OF 18F-MEFWAY PRECURSOR
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The present invention relates a novel method for preparing an 18F-mefway precursor. The present invention provides an efficient synthetic method of an 18F-mefway precursor, which comprises an improved the acid chloride coupling react
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Page/Page column 7
(2012/06/16)
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- HETEROBIARYL-CYCLOHEXYL-TETRAAZABENZO[E]AZULENES
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The present invention relates to heterobiaryl-cyclohexyl-tetraazabenzo[e]azulenes of formula I wherein R1, R2 and R3 are as described herein. The compounds according to the invention act as V1a receptor modulators, and in
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Page/Page column 20
(2011/11/06)
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- HETEROBIARYL-CYCLOHEXYL-TETRAAZABENZO[E]AZULENES
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The present invention relates to heterobiaryl-cyclohexyl-tetraazabenzo[e]azulenes of formula (I), wherein R1, R2 and R3 are as described herein. The compounds according to the invention act as V1a receptor modulators, and in particular as V1a receptor ant
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Page/Page column 42-43
(2011/11/13)
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- Reducing the cost, smell, and toxicity of the Barton reductive decarboxylation: Chloroform as the hydrogen atom source
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When used as solvent, chloroform was found to act as a hydrogen atom donor in Barton reductive decarboxylation reactions. Chloroform offers a substantial practical advantage over pre-existing hydrogen atom donors.
- Ko, Eun Jung,Williams, Craig M.,Savage, G. Paul,Tsanaktsidis, John
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supporting information
p. 1944 - 1947
(2015/02/18)
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- COMPOSITIONS AND METHODS RELATED TO SEROTONIN 5-HT1A RECEPTORS
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Contemplated substituted arylpiperazinyl compounds, and most preferably 18F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high b
- -
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Page/Page column 7
(2008/06/13)
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- Structure determination of metabolites isolated from urine and bile after administration of AY4166, a novel D-phenylalanine-derivative hypoglycemic agent
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Molecular structures of 10 metabolites, which were isolated from urine (M1-M8) or bile (M9 and M10) after administration of AY4166 (N-(trans-4- isopropylcyclohexanecarbonyl)-D-phenylalanine), a novel amino acid derivative with hypoglycemic activity, have
- Takesada, Hiroko,Matsuda, Keizo,Ohtake, Ryoko,Mihara, Ryuichi,Ono, Ichiro,Tanaka, Kenzo,Naito, Masaki,Yatagai, Masanobu,Suzuki, Ei-Ichiro
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p. 1771 - 1781
(2007/10/03)
-
- Magnetic Field Dependent Reaction Yields from Radical Ion Pairs Linked by a Partially Rigid Aliphatic Chain
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The electron donor-acceptor compound pyrene-(CH2)3-cyclohexane-(CH2)3-dimethylaniline, abbreviated as Py3(C6)3DMA, has been investigated.Photoinduced electron transfer leads to the singlet radical ion pair Py-3(C6)3DMA+.An extraordinary large and distinct magnetic field effect is observed in the yield of the locally excited triplet state of the pyrene moiety, the recombination product of the triplet radical ion pair.The half-width of the "J-resonance" maximum in the magnetic field dependent triplet yield curve is just 66 G, corresponding to 7.7*10-7 eV or 6.2*10-3 cm-1.This is due to the influence of the rigid trans-cyclohexane part in the aliphatic chain, which leads to a reduced intramolecular mobility and to a narrow probability distribution of the radical ion pair distance, as predicted by Monte-Carlo computer simulations.The magnetic field dependence of the triplet generation is further transmitted to secondary reactions like triplet-triplet annihilation, thus leading to a magnetic field dependent delayed fluorescence and to a delayed excimer fluorescence.
- Werner, Udo,Kuehnle, Wolfgang,Staerk, Hubert
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p. 9280 - 9287
(2007/10/02)
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- Monic acid derivatives
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Compounds of formula (I): wherein, is a divalent or a trivalent, 5-membered heterocyclic group having a 6-? electron system, and containing from 1 to 4 heteroatoms, each selected from oxygen, nitrogen and sulphur;, R1 is a substituted C3 7 cycloalkyl group attached to a carbon or nitrogen of and where appropriate, R2 is a group attached to a carbon or nitrogen of and, when present, is selected from optionally substituted C1 20 alkyl, optionally substituted C3 7 cycloalkyl, optionally substituted C2 8 alkenyl, aryl, aralkyl, heterocyclyl and hydrogen;, and where the trisubstituted carbon-carbon double bond preferably has the E- configuration;, have anti-bacterial activity.
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- About the Influence of Geometrical Factors on Liquid Crystalline Properties-The Methylene Group as a Central Spacer Unit
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The preparation and liquid crystalline properties of four classes of substance with a central methylene spacer unit are described.As a result of our investigations, it is shown that a "one-atomic" central spacer, such as a methylene group, combined with a
- Frach, R.,Deutscher, H. -J.,Zaschke, H.,Altmann, H.
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p. 151 - 164
(2007/10/02)
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- Thermotropic Liquid Crystals Containing the Dispirotetradecane Unit
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Several 3,11-disubstituted dispirotetradecane-7,14-dions were prepared and the cis/trans-isomers were separated.The trans-stereoisomers were converted into the gem-dihalide ketones and mono- and dithioketones.The phase transfer temperatures were
- Calaminus, W.,Voegtle, F.,Eidenschink, R.
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p. 1011 - 1014
(2007/10/02)
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