- Tyrosine kinase inhibitors implant he loni and its key intermediate for the preparation of
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The invention discloses tyrosine kinase inhibitor implant he loni and its key intermediate of the preparation method, which belongs to the medicine, in the field of fine chemicals. The invention of the preparation method of gefitinib, is a brand-new preparation scheme, from whatever a intermediate starting, can be obtained in accordance with the requirements of the target compound. The method of the invention has short steps, the reaction operation is simple, safe and reliable, high yield, low cost, high purity, pollution little and simple operation and the like.
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Paragraph 0076; 0086-0088
(2018/10/19)
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- Preliminary investigations into the synthesis and antimicrobial activities of boron-containing capsaicinoids
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This preliminary study reports on the synthesis of two new boron-capsaicin derivatives containing either a short or long chain aliphatic tail group using an iridium catalyzed hydroboration reaction with pinacolborane. The boronate ester groups reside on the terminal position of the tail group and are necessary for the bioactivity of these compounds. Indeed, both compounds showed considerable activity against two Gram-positive bacteria, including Vancomycin-resistant Enterococcus. Vancomycin is considered the last resort medication for the treatment of septicemia, and new antibacterial agents that can treat sepsis are of paramount importance. The more lipophilic boron compound with the longer aliphatic chain also showed antifungal activity against Saccharomyces cerevisiae.
- Ramsaywack, Sharwatie,Bos, Allyson,Vogels, Christopher M.,Gray, Christopher A.,Westcott, Stephen A.
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supporting information
p. 1065 - 1070
(2018/11/24)
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- An alternative synthesis of Vandetanib (Caprelsa) via a microwave accelerated Dimroth rearrangement
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Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12–14).
- Brocklesby, Kayleigh L.,Waby, Jennifer S.,Cawthorne, Chris,Smith, Graham
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supporting information
p. 1467 - 1469
(2017/03/23)
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- BLOCKING TOLL-LIKE RECEPTOR 9 SIGNALING WITH SMALL MOLECULE ANTAGONIST
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The present invention relates to small molecule4-(piperazin-1-yl)quinazolin-2-amino compounds with formula (I) useful for inhibiting signalling by certain toll-like receptors (TLRs), especially TLR9. Toll-like receptors (TLRs) are members of the larger family of evolutionarily conserved pattern recognition receptors which are critical first line of defence for self-nonself discrimination by the host immune response. Aberrant TLR9 activation is implicated in autoreactive inflammation in different autoimmune diseases. The invention depicts compounds with formula (I), composition and methods can be used in a number of clinical applications, including as pharmaceutical agents and methods for treating conditions involving unwanted immune activity due to TLR9 activation.
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Page/Page column 27; 28
(2017/10/13)
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- Cellular Compositions Used To Restore Stem Cell or Progenitor Cell Function and Methods Related Thereto
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This disclosure relates to compounds, compositions and methods of epigenetically transforming cells. In certain embodiments, the disclosure relates to methods of generating epigenetically altered cells comprising mixing isolated cells with compositions di
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Paragraph 0137
(2017/07/01)
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- Identification and Structure–Activity Relationship Studies of Small-Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1
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The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small-molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure- and ligand-based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4-aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure–activity relationships of these inhibitor series.
- Robaa, Dina,Wagner, Tobias,Luise, Chiara,Carlino, Luca,McMillan, Joel,Flaig, Ralf,Schüle, Roland,Jung, Manfred,Sippl, Wolfgang
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supporting information
p. 2327 - 2338
(2016/10/24)
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- Compounds and compositions used to epigenetically transform cells and methods related thereto
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This disclosure relates to compounds, compositions and methods of epigenetically transforming cells. In certain embodiments, the disclosure relates to methods of generating epigenetically altered cells comprising mixing isolated cells with compositions di
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Page/Page column 14
(2016/10/24)
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- Diaryl-1,2,4-oxadiazole antioxidants: Synthesis and properties of inhibiting the oxidation of DNA and scavenging radicals
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Six 1,2,4-oxadiazole derivatives were prepared in order to compare their abilities to protect DNA against radical-mediated oxidation and to scavenge radicals. These derivatives had a structure based on disubstituted 1,2,4-oxadiazole, in which a vanillin group (A ring) and a substituted benzene group (B ring) were the substituents. The functional group at B ring was assigned as ortho- or meta-hydroxylbenzene group, ortho-chlorobenzene group, no group contained, and pyridine group or vanillin group at B ring. It was found that the compound with two vanillin groups attaching to oxadiazole can trap 2.05 radicals in protecting DNA against 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation, and the compound with an ortho-hydroxylbenzene group at B ring can trap 1.78 radicals. The compound with an ortho-chlorobenzene group at B ring exhibited the highest ability to inhibit ·OH-induced oxidation of DNA, while the compound with a meta-hydroxylbenzene group at B ring inhibited Cu2+/glutathione (GSH)-induced oxidation of DNA efficiently. The ortho- and para-hydroxylbenzene groups at B ring made the compounds possess the highest rate constant (k) in scavenging 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS+.) and 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH). Therefore, only a few hydroxyl groups can markedly enhance the activity of the core-branched antioxidant, which may be a novel structural feature in designing antioxidant.
- Zhao, Chao,Liu, Zai-Qun
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p. 842 - 849
(2013/04/24)
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- Design and Synthesis of 3,5-Disubstituted-1,2,4-Oxadiazoles as Potent Inhibitors of Phosphodiesterase4B2
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A series of 3,5-disubstituted-1,2,4-oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC50=5.28μm). Structure-activity relationship studies of 3,5-disubstituted-1,2,4-oxadiazoles revealed that substituents 3-cyclopentyloxy-4-methoxyphenyl group at 3-position and cyclic ring bearing heteroatoms at 5-position are important for activity. Molecular modeling study of the 3,5-disubstituted-1,2,4-oxadiazoles with PDE4B has shown similar interactions of 3-cyclopentyloxy-4-methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (9a) exhibited good analgesic and antiinflammatory activities in formalin-induced pain in mice and carrageenan-induced paw edema model in rat.
- Kumar, Dalip,Patel, Gautam,Vijayakrishnan, Lalitha,Dastidar, Sunanda G.,Ray, Abhijit
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scheme or table
p. 810 - 818
(2012/06/18)
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- Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy- quinazolines
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Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described.
- Liu, Feng,Barsyte-Lovejoy, Dalia,Allali-Hassani, Abdellah,He, Yunlong,Herold, J. Martin,Chen, Xin,Yates, Christopher M.,Frye, Stephen V.,Brown, Peter J.,Huang, Jing,Vedadi, Masoud,Arrowsmith, Cheryl H.,Jin, Jian
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scheme or table
p. 6139 - 6150
(2011/10/09)
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- Protein lysine methyltransferase g9a inhibitors: Design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
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Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a?10 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison Ki = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.
- Liu, Feng,Chen, Xin,Allali-Hassani, Abdellah,Quinn, Amy M.,Wigle, Tim J.,Wasney, Gregory A.,Dong, Aiping,Senisterra, Guillermo,Chau, Irene,Siarheyeva, Alena,Norris, Jacqueline L.,Kireev, Dmitri B.,Jadhav, Ajit,Herold, J. Martin,Janzen, William P.,Arrowsmith, Cheryl H.,Frye, Stephen V.,Brown, Peter J.,Simeonov, Anton,Vedadi, Masoud,Jin, Jian
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experimental part
p. 5844 - 5857
(2010/10/03)
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- Solvent free, microwave assisted conversion of aldehydes into nitriles and oximes in the presence of NH2OH · HCl and TiO2
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Aromatic aldehydes bearing electron-donating groups are easily converted into their respective nitriles using NH2OH · HCl and TiO 2 under microwave irradiation, while those bearing an electron-withdrawing group give the corresponding oximes.
- Hoelz, Lucas Villas-Boas,Goncalves, Biank Tomaz,Barros, Jose Celestino,Silva, Joaquim Fernando Mendes Da
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experimental part
p. 94 - 99
(2010/05/18)
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- Synthesis and antitumor activity of 2-aryl-1, 2, 4-triazolo[1, 5-a] pyridine derivatives
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A novel series of 2-aryl-1, 2, 4-triazolo [1, 5-a] pyridine derivatives have been synthesized and evaluated for their cytotoxic activities in vitro against Human ovarian cancer cell line (HO-8910) and Human liver cancer cell line (Bel 7402). Most compounds showed high or mediate activity against the cancer cell lines when compared with Cisplatin. Two of them were tested the apoptosis on Bel 7402.
- Tao, Xuefen,Hu, Yongzhou
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experimental part
p. 65 - 69
(2011/12/14)
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- Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a
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SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.
- Liu, Feng,Chen, Xin,Allali-Hassani, Abdellah,Quinn, Amy M.,Wasney, Gregory A.,Dong, Aiping,Barsyte, Dalia,Kozieradzki, Ivona,Senisterra, Guillermo,Chau, Irene,Siarheyeva, Alena,Kireev, Dmitri B.,Jadhav, Ajit,Herold, J. Martin,Frye, Stephen V.,Arrowsmith, Cheryl H.,Brown, Peter J.,Simeonov, Anton,Vedadi, Masoud,Jin, Jian
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supporting information; experimental part
p. 7950 - 7953
(2010/08/13)
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- Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors
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The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate tha
- Jung, Frédéric H.,Pasquet, Georges,Lambert-Van Der Brempt, Christine,Lohmann, Jean-Jacques M.,Warin, Nicolas,Renaud, Fabrice,Germain, Hervé,De Savi, Chris,Roberts, Nicola,Johnson, Trevor,Dousson, Cyril,Hill, George B.,Mortlock, Andrew A.,Heron, Nicola,Wilkinson, Robert W.,Wedge, Stephen R.,Heaton, Simon P.,Odedra, Rajesh,Keen, Nicholas J.,Green, Stephen,Brown, Elaine,Thompson, Katherine,Brightwell, Stephen
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p. 955 - 970
(2007/10/03)
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- Imidazopyrimidine derivatives and triazolopyrimidine derivatives
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A compound of the formula (I) wherein R1 is —X—R4, an optionally substituted heterocyclic residue, an optionally substituted carbocyclic residue or optionally substituted condensed ring moiety; X is CR5R6, O, S, SO, SO2 or NR7; Y is CH or N; R2 is H, an optionally substituted C1-C10 alkyl,etc.; R3 is an optionally substituted aryl, or an optionally substituted heteroaryl, etc.; R4 is an optionally substituted aryl, an optionally substituted heteroaryl, etc.; R5, R6, and R7 can be identical or different and represent H, an optionally substituted C1-C10 alkyl, etc. The compound has an excellent anti-allergic activity and the like.
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- PHOSPHONOOXY QUINAZOLINE DERIVATIVES AND THEIR PHARMACEUTICAL USE
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Quinazoline derivatives of formula (I) wherein A is 5-membered heteroaryl containing a nitrogen atom and one or two further nitrogen atoms; compositions containing them, processes for their preparation and their use in therapy.
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- QUINAZOLINE COMPOUNDS
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Quinazoline derivatives of formula (I) wherein A is 5-membered heteroaryl containing a sulphur atom and optionally containing one or more nitrogen atoms; compositions containing them, processes for their preparation and their use in therapy.
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- SUBSTITUTED QUINAZOLINE DERIVATIVES AND THEIR USE AS INHIBITORS
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The use of a compound of formula (I) 1 or a salt, ester or amide thereof; where X is O, or S, S(O) or S(O)2, or NR6 where R6 is hydrogen or C1-6 alkyl,; R5 is an optionally substituted 5-membered heteroaromatic ring, R1, R2 ,R3, R4 are independently selected from various specified moieties, in the preparation of a medicament for use in the inhibition of aurora 2 kinase. Certain compounds are novel and these, together with pharmaceutical compositions containing them are also described and claimed
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- A new one pot method for the conversion of aldehydes into nitriles using hydroxyamine and phthalic anhydride
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The aryl and alkyl aldehydes were readily converted to give the corresponding nitrites in good yields using hydroxyamine and phthalic anhydride as reagents in one pot.
- Wang, Eng-Chi,Lin, Gow-Juin
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p. 4047 - 4050
(2007/10/03)
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- PHELLODENDRINE ANALOGS AND ALLERGY TYPE IV SUPPRESSOR CONTAINING THE SAME AS ACTIVE INGREDIENT
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Phellodendrine analogs represented by general formula (I), wherein A represents the group (a); B represents hydrogen, lower alkyl or lower acyl, or alternatively A and B together with the adjacent nitrogen atom form a substituted 1,2,3,4-tetrahydroisoquinoline ring represented by general formula (II), R11, R12, R21, R22, R31 and R32 represent each hydrogen, hydroxyl or lower alkoxy; n1 represents a number of 0 to 2; n2 represents a number of 1 and 2; and m1 represents a number of 0 to 1, provided tsat when A represents the group (b), and n2 is 2, B is lower acyl, and that when A and B together form a substituted 1,2,3,4-tetrahydroisoquinoline ring, n1 is 1 and m1 is not 0. These analogs (I) and related compounds have an excellent activity of suppressing allergy type IV and hence are utilizable as a medicine efficacious against diseases wherein allergy type IV participates, such as chronic hepatitis, intractable asthma, nephrotic syndrome or rheumatism.
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