- MODULATORS OF HEMOGLOBIN
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The present disclosure relates generally to compounds and pharmaceutical compositions suitable as modulators of hemoglobin and methods for their use in treating disorders mediated by hemoglobin. (Formula (I))
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Paragraph 0175-0176
(2021/10/11)
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- Photophysical behavior of a novel 4-aza-indole derivative in different solvents: reverse solvatochromism
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The photophysical properties of a new 4-aza-indole derivative [ethyl 1-((2-(2-ethoxy-2-oxoethyl)pyridin-3-yl)carbamoyl)-2-hydroxy-1H-pyrrolo-[3,2-b]pyridine-3-carboxylate, 12] were determined in different solvents. Compound 12 exhibited an absorbance peak at 340–360?nm with high fluorescence intensity in the wavelength range from 405 to 417?nm in all solvents except N,N-dimethylformamide (DMF). Compound 12 exhibited reverse solvatochromism behavior depending on the solvent polarity. Furthermore, compound 12 showed very high quantum yield in all solvents independent of their polarity. The results suggest that this novel dye could be used for many applications, e.g., as a labeling agent and in bio- or analytical sensors and/or optoelectronic devices.
- Bozkurt, Ebru,Dogan, Sengul Dilem
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p. 863 - 872
(2018/11/01)
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- Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders
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Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials.
- Mikami, Satoshi,Nakamura, Shinji,Ashizawa, Tomoko,Nomura, Izumi,Kawasaki, Masanori,Sasaki, Shigekazu,Oki, Hideyuki,Kokubo, Hironori,Hoffman, Isaac D.,Zou, Hua,Uchiyama, Noriko,Nakashima, Kosuke,Kamiguchi, Naomi,Imada, Haruka,Suzuki, Noriko,Iwashita, Hiroki,Taniguchi, Takahiko
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supporting information
p. 7677 - 7702
(2017/10/06)
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- Synthesis of new 4-aza-indoles via acyl azides
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We hereby report the preparation of new azaindole derivatives starting from 2-(2-ethoxy-2-oxoethyl)nicotinic acid. Conversion of a half ester into acyl azide followed by Curtius rearrangement gave the corresponding isocyanate. Trapping of the isocyanate with different nucleophiles produced urea and urethane derivatives. Intramolecular cyclization reactions gave the target compounds.
- Do?an, Sengul Dilem,Demirpolat, Eren,Yerer Aycan, Mükerrem Betül,Balci, Metin
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p. 252 - 258
(2015/02/02)
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- SUBSTITUTED PYRIDINONE COMPOUNDS AS MEK INHIBITORS
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The invention provides novel substituted heterocyclic compounds represented by Formula I and Formula II, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as inhibitors of MEK and are useful in the treatment of inflammatory diseases, cancer and other hyperproliferative diseases. The invention further provides a method of treatment for inflammatory diseases, cancer and other hyperproliferative diseases in mammals, especially humans.
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Page/Page column 43; 44
(2015/01/07)
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- 7-(lH-PYRAZOL-4-YL)-1,6-NAPHTHYRIDINE COMPOUNDS AS SYK INHIBITORS
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The present invention relates to a compound of formula (I): or a salt thereof; which is an inhibitor of spleen tyrosine kinase (Syk) and therefore potentially of use in treating diseases resulting from inappropriate activation of mast and/or basophil cells, macrophages, and B-cells and related inflammatory responses and tissue damage, for instance inflammatory disease and/or allergic disorders, and in cancer therapy, specifically heme malignancies, chronic spontaneous urticaria and autoimmune conditions.
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Paragraph 0471-0473
(2013/03/26)
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- 7-(1H-PYRAZOL-4-YL)-1,6-NAPHTHYRIDINE COMPOUNDS AS SYK INHIBITORS
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A compound of formula (I) or a salt thereof; which is an inhibitor of spleen tyrosine kinase (Syk) and therefore potentially of use in treating diseases resulting from inappropriate activation of mast and/or basophil cells, macrophages, and B-cells and related inflammatory responses and tissue damage, for instance inflammatory disease and/or allergic disorders, and in cancer therapy, specifically heme malignancies, chronic spontaneous urticaria and autoimmune conditions.
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Page/Page column 15; 16; 70
(2011/11/13)
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