The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

Inhibitors of histone deacetylase

They function as potent inhibitors of glycoproteins; including DC-SIGN, which facilitates the spread of viruses such as HIV, Hepatitis C, or Ebola; or CETP, which in its inhibited state counteracts atherosclerosis. Furthermore, they have been reported to open calcium channels; or serve as highly selective antagonists for diverse receptors, for example Kinin B1, which is associated with inflammation and pain in septicemia. An example of a promising dihydroquinoxalinone is GW420867X, a non-nucleoside HIV-1 reverse transcriptase inhibitor, which is currently in clinical trials. Furthermore, due to the similarity in their structure, tetrahydroquinoxalines are used as models for tetrahydrofolic acids (coenzyme F) and their derivatives, for example, leucovorine. The latter serves as a “rescue agent” in chemotherapy together with methotrexate. Even though it is only the natural diastereomer of leucovorine that acts as a competitive inhibitor, and the possibility that long-term use of the unnatural diasteromer may be toxic, leucovorine is still generally used as a racemate due to the lack of alternative synthetic methods. Despite the great importance of the tetahydroquinoxalines and dihydroquinoxalinones there are only very few enantioselective synthetic routes. To date efficient synthetic methods include catalytic reactions or solid-phase synthesis. However, they generally require multiple reaction steps and the introduction of a chiral amino alcohol or a corresponding amino acid. With particular emphasis on economic and ecologically valuable processes, asymmetric hydrogenation represents a highly efficient and atom-economic approach. General, catalytic, enantioselective hydrogenations of quinoxalines and quinoxalinones are not known, yet they represent the simplest method for synthesizing optically active tetrahydroquinoxalines and dihydroquinoxalinones. To date only the catalytic enantioselective reduction of 2-methylchinoxaline has been described. However, for instance in the case of DC-SIGN, as is often the case with tetrahydroquinoxalinones, the ones with aromatic substituents in the 2position are more biologically active. Therefore, we decided to examine a general, catalytic, enantioselective reduction of both quinoxalines and quinoxalinones. In particular, we wanted to concentrate on arylsubstituted derivatives, as these have been shown to be especially biologically active. As our initial work towards a metal-catalyzed, asymmetric reduction did not deliver the desired results with regard to high reactivity and selectivity, we decided to also examine metal-free transfer hydrogenations. 16] Here, the initial experiments showed that various Bronsted acids such as diphenylphosphate are able to catalyze the transfer hydrogenation of quinoxaline 1a to the corresponding 2-phenyl-tetrahydroquinoxaline 3a in the presence of the Hantzsch dihydropyridine 2a as a hydride source. Further, it was shown that the concentration of the solvent is a determining reaction parameter, especially with regard to the reactivity: The reactivity continuously increases with increasing solvent concentration. The following studies concentrated on the development of the first asymmetric variant in which the chiral phosphoric [a] Prof. Dr. M. Rueping, Dr. F. Tato, F. R. Schoepke Institute of Organic Chemisty, RWTH Aachen Landoltweg 1, 52074 Aachen (Germany) Fax: (+49)241-809-2127 E-mail : magnus.rueping@rwth-aachen.de Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200902907.

The first general, efficient and highly enantioselective reduction of quinoxalines and quinoxalinones.

Disclosed are compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof. Such compounds are MEK inhibitors and are useful in the treatment of proliferative diseases, such as cancer. Also disclosed are pharmaceutical compositions containing such compounds as well as methods of using the compounds and compositions of the invention in the treatment of cancer.

Azetidines as mek inhibitors for the treatment of proliferative diseases

The 1,2,3,4-tetrahydroquinoxaline ring system is an important structural unit in many bioactive compounds. Optically pure tetrahydroquinoxaline derivatives have shown great potential for pharmaceutical applications. For example, chiral compound A has been pursued as a potent vasopressin V2 receptor antagonists, and optically pure compound B is a promising inhibitor of cholesteryl ester transfer protein. In both cases, the chirality of the compounds was found to play a very important role in the relevant bioactivity of these compounds. The most convenient and straightforward route to chiral tetrahydroquinoxalines is the asymmetric hydrogenation of quinoxalines. Although several kinds of heteroaromatic compounds, such as quinolines, indoles, furans, pyridines, and pyrazines have been successfully hydrogenated with good to excellent enantioselectivities and yields in the presence of chiral transition-metal catalysts, the enantioselective hydrogenation of substituted quinoxaline derivatives has been less extensively studied. In 1987, Murata et al. first reported the rhodium-catalyzed asymmetric hydrogenation of 2-methylquinoxaline with only 3% ee. Later Bianchini et al. enantioselectively hydrogenated 2-methylquinoxaline with an orthomelated dihydride iridium complex to produce the product with up to 90% ee, but the reduction suffered from lower conversions. The performance of [RuCl2(diphosphine)(diamine)] complexes [3d,e] and Ir/PQphos (PQ-phos = (R)-[6,6-(2S,3S-butadioxy)]-(2,2’)-bis(diphenylphosphino)-(1,1’)-biphenyl) was also investigated, but only gave medium to low ee values. Given the importance of chiral tetrahydroquinoxalines and in view of the lack of efficient methods for the preparation of these compounds, the development of a practical and highly efficient catalytic asymmetric synthetic method appeared to be of great importance. Herein we describe the asymmetric hydrogenation of quinoxalines with an easily accessible Ir/diphosphinite catalyst. Good to excellent enantioselectivity (up to 98 % ee), unprecedented high catalytic activity (TOF up to 5620 h ), and productivity (TON up to 18 140) were observed for a wide range of substrates. Recently, the combination of transition metals and chiral phosphinite ligands has led to efficient catalysts for the asymmetric hydrogenation of prochiral olefins. In comparison with diphosphines, diphosphinites offer the advantages of easy preparation and derivatization. Recently, we have demonstrated that the easily accessible chiral diphosphinite ligands derived from (R)-H8-binol (binol = (1,1’-bi-2-naphthyl)) and (R)-1,1-spirobiindane-7,7-diol provided excellent catalytic activity and/or enantioselectivity in the Ir-catalyzed asymmetric hydrogenation of quinolines. Based on our previously optimized reaction conditions, we first investigated the performance of the [{IrCl(cod)}2] (cod = 1,5-cyclooctadiene)/(R)-H8-binapo or the (R)-sdpo/I2 catalyst system in THF for the asymmetric hydrogenation of 2-methylquinoxaline (1 a). To our delight, both catalysts worked efficiently with full conversions and good enantioselectivities (Table 1, entries 1 and 2), and (R)-H8-binapo gave the desired product in somewhat better enantiomeric excess. In sharp contrast to [*] Dr. W. Tang, J. Wang, Dr. B. Fan, Prof. Z. Zhou, Dr. K.-h. Lam, Prof. A. S. C. Chan Department of Applied Biology and Chemical Technology and Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis The Hong Kong Polytechnic University, Hong Kong (China) E-mail: bcachan@polyu.edu.hk

Asymmetric Hydrogenation of Quinoxalines With Diphosphinite Ligands: A Practical Synthesis of Enantioenriched, Substituted Tetrahydroquinoxalines

The present invention relates to modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating diseases using modulators of CFTR.

Modulators of cystic fibrosis transmembrane conductance regulator

This invention relates to inhibitors of p38, and methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing the inhibitors and pharmaceutical compositions in the treatment and prevention of various disorders mediated by p38.

P38 inhibitors and methods of use thereof

L'invention porte sur des inhibiteurs de la p 38 et leurs procedes de production, sur des preparations pharmaceutiques les contenant, et sur des procedes d'utilisation desdits inhibiteurs et desdites preparations pour le traitement et la prevention de differents troubles medies par la p38

Inhibiteurs de la p 38 et leurs procedes d'utilisation

Compounds having the Formula:
 
wherein Y, A, W, B, U, V, X and Ar 1 have the meanings given in the specification are useful in therapy as p38-inhibitors.

Indazole, benzoxazole and pyrazolopyridine derivatives for medical use

Indazol-, Benzoxazol- und Pyrazolopyridin-Derivate zur medizinischen Anwendung

Heterobizyklische Verbindungen als P38-Hemmer

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Devan Balachari

Author Tools

Chat about Author