- COMPOUNDS AND METHOD FOR TREATING CYTOKINE RELEASE SYNDROME
-
Disclosed herein are embodiments of a method for treating or preventing cytokine release syndrome (CRS). In certain embodiments, the method comprises administering a compound, or a salt, solvate, prodrug or pharmaceutical composition thereof, to a subject experiencing, or at risk of developing, CRS. The compound may be a kinase inhibitor, such as a JAK inhibitor and/or an IRAK inhibitor, and/or the compound may have a structure according to Formulas I, III, IV or VII. And the method may comprise administering the compound to a subject who is has received, is currently receiving, and/or will be receiving a cell therapy.
- -
-
Page/Page column 132-133
(2021/02/12)
-
- MALT1 INHIBITORS AND USES THEREOF
-
The invention provides compounds of formula (I) wherein R1, R2, R3, R4 and R5 are as defined in the specification which are potent inhibitors of the enzyme MALT1 and are useful in the treatment of autoimmune disorders and diseases and as an immunooncology approach to the treatment of cancer, especially bladder cancer, colon cancer, hepatocellular cancer and small cell or non-small cell lung cancer.
- -
-
Page/Page column 74-75
(2021/10/15)
-
- FUSED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOF
-
The present disclosure relates to a class of fused pyrimidine compounds of Formula I, their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The present disclosure also relates to a process of preparation of these fused pyrimidine compounds, and to pharmaceutical compositions containing them.
- -
-
Paragraph 0207; 0234
(2021/04/02)
-
- BENZIMIDAZOLE AND HYDROGENATED CARBAZOLE DERIVATIVES AS GPX4 INHIBITORS
-
This present disclosure relates to compounds with ferroptosis inducing activity, a method of treating a subject with cancer with the compounds, and combination treatments with a second therapeutic agent.
- -
-
Page/Page column 57-58
(2021/03/05)
-
- C-TERMINAL SRC KINASE INHIBITORS
-
Provided herein are novel C-terminal Srk Kinase (CSK) inhibitors, e.g., having Formula G, I, II, or III. Also provided are methods of preparing the novel CSK inhibitors and method of using the novel CSK inhibitors for treating diseases or disorder such as cancer or for promoting immune response in a subject in need thereof. (G)
- -
-
Paragraph 147; 148
(2020/07/14)
-
- 5-HETEROARYL SUBSTITUTED INDAZOLE-3-CARBOXAMIDES AND PREPARATION AND USE THEREOF
-
Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., tendinopathy, dermatitis, psoriasis, morphea, ichthyosis, Raynaud's syndrome, Darier's disease, scleroderma, cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as neurological conditions/disorders/diseases linked to overexpression of DYRK1A.
- -
-
Paragraph 0727; 0729; 0730; 0735
(2019/09/06)
-
- NEW BENZAMIDE DERIVATIVES AS PPAR-GAMMA MODULATORS
-
The present invention relates to novel benzamides derivatives of formula (I) as modulators of PPAR-gamma receptor, to processes for their preparation, to pharmaceutical compositions comprising said compounds and to said compound for use in the treatment of pathological conditions, disorders or diseases that can improve by modulation of PPAR-gamma receptor, such as cancer; metabolic diseases, inflammatory diseases, respiratory disorders, autoimmune diseases, neurodegenerative diseases, cardiovascular diseases and renal diseases.
- -
-
Paragraph 0122-0123; 0125-0126
(2019/06/27)
-
- First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent
-
Kinase irregularity has been correlated with several complex neurodegenerative tauopathies. Development of selective inhibitors of these kinases might afford promising anti-tauopathy therapies. While DAPK1 inhibitors halt the formation of tau aggregates and counteract neuronal death, CSF1R inhibitors could alleviate the tauopathies-associated neuroinflammation. Herein, we report the design, synthesis, biological evaluation, mechanistic study, and molecular docking study of novel CSF1R/DAPK1 dual inhibitors as multifunctional molecules inhibiting the formation of tau aggregates and neuroinflammation. Compound 3l, the most potent DAPK1 inhibitor in the in vitro kinase assay (IC50 = 1.25 μM) was the most effective tau aggregates formation inhibitor in the cellular assay (IC50 = 5.0 μM). Also, compound 3l elicited potent inhibition of CSF1R in the in vitro kinase assay (IC50 = 0.15 μM) and promising inhibition of nitric oxide production in LPS-induced BV-2 cells (55% inhibition at 10 μM concentration). Kinase profiling and hERG binding assay anticipated the absence of off-target toxicities while the PAMPA-BBB assay predicted potentially high BBB permeability. The mechanistic study and selectivity profile suggest compound 3l as a non-ATP-competitive DAPK1 inhibitor and an ATP-competitive CSF1R inhibitor while the in silico calculations illustrated binding of compound 3l to the substrate-binding site of DAPK1. Hence, compound 3l might act as a protein-protein interaction inhibitor by hindering DAPK1 kinase reaction through preventing the binding of DAPK1 substrates.
- Farag, Ahmed Karam,Hassan, Ahmed H.E.,Jeong, Hyeanjeong,Kwon, Youngji,Choi, Jin Gyu,Oh, Myung Sook,Park, Ki Duk,Kim, Yun Kyung,Roh, Eun Joo
-
p. 161 - 175
(2018/11/23)
-
- Streamlined Synthesis of Diaminopyridines by Pd-Catalyzed Ammonia Coupling with Deactivated Amino-Chloropyridines
-
An efficient and cost-effective two-step synthesis of diaminopyridines, fundamental building blocks of biologically active compounds, is reported. The advantages over previously reported routes include cost and wider availability of the bromo-chloropyridine starting materials and the straightforward accessibility to an extended array of diaminopyridine regioisomers. The key enabler of this synthetic strategy is the development of an unprecedented palladium-catalyzed coupling reaction of ammonia with chloropyridines deactivated by the presence of an alkylamino substituent. The coupling reaction was accomplished with very low catalyst loadings under remarkably mild reaction conditions, making the system particularly suitable for both academic and industrial applications. The utility of this methodology is exemplified by the application to the synthesis of highly relevant scaffolds, including the synthetic intermediates of the marketed drugs Ribociclib and Palbociclib.
- Bourriquen, Florian,Bruneau-Voisine, Antoine,Jeandin, Aliénor,Stihle, Etienne,Fantasia, Serena
-
p. 9006 - 9011
(2019/06/24)
-
- METHODS OF USING INDAZOLE-3-CARBOXAMIDES AND THEIR USE AS WNT/B-CATENIN SIGNALING PATHWAY INHIBITORS
-
This disclosure features the use of one or more indazole-3-carboxamide compounds or salts or analogs thereof, in the treatment of one or more diseases or conditions independently selected from the group consisting of a tendinopathy, dermatitis, psoriasis, morphea, ichthyosis, Raynaud's syndrome, and Darier's disease; and/or for promoting wound healing. The methods include administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of one or more indazole-3-carboxamide compounds or salts or analogs thereof as described anywhere herein.
- -
-
Paragraph 0335; 0337; 0341
(2018/05/16)
-
- Discovery of N2-(4-Amino-cyclohexyl)-9-cyclopentyl- N6-(4-morpholin-4-ylmethyl-phenyl)- 9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations
-
FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive. The MV4-11 cells treated with 7d suppressed the phosphorylation of FLT3 and its downstream signaling pathways, with subsequent G1 cell cycle arrest and apoptosis. Additionally, a single dose of 7d in mice with subcutaneous MV4-11 xenografts caused sustained inhibition of FLT3 and STAT5 phosphorylation over 48 h, in contrast to the shorter effect observed after administration of the reference FLT3 inhibitor quizartinib.
- Gucky, Tomá?,?ezní?ková, Eva,Rado?ová Muchová, Tereza,Jorda, Radek,Klejová, Zuzana,Malínková, Veronika,Berka, Karel,Bazgier, Václav,Ajani, Haresh,Lep?ík, Martin,Divoky, Vladimír,Kry?tof, Vladimír
-
p. 3855 - 3869
(2018/05/14)
-
- NOVEL FUSED PYRIDINE DERIVATIVES USEFUL AS FAK/AURORA KINASE INHIBITORS
-
This invention relates to certain novel pyrimidine derivatives of the Formula (I). The invention also relates to process for the preparation of the compound of the formula (I), pharmaceutical agents or compositions containing the compound or a method of using the compound for the treatment of proliferative diseases, such as cancer.
- -
-
Page/Page column 39; 40
(2018/02/28)
-
- Design, synthesis and biological evaluation N2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives bearing acylamino or DBTD ‘head’ as potential ALK inhibitors
-
Aiming to develop promising ALK inhibitors, two series of N2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives (22a-x and 23a-d) were designed according to scaffold hopping and bioisosterism principles. All compounds were efficiently synthesized by concise reactions and anti-proliferative activities on ALK-addicted H2228, Karpas299 cells and EGFR-expressive A549 cell were evaluated by MTT assay. Several compounds exhibited potential cytotoxic activities with IC50 values below 0.10 μM. Five compounds (22g, 22h, 22l, 22s and 23a) were selected for further enzymatic determination, resulting in the discovery of 22l against ALK and ALKL1196M with IC50 values of 2.1 nM and 3.8 nM. Particularly, western blot and cell apoptosis assays identified 22l as a promising ALK inhibitor, which was capable of obviously inhibiting cellular ALK activity and inducing cell apoptosis. Eventually, molecular docking modes of 22l with ALK confirmed structural basis in accordance with the SARs analysis.
- Xing, Lingyun,Jing, Tongfei,Zhang, Junlong,Guo, Ming,Miao, Xiuqi,Jiang, Feng,Zhai, Xin
-
p. 689 - 699
(2018/10/02)
-
- Synthesis of 2,6-diamino-substituted purine derivatives and evaluation of cell cycle arrest in breast and colorectal cancer cells
-
Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1-3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1-3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.
- Bosco, Bartolomeo,Defant, Andrea,Messina, Andrea,Incitti, Tania,Sighel, Denise,Bozza, Angela,Ciribilli, Yari,Inga, Alberto,Casarosa, Simona,Mancini, Ines
-
-
- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
-
The invention relates to the field of medicine, discloses new nitrogen heterocyclic derivatives, preparation method thereof and as medicament in particular as the treatment and prevention of treating tissue fibrosis of the medicament. The invention also discloses a pharmaceutically acceptable compound of the present invention comprise a pharmaceutical composition and methods for using the composition for the treatment of the human or animal tissue fibrosis of diseases, in particular for treating the human or animal renal interstitial fibrosis, glomerular sclerosis, hepatic fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, after the operation of adhering, benign prostate hypertrophy, bone-myocardial, scleroderma, multiple sclerosis, pancreas fibrosis, liver cirrhosis, myosarcoma, neurofibromatosis, interstitial pulmonary fibrosis, diabetic nephropathy, Alzheimer's disease or vascular fibrosis disease in use. (by machine translation)
- -
-
Page/Page column 144
(2018/06/01)
-
- New pyridine derivatives as antiurease inhibitors: Synthesis and their evaluation for antimicrobial activities
-
6-Morpholin-4-ylpyridin-3-amine (3) gathered starting from morpholine by two steps was converted into the corresponding arylidenehydrazides through the reaction with several aromatic aldehydes. The treatment of compound 3 with phenylisothiocy-anate generated N-(6-morpholin-4-ylpyridin-3-yl)-N'-phenylthio-urea (6). The synthesis of 1,3-thiazolidine (7) and 1,3-thiazole derivatives was performed from the reaction of 6 with 4-chlorophenacyl bromide and ethyl bromoacetate, respectively. All synthesized compounds were inspected for their antimicrobial and antiurease activites. (Chemical Equation Presented).
- Bektas, Hakan,Albay, Canan,Mentese, Emre,Demirbas, Neslihan
-
p. 199 - 205
(2017/07/22)
-
- Design, synthesis, and biological evaluation of structurally modified isoindolinone and quinazolinone derivatives as hedgehog pathway inhibitors
-
The Hedgehog (Hh) signaling pathway is associated with diverse aspects of cellular events, such as cell migration, proliferation, and differentiation throughout embryonic development and tissue patterning. An abnormal Hh signaling pathway is linked to numerous human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB), lung cancer, prostate cancer, and ovarian cancer, and it is therefore a promising target in cancer therapy. Using a structure-hopping approach, we designed new Hh signaling pathway inhibitors with isoindolinone or quinazolinone moieties, which were synthesized and biologically evaluated using an 8xGli-luciferase (Gli-Luc) reporter assay in NIH3T3 cells. Compounds 9–11 and 14 with isoindolinone scaffolds demonstrated moderate Hh inhibitory activity; whereas quinazolinone derivatives 24, 29, 32, 34, and 35 exhibited good potency with submicromolar IC50values and the analog 28 showed nanomolar IC50value. Although sonidegib shows a decrease in inhibitory effect on vismodegib resistance-conferring Smo mutants, the structurally modified new compounds not only possess the pharmacophoric properties of Hh pathway inhibition but also preserve the suppressive potency in drug-resistant Smo mutants. Mechanistically, quinazolinone derivatives 28 and 34 suppress Hh signaling by blocking Smo and Gli translocation into the cilia, similar to vismodegib and sonidegib. Additionally, the human microsomal stability of the representative analogs 28 and 34 were determined to be comparable to that of the reference compound sonidegib. Thus, these new scaffolds can serve as a platform for the development of novel cancer therapeutics targeting the Hh pathway.
- Bhattarai, Deepak,Jung, Joo Hyun,Han, Seunghyeon,Lee, Hankyu,Oh, Soo Jin,Ko, Hyuk Wan,Lee, Kyeong
-
p. 1036 - 1050
(2016/11/11)
-
- Discovery of N-(Naphthalen-1-yl)-N′-alkyl Oxalamide Ligands Enables Cu-Catalyzed Aryl Amination with High Turnovers
-
A class of N-(naphthalen-1-yl)-N′-alkyl oxalamides have been proven to be powerful ligands, making a coupling reaction of (hetero)aryl iodides with primary amines proceed at 50 °C with only 0.01 mol % of Cu2O and ligand as well as a coupling reaction of (hetero)aryl bromides with primary amines and ammonia at 80 °C with only 0.1 mol % of Cu2O and ligand. A wide range of coupling partners work well under these conditions, thereby providing an easy to operate method for preparing (hetero)aryl amines.
- Gao, Jie,Bhunia, Subhajit,Wang, Kailiang,Gan, Lu,Xia, Shanghua,Ma, Dawei
-
supporting information
p. 2809 - 2812
(2017/06/07)
-
- A sensitive method for the determination of gold and palladium based on dispersive liquid-liquid microextraction combined with flame atomic absorption spectrometric determination using: N -(6-morpholin-4-ylpyridin-3-yl)- N ′-phenylthiourea
-
A new method for the determination of gold and palladium was developed by dispersive liquid-liquid microextraction separation-preconcentration and flame atomic absorption spectrometry detection. In the proposed approach, N-(6-morpholin-4-ylpyridin-3-yl)-N′-phenylthiourea (MPPT) was synthesized as a complexing agent. The complexation ability of the MPPT was explored by examining the effect of a series of heavy metal ions, including Mn2+, Pd2+, Ni2+, Cd2+, Co2+, Cu2+, Au3+, Pb2+, Zn2+ and Fe3+, using the DLLME procedure. The MPPT exhibited pronounced selectivity toward Pd2+ and Au3+ ions at different pH levels. Factors influencing the extraction efficiency and complex formation were examined, i.e. the pH of the sample solution, the concentration of the chelating agent, the extraction and dispersive solvent type and volume, the sample volume, and foreign ions, etc. Optimal conditions for quantitative recoveries were pH 5.5 for gold and pH 1.5 for palladium, 125 μL of % 0.4 MPPT, 1200 μL of methanol and 125 μL of carbon tetrachloride. The presented method showed a good linearity within a range of 30-230 and 25-200 μg L-1 with the detection limits of 1.75 and 1.65 μg L-1 for Au and Pd, respectively. The relative standard deviation (RSD) was below 2.8% at 50 μg L-1 for both ions (n = 10). The developed method was simple, fast, cost efficient, and sensitive for the extraction and preconcentration of gold and palladium in samples of liquids (sea, stream water) and solids (stream sediment, ores, and electronic waste).
- Bahadir, Zekeriyya,Bulut, Volkan Numan,Bekta?, Hakan,Soylak, Mustafa
-
p. 6896 - 6904
(2016/07/12)
-
- Discovery of novel dual inhibitors of VEGFR and PI3K kinases containing 2-ureidothiazole scaffold
-
A series of compounds possessing 2-(3-phenyl)ureidothiazol-4-formamide derivatives with a 2-ureidothiazole scaffold were designed and synthesized. Some compounds demonstrated inhibition of cell proliferation against both MDA-MB-231 and HepG2 cell lines using Sorafenib as the positive control. Compounds 6i showed a good to moderate inhibition on VEGFR-2 and PI3Kα which was proved by further molecular docking study. This study suggests that compound 6i is a potential dual inhibitor of VEGFR-2 and PI3Kα and is applicable for further investigation.
- Li, Lin,Zhang, Cun-Long,Song, Hong-Rui,Tan, Chun-Yan,Ding, Huai-Wei,Jiang, Yu-Yang
-
supporting information
p. 1 - 6
(2016/01/25)
-
- 5-SUBSTITUTED INDAZOLE-3-CARBOXAMIDES AND PREPARATION AND USE THEREOF
-
Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, fibrotic disorders, cartilage (chondral) defects, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, and neurological conditions/disorders/diseases linked to overexpression of DYRK1A.
- -
-
Paragraph 1279; 1281; 1282; 1289
(2015/11/09)
-
- Nitrogenous Heterocyclic Derivatives And Their Application In Drugs
-
The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
- -
-
Paragraph 0638
(2015/03/31)
-
- Five-And-Six-Membered Heterocyclic Compound, And Preparation Method, Pharmaceutical Composition And Use Thereof
-
A five-and-six-membered heterocyclic compound as represented by general formula I, pharmaceutically acceptable salt, metabolite, metabolic precursors or drug precursors thereof, preparation method, pharmaceutical composition, and use thereof; the five-and-six-membered heterocyclic compound has activity as a Janus kinase (JAK) inhibitor, and can be used to prepare drugs for treating diseases caused by the abnormal activity of kinase, such as cell proliferation diseases like cancer.
- -
-
Paragraph 0391; 0393
(2015/12/07)
-
- TYK2 INHIBITORS AND USES THEREOF
-
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
- -
-
Paragraph 00980; 00982
(2015/09/28)
-
- Synthesis and antiproliferative activity of novel 4-substituted-phenoxy-benzamide derivatives
-
A series of novel 4-substituted-phenoxy-benzamide derivatives bearing an aryl cycloaliphatic amine moiety were synthesized and evaluated for antiproliferative activity against SW620, HT29 and MGC803 cancer cell lines in vitro. The pharmacological data demonstrated that the majority of target compounds exhibited moderate efficacy in HT29 and MGC803 cell lines. Compound 10c showed promising inhibition of hedgehog (Hh) signaling pathway in an Hh-related assay. In addition, the superposition pattern of 10c showed a good fit for a pharmacophoric model generated by Hh inhibitors and provided a basis for further structural optimization.
- Sun, Chi-Yu,Li, Yang-Sheng,Shi, Ai-Long,Li, Ya-Fei,Cao, Rui-Fang,Ding, Huai-Wei,Yin, Qing-Qing,Zhang, Li-Juan,Zheng, Hua-Chuan,Song, Hong-Rui
-
supporting information
p. 1307 - 1310
(2015/12/31)
-
- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
-
The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.
- -
-
Paragraph 00355
(2014/02/15)
-
- TRI-HETEROCYCLIC DERIVATIVES, PREPARATION PROCESS AND USES THEREOF
-
The present invention relates to a tri-heterocyclic derivatives, preparation process and uses thereof, specifically relates to a tri-heterocyclic derivatives of the formula (I) or a pharmaceutically acceptable salt thereof, preparation process, and further relates to a pharmaceutically acceptable composition comprising compounds of formula (I), or a pharmaceutically acceptable salt thereof, and their pharmaceutical use as inhibitors of kinase.
- -
-
Paragraph 0124; 0320; 0321
(2014/11/13)
-
- INDAZOLE-3-CARBOXAMIDES AND THEIR USE AS WNT/B-CATENIN SIGNALING PATHWAY INHIBITORS
-
lndazole-3-carboxamide compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an indazole-3- carboxamide compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
- -
-
-
- SUBSTITUTED BICYCLIC AZA-HETEROCYCLES AND ANALOGUES AS SIRTUIN MODULATORS
-
Provided herein are novel substituted bicyclic aza-heterocycle 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 example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided, are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
- -
-
Page/Page column 84
(2013/05/09)
-
- SULFONAMIDE COMPOUNDS AND USES AS TNAP INHIBITORS
-
Described herein are compounds that modulate the activity of TNAP. In some embodiments, the compounds described herein inhibit TNAP. In certain embodiments, the compounds described herein are useful in the treatment of conditions associated with hyper- mineralization.
- -
-
Paragraph 00643
(2013/09/12)
-
- TRI-HETEROCYCLIC DERIVATIVES, PREPARATION PROCESS AND USES THEREOF
-
The present invention relates to a tri-heterocyclic derivatives, preparation process and uses thereof, specifically relates to a tri-heterocyclic derivatives of the formula (I) or a pharmaceutically acceptable salt thereof, preparation process, and further relates to a pharmaceutically acceptable composition comprising compounds of formula (I), or a pharmaceutically acceptable salt thereof, and their pharmaceutical use as inhibitors of kinase
- -
-
Page/Page column 37
(2013/07/05)
-
- Synthesis and cytotoxic activity of some novel N-pyridinyl-2-(6- phenylimidazo[2,1-b]thiazol-3-yl)acetamide derivatives
-
A series of novel compounds bearing imidazo[2,1-b]thiazole scaffolds were designed and synthesized based on the optimization of the virtual screening hit compound N-(6-morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl) acetamide (5a), and tested for their cytotoxicity against human cancer cell lines, including HepG2 and MDA-MB-231. The results indicated that the compound 2-(6-(4-chlorophenyl)imidazo [2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl) piperazin-1-yl)pyridin-3-yl)acetamide (5l), with slightly higher inhibition on VEGFR2 than 5a (5.72% and 3.76% inhibitory rate at 20 μM, respectively), was a potential inhibitor against MDA-MB-231 (IC50 = 1.4 μM) compared with sorafenib (IC50 = 5.2 μM), and showed more selectivity against MDA-MB-231 than HepG2 cell line (IC50 = 22.6 μM).
- Ding, Huaiwei,Chen, Zhe,Zhang, Cunlong,Xin, Tian,Wang, Yini,Song, Hongrui,Jiang, Yuyang,Chen, Yuzong,Xu, Yongnan,Tan, Chunyan
-
experimental part
p. 4703 - 4716
(2012/07/01)
-
- Synthesis and solid state study of pyridine- and pyrimidine-based fragment libraries
-
A library of pyridines and pyrimidines has been synthesised in excellent yields employing microwave and flow chemistry methodologies. Work-up bottlenecks have been facilitated substantially by the use of supported reagents and many of the final compounds have been studied in the solid state by single crystal X-ray diffraction.
- Spencer, John,Patel, Hiren,Callear, Samantha K.,Coles, Simon J.,Deadman, John J.
-
supporting information; experimental part
p. 5905 - 5909
(2011/11/14)
-
- N -pyridyl and pyrimidine benzamides as KCNQ2/Q3 potassium channel openers for the treatment of epilepsy
-
A series of N-pyridyl benzamide KCNQ2/Q3 potassium channel openers were identified and found to be active in animal models of epilepsy and pain. The best compound 12 [ICA-027243, N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide] has an EC50 of 0.38 μM and is selective for KCNQ2/Q3 channels. This compound was active in several rodent models of epilepsy and pain but upon repeated dosing had a number of unacceptable toxicities that prevented further development. On the basis of the structure-activity relationships developed around 12, a second compound, 51, [N-(2-chloro-pyrimidin-5-yl)-3,4-difluoro- benzamide, ICA-069673], was prepared and advanced into a phase 1 clinical study. Herein, we describe the structure-activity relationships that led to the identification of compound 12 and to the corresponding pyrimidine 51.
- Amato, George,Roeloffs, Rosemarie,Rigdon, Greg C.,Antonio, Brett,Mersch, Theresa,McNaughton-Smith, Grant,Wickenden, Alan D.,Fritch, Paul,Suto, Mark J.
-
scheme or table
p. 481 - 484
(2011/08/22)
-
- Discovery and optimization of 2-phenyloxazole derivatives as diacylglycerol acyltransferase-1 inhibitors
-
In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide 1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor 25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound 25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.
- Yun, Weiya,Ahmad, Mushtaq,Chen, Yingsi,Gillespie, Paul,Conde-Knape, Karin,Kazmer, Sonja,Li, Shiming,Qian, Yimin,Taub, Rebecca,Wertheimer, Stanley J.,Whittard, Toni,Bolin, David
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scheme or table
p. 7205 - 7209
(2012/01/15)
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- THIAZOLE SULFONAMIDE AND OXAZOLE SULFONAMIDE KINASE INHIBITORS
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The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents
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Page/Page column 106
(2010/10/03)
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- COMPOSITIONS AND METHODS FOR INHIBITION OF THE JAK PATHWAY
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Disclosed are compounds of formula I, compositions containing them, and methods of use for the compounds and compositions in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK 2 and JAK3, are therapeutically useful.
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Page/Page column 85
(2010/08/07)
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- THIAZOLE AND OXAZOLE KINASE INHIBITORS
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The present invention provides thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 148
(2009/04/25)
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- THIAZOLE AND OXAZOLE KINASE INHIBITORS
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The present invention provides thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 237
(2009/07/17)
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- SUBSTITUTED PYRIDAZINE CARBOXAMIDE COMPOUNDS AS KINASE INHIBITOR COMPOUNDS
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Pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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Page/Page column 35
(2010/01/12)
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- Diacylglycerol acyltransferase inhibitors
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.
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Page/Page column 12
(2010/11/27)
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- Research and development of an efficient process for the construction of the 2,4,5-substituted pyridines of NK-1 receptor antagonists
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Roche has identified a 2,4,5-trisubstituted pyridine template for a new class of potent NK1 receptor antagonists. Previous strategies for construction of the pyridine core of these NK-1 receptor antagonists involved functionalization of a 2,5-disubstituted pyridine. We now report on construction of the pyridine core from commodity components. Shestopalov reported the synthesis of trans-4′-aryl-5′-cyano-1′,2′,3′, 4′-tetrahydro-6′-hydroxy-2′-oxo-1,3′-bipyridinium inner salts from 1-(2-amino-2-oxo-ethyl)pyridinium chloride, aromatic aldehydes, and ethyl cyanoacetate in the presence of a base. Reaction of these salts with phosphorus oxychloride affords 4-aryl-3-cyano-2,6-dichloropyridines. These are efficiently converted to nicotinamide precursors of the Roche NK-1 receptor antagonists by regioselective displacement of one chlorine by an amine, hydrogenolysis of the remaining chlorine, and nitrile hydrolysis.
- Harrington, Peter J.,Johnston, Dave,Moorlag, Henk,Wong, Jim-Wah,Hodges, L. Mark,Harris, Les,McEwen, Gerald K.,Smallwood, Blair
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p. 1157 - 1166
(2012/12/23)
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- 2-(Pyridin-3-ylamino)-pyrido[2,3-D]pyrimidin-7-ones
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This invention provides compounds of formula I: wherein R1, R2, R3, R4, and X1 are as defined in the specification. The 2-(pyridin-3-ylamino)-pyrido[2,3-d]pyrimidin-7-one compounds of formula I, which are inhibitors of cyclin-dependent kinases 2 and 4 (CDK2 and CDK4), are useful in treating cell proliferative disorders.
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Page/Page column 12
(2008/06/13)
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- 20-HYDROXYEICOSATETRAENOIC ACID PRODUCTION INHIBITORS
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A hydroxyformamidine compound represented by the following formula or a pharmaceutically acceptable salt thereof. [wherein R1 represents a substituted morpholino group, a substituted piperidino group, a piperazin-1-yl group, a substituted piperazin-1-yl group, a thiomorpholin-1-yl group, a perhydroazepin-1-yl group, a perhydroazocin-1-yl group, a tetrahydropyridin-1-yl group, a pyrrolin-1-yl group, etc.; X represents a nitrogen atom or a group represented by CR5; and R2 to R5 are the same or different and each represents a hydrogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a trifluoromethyl group or a halogen atom.] There is provided a drug which inhibi ts an enzyme producing 20-HETE participating in a contracting or dilating action for microvessels and an inducing action for cell proliferation in main organs such as kidney and cerebrovascular vessels.
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- Pyrazole compounds
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Pharmaceutical compositions and compounds are provided. The compounds of the invention demonstrate anti-proliferative activity, and may promote apoptosis in cells lacking normal regulation of cell cycle and death. In one embodiment of the invention, pharmaceutical compositions of the compounds in combination with a physiologically acceptable carrier are provided. The pharmaceutical compositions are useful in the treatment of hyperproliferative disorders, which disorders include tumor growth, lymphoproliferative diseases, angiogenesis. The compounds of the invention are substituted pyrazoles and pyrazolines.
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- Neuropeptide Y antagonists
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The compound is a neuropeptide Y antagonist and is effective in treating feeding disorders, cardiovascular diseases and other physiological disorders.
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Page column 34
(2010/02/05)
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