- Novel benzoazepine compound, composition and applications of novel benzoazepine compound and composition
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The invention relates to a novel benzoazepine compound, which comprises a pharmaceutically acceptable salt thereof. The invention also provides a pharmaceutical composition containing the compound and the pharmaceutically acceptable salt thereof. The pres
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Paragraph 0146; 0151-0153
(2021/05/29)
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- Strategic engineering of alkyl spacer length for a pH-tolerant lysosome marker and dual organelle localization
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Long-term visualization of lysosomal properties is extremely crucial to evaluate diseases related to their dysfunction. However, many of the reported lysotrackers are less conducive to imaging lysosomes precisely because they suffer from fluorescence quenching and other inherent drawbacks such as pH-sensitivity, polarity insensitivity, water insolubility, slow diffusibility, and poor photostability. To overcome these limitations, we have utilized an alkyl chain length engineering strategy and synthesized a series of lysosome targeting fluorescent derivatives namelyNIMCsby attaching a morpholine moiety at theperiposition of the 1,8-naphthalimide (NI) ring through varying alkyl spacers between morpholine and 1,8-naphthalimide. The structural and optical properties of the synthesizedNIMCswere explored by1H-NMR, single-crystal X-ray diffraction, UV-Vis, and fluorescence spectroscopy. Afterward, optical spectroscopic measurements were carefully performed to identify a pH-tolerant, polarity sensitive, and highly photostable fluoroprobes for further live-cell imaging applications.NIMC6displayed excellent pH-tolerant and polarity-sensitive properties. Consequently, allNIMCswere employed in kidney fibroblast cells (BHK-21) to investigate their applicability for lysosome targeting and probing lysosomal micropolarity. Interestingly, a switching of localization from lysosomes to the endoplasmic reticulum (ER) was also achieved by controlling the linker length and this phenomenon was subsequently applied in determining ER micropolarity. Additionally, the selected probeNIMC6was also employed in BHK-21 cells for 3-D spheroid imaging and inCaenorhabditis elegans(C. elegans) forin vivoimaging, to evaluate its efficacy for imaging animal models.
- Bhowal, Rohit,Biswas, Suprakash,Chopra, Deepak,Dutta, Tanoy,Koner, Apurba L.,Silswal, Akshay
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p. 9630 - 9644
(2021/07/28)
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- Synthesis and biological evaluation of heteroalicyclic cyanoguanidines at histamine receptors
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Recent studies on histamine receptor (HR) subtypes identified imidazolyl butyl cyanoguanidines, like UR-PI376, as highly potent agonists at the human histamine H4 receptor (hH4R). While imidazole-containing compounds display drawbacks in pharmacokinetics, we studied the possibility of?replacing?the heteroaromatic cycle by nonaromatic six-membered heterocycles (piperidine, morpholine, thiomorpholine, and?N-methylpiperazine) as potential bioisosteres. Beyond that, this approach should give more information about the indispensability of the?aromatic ring as a basic head group. Besides these changes, a variation of the spacer length (C3–C5) connecting the heterocycle and the cyanoguanidine moiety has been made to possibly trigger the selectivity towards the respective HRs. Investigations in radioligand-binding assays exhibited only very weak activity at the hH1R and hH3R, while nearly all compounds were inactive at the hH2R and hH4R. In the case of piperidine-containing compounds, moderate affinities at the hH3R over the single-digit micromolar range were detected.
- Soliman, Beatrice,Wang, Ning,Zagotto, Giuseppe,Pockes, Steffen
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- Highly Selective Butyrylcholinesterase Inhibitors with Tunable Duration of Action by Chemical Modification of Transferable Carbamate Units Exhibit Pronounced Neuroprotective Effect in an Alzheimer's Disease Mouse Model
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In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding to the enzyme. A set of compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle) in the carbamate residue was synthesized and characterized in vitro for their binding affinity, binding kinetics, and carbamate hydrolysis. These novel BChE inhibitors are highly selective for hBChE over human acetycholinesterase (hAChE), yielding short-, medium-, and long-acting nanomolar hBChE inhibitors (with a half-life of the carbamoylated enzyme ranging from 1 to 28 h). The inhibitors show neuroprotective properties in a murine hippocampal cell line and a pharmacological mouse model of Alzheimer's disease (AD), suggesting a significant benefit of BChE inhibition for a disease-modifying treatment of AD.
- Hoffmann, Matthias,Stiller, Carina,Endres, Erik,Scheiner, Matthias,Gunesch, Sandra,Sotriffer, Christoph,Maurice, Tangui,Decker, Michael
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p. 9116 - 9140
(2019/11/03)
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- Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents
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The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC50 value of 0.56 ± 0.02 μM for AChE and an IC50 value of 1.17 ± 0.09 μM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aβ-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.
- Patel, Dushyant V.,Patel, Nirav R.,Kanhed, Ashish M.,Patel, Sagar P.,Sinha, Anshuman,Kansara, Deep D.,Mecwan, Annie R.,Patel, Sarvangee B.,Upadhyay, Pragnesh N.,Patel, Kishan B.,Shah, Dharti B.,Prajapati, Navnit K.,Murumkar, Prashant R.,Patel, Kirti V.,Yadav, Mange Ram
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p. 3635 - 3661
(2019/08/20)
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- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
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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)
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Page/Page column 150
(2018/06/01)
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- Nitrogenous Heterocyclic Derivatives And Their Application In Drugs
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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.
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Paragraph 0675
(2015/03/31)
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- Anti-Markovnikov Hydroamination of Homoallylic Amines
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The development of an anti-Markovnikov-selective hydroamination of unactivated alkenes is a significant challenge in organometallic chemistry. Herein, we present the rhodium-catalyzed anti-Markovnikov-selective hydroamination of homoallylic amines. The proximal Lewis basic amine serves to promote reactivity and enforce regioselectivity through the formation of the favored metallacycle, thus over-riding the inherent reactivity of the alkene. The scope of both the amine nucleophiles and homoallylic amines that participate in the reaction is demonstrated.
- Ensign, Seth C.,Vanable, Evan P.,Kortman, Gregory D.,Weir, Lee J.,Hull, Kami L.
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supporting information
p. 13748 - 13751
(2016/01/15)
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- NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
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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.
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Paragraph 00379
(2014/02/15)
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- Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333
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Several lines of experimental evidence support the involvement of the α7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the α7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel α7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at α7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted.
- Beinat, Corinne,Reekie, Tristan,Hibbs, David,Xie, Teresa,Olson, Thao T.,Xiao, Yingxian,Harvey, Andrew,O'Connor, Susan,Coles, Carolyn,Tsanaktsidis, John,Kassiou, Michael
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supporting information
p. 200 - 205
(2014/08/05)
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- N-Cinnamoylated chloroquine analogues as dual-stage antimalarial leads
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The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood-and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads.
- Pérez, Bianca C.,Teixeira, Cátia,Albuquerque, Ine?s S.,Gut, Jiri,Rosenthal, Philip J.,Gomes, José R. B.,Prude?ncio, Miguel,Gomes, Paula
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p. 556 - 567
(2013/04/23)
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- Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues
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Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cel
- Perez, Bianca C.,Fernandes, Iva,Mateus, Nuno,Teixeira, Catia,Gomes, Paula
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supporting information
p. 6769 - 6772
(2014/01/06)
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- Synthesis and biological evaluation of 2,4-diaminoquinazoline derivatives as novel heat shock protein 90 inhibitors
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Novel 2,4-diaminoquinazoline derivatives originating from a virtual screening approach were designed, synthesized and their biological activities as heat shock protein 90 (Hsp90) inhibitors were evaluated. The prepared compounds exhibited significant anti-proliferative activities against DU-145, HT-29, HCT-116, A375P and MCF-7 cancer cell lines. The selected compounds were tested against Her2, a client protein of Hsp90, and showed significant reduction in Her2 protein expression. Compound 6b was found the most potent, reduced Her2 protein expression levels and induced Hsp70 protein expression levels significantly.
- Thorat, Dhanaji Achyutrao,Doddareddy, Munikumar Reddy,Seo, Seon Hee,Hong, Tae-Joon,Cho, Yong Seo,Hahn, Ji-Sook,Pae, Ae Nim
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scheme or table
p. 1593 - 1597
(2011/05/05)
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- Novel alpha-7 nicotinic acetylcholine receptor agonists containing a urea moiety: Identification and characterization of the potent, selective, and orally efficacious agonist 1-[6-(4-Fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1- ylbutyl) Urea (SEN34625/WYE-103914)
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Alpha-7 nicotinic acetylcholine receptor (α7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the α7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the α7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
- Ghiron, Chiara,Haydar, Simon N.,Aschmies, Suzan,Bothmann, Hendrick,Castaldo, Cristiana,Cocconcelli, Giuseppe,Comery, Thomas A.,Di, Li,Dunlop, John,Lock, Tim,Kramer, Angela,Kowal, Dianne,Jow, Flora,Grauer, Steve,Harrison, Boyd,La Rosa, Salvatore,MacCari, Laura,Marquis, Karen L.,Micco, Iolanda,Nencini, Arianna,Quinn, Joanna,Robichaud, Albert J.,Roncarati, Renza,Scali, Carla,Terstappen, Georg C.,Turlizzi, Elisa,Valacchi, Michela,Varrone, Maurizio,Zanaletti, Riccardo,Zanelli, Ugo
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experimental part
p. 4379 - 4389
(2010/09/04)
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- OXADIAZOLE DERIVATIVES AND THEIR USE AS NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS
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Oxadiazole derivatives of formula (I) where ring A is a bicyclic or tricyclic system. Claimed compounds are active on nicotinic acetylcholine receptors (nAChRs), and are useful to treat neurological, psychiatric, and gastrointestinal disorders, as well as sepsis and obesity.
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Page/Page column 27-28
(2009/07/17)
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- 5-ARYL-1,3,4-OXADIAZOLE-2-AMINES AS NICOTINIC ACETYLCHOLINE RECEPTOR AGONISTS
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The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, compositions containing them and their use in the treatment of neurological, psychiatric disorders and gastrointestinal disorders. wherein R1 and R2 independently represent hydrogen, C1-6 alkyl or C3-6 cycloalkyl; or R1 and R2 together with the nitrogen atom to which they are attached form a nitroge containing heterocyclyl group which is unsubstituted or substituted with 1, 2, or 3 substituents selected from methyl or fluoro; Q represents -(CH2)n- wherein n represents 3 or 4; A represents a phenyl ring and B represents a 5 or 6 membered heteroaryl ring or B represents a phenyl ring and A represents a 5 or 6 membered heteroaryl ring; R3 and R4 independently represent C1-6 alkyl, C1-6 alkoxy and halo; t and m independently represent an integer from 0 to 3. Compounds of formula (I) and their pharmaceutically acceptable salts may have affinity for and be agonists at the nicotinic α7 receptor and are believed to be of potential use in the treatment of neurological diseases including Alzheimer's disease.
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Page/Page column 24
(2009/07/17)
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- 2-PHENYL-5-AMINO-1,3,4-OXADIAZOLES AND THEIR USE AS NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS
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The present invention relates to novel oxadiazole derivatives of formula (1) having pharmacological activity, processes for their preparation, compositions containing them and their use in the treatment of neurological, psychiatric disorders and gastrointestinal disorders through modulation of the nicotinic α7 receptor formula (I).
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Page/Page column 27
(2008/06/13)
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- MODULATORS OF ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTORS AND THERAPEUTIC USES THEREOF
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The present invention relates to compounds with α7 nAChR agonistic activity, processes for their preparation, pharmaceutical compositions containing the same and the use thereof for the treatment of neurological, psychiatric, cognitive, immunological and inflammatory disorders.
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Page/Page column 17
(2010/02/15)
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- TRICYCLIC 1,2,4-TRIAZINE OXIDES AND COMPOSITIONS THEREFROM FOR THERAPEUTIC USE IN CANCER TREATMENTS
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The invention relates to novel tricyclic 1,2,4-triazine-1-oxides and novel tricyclic 1,2,4-triazine-1,4-dioxides of formula: (I); and to related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.
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Page/Page column 173
(2008/06/13)
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- 4-Amino-thieno[3,2-c]pyridine-7-carboxylic acid amides
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Disclosed are novel 4-amino-thieno[3,2-c]pyridine-7-carboxylic acid amides, and their pharmaceutically acceptable salts and esters, that are selective inhibitors of KDR and/or FGFR kinases. These compounds and their pharmaceutically acceptable salts are anti-proliferative agents useful in the treatment or control of solid tumors, in particular solid cancerous tumors of the breast, colon, lung and prostate. Also disclosed are pharmaceutical compositions containing these compounds and methods of treating cancer using these compounds.
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Page/Page column 15
(2010/02/14)
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- Quinazolines as MMP-13 inhibitors
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A compound selected from those of formula (I): in which: R1 represents a group selected from hydrogen, amino, alkyl, alkenyl, aminoalkyl, aryl, arylalkyl, heterocycle, and cycloalkylalkyl, optionally substituted, W represents oxygen, sulfhur, or ═N—R′, in which R′ is as defined in the description, X1, X2 and X3 represent nitrogen or —C—R6 in which R6 is as defined in the description, Y represents oxygen, sulfhur, —NH, or —N(C1-C6)alkyl, Z represents oxygen, sulfhur, —NR7 in which R7 is as defined in the description, and 59 optionally carbon atom, n is an integer from 1 to 8 inclusive, Z1 represents —CR8R9 wherein R8 and R9 are as defined in the description, A represents aromatic or non-aromatic, heterocyclic or non-heterocyclic ring system, m is an integer from 0 to 7 inclusive, the group(s) R2 is (are) is as defined in the description, R3 represents hydrogen, alkyl, alkenyl, alkynyl, ot a group of formula: in which Z2, B, R5, P and q are as defined in the description, optionally, the racemic forms thereof, isomers thereof, N-oxydes thereof, and the pharmaceutically acceptable salts thereof, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix metalloprotease.
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- Isonitrile intermediates for the preparation of tri-substituted imidazole compounds with multiple therapeutic properties
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The invention relates to a novel group of isonitrile compounds and a process for their preparation, useful in the preparation of tri-substituted imadazoles having multiple therapeutic properties.
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- Imine intermediates for the preparation of trisubstituted imidazole compounds with multiple therapeutic properties
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The invention relates to a novel group of iminc compounds and a process for their preparation, useful in the preparation of tri-substituted imadazoles having multiple therapeutic properties.
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- Formamide intermediates for the preparation of tri-substituted imidazole compounds with multiple therapeutic properties
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The invention relates to a novel group of formamide compounds and a process for their preparation, useful in the preparation of tri-substituted imadazoles having multiple therapeutic properties.
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- Imidazole compounds, use and process of making
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Compounds
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Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Pyridyl imidazole compounds and compositions
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Novel 1, 4, 5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.
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- Tyrosine kinase inhibitors. 13. Structure - Activity relationships for soluble 7-substituted 4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidines designed as inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor
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The general class of 4-(phenylamino)quinazolines are potent (some members with IC50 values 40 mM) and retention of overall inhibitory activity (IC50's of 0.5-10 nM against isolated enzyme and 8-40 nM for inhibition of EGFR autophosphorylation in A431 cells) were weakly basic amine derivatives. These results are broadly consistent with a proposed model for the binding of these compounds to EGFR, in which the 6- and 7-positions of the pyridopyrimidine ring are in a largely hydrophobic binding region of considerable steric freedom, at the entrance of the adenine binding cleft. The most active cationic analogues have a weakly basic side chain where the amine moiety is three or more carbon atoms away from the nucleus. Two of the compounds (bearing weakly basic morpholinopropyl and strongly basic (dimethylamino)butyl solubilizing groups) produced in vivo tumor growth delays of 13-21 days against advanced stage A431 epidermoid xenografts in nude mice, when administered ip twice per day on days 7-21 posttumor implant. Treated tumors did not increase in size during therapy and resumed growth at the termination of therapy, indicating an apparent cytostatic effect for these compounds under these treatment conditions. The data suggest that continuous long-term therapy with these compounds may result in substantial tumor growth inhibition.
- Thompson, Andrew M.,Murray, Donna K.,Elliott, William L.,Fry, David W.,Nelson, James A.,Showalter, H.D. Hollis,Roberts, Bill J.,Vincent, Patrick W.,Denny, William A.
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p. 3915 - 3925
(2007/10/03)
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- Renin inhibitors
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A renin inhibiting compound of the formula: STR1 wherein X is O, NH or S and G is a mimic of the Leu-Val cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that the compound is not N-(3-(4-M
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