- AZETIDINE CYCLIC UREAS
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Provided are azetidine cyclic urea compounds that inhibit cellular necrosis and/or human receptor interacting protein 1 kinase (RIP1), including corresponding sulfonamides, and pharmaceutically acceptable salts, hydrates and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition.
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Page/Page column 57-58
(2021/11/26)
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- Continuous Hydrogenolysis of N-Diphenylmethyl Groups in a Micropacked-Bed Reactor
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In recent years, with the advancements in continuous flow technology and the ever-increasing demand for green processes, continuous flow chemistry has become more and more widely adopted in the pharmaceutical industry. In this work, the continuous hydrogenolysis of N-diphenylmethylazetidin-3-ol to 3-azetidinol in micropacked bed reactors was demonstrated. The effects of different catalysts, solvent types, and the additives on the reaction in a micropacked-bed reactor were investigated. The results indicate that the reaction rate per reactor volume is increased by 100 times because of the larger interfacial area and shorter diffusion distance in micropacked reactors. To further study the long-term stability of the reaction system, the flow system was successfully operated for 240 h by adjusting the reaction temperature and liquid flow rate. The reaction kinetics model for the hydrogenation of N-diphenylmethylazetidin-3-ol in methanol was studied after the internal and external diffusion limitations were eliminated. In addition, the type of adsorption of the reactants on the catalyst and the rate-determining step of the reaction were investigated.
- Tu, Jiacheng,Sang, Le,Cheng, Han,Ai, Ning,Zhang, Jisong
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supporting information
p. 59 - 66
(2020/01/02)
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- JAK INHIBITOR
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The present invention discloses a series of JAK inhibitors, and particularly discloses a compound of formula (I) or a pharmaceutically acceptable salt thereof and the use thereof in preparation of drugs for treating diseases related to JAK.
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Paragraph 0289; 0290; 0292
(2017/12/15)
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- CATALYST FOR SYNTHESIZING ETHYLENIMINE AS WELL AS PREPARATION METHOD AND APPLICATION THEREOF
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The present invention relates to a catalyst for synthesizing ethylenimine as well as a preparation method and application thereof. The related catalyst comprises a carrier and metal ions loaded on the carrier; the carrier is a composite oxide comprising titanium, silicon and phosphorus elements; the metal ions are magnesium ions, iron ions and cesium ions; the molar ratio of the magnesium ions to the iron ions to the cesium ions is (1-10):1:0.1; the mass of all metal ions is 0.5-10 percent of that of the carrier. In the related preparation method, a catalyst precursor is roasted at the temperature of 350-650° C., so that the catalyst is obtained; the catalyst precursor is the mixture of the carrier, soluble salt of magnesium, soluble salt of iron and soluble salt of cesium. The present invention also provides the application of the catalyst to synthesis of the ethylenimine by using amino alcohol as the raw material. Compared with a common catalyst which has the requirement on the temperature of over 400° C., the catalyst of the present invention obviously reduces the reaction temperature. The prepared catalyst can catalyze the intramolecular dehydration reaction of the amino alcohol and has relatively excellent selectivity.
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Paragraph 0043
(2016/11/17)
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- PYRIDINE DERIVATIVES AND APPLICATION OF ANTI-MACOBACTERIUM THEREOF
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The present invention provides a series of pyridine derivatives and their preparation method and application thereof. The series of pyridine derivatives can be applied to treating mycobacterium-related diseases, especially to treatments of fatal mycobacterium-related diseases. The fatal diseases may be related to mycobacterium tuberculosis, mycobacterium bovis, mycobacterium avium, and mycobacterium marinum.
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Paragraph 0589; 0590
(2016/10/08)
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- Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors
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Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimers disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.
- Claffey, Michelle M.,Helal, Christopher J.,Verhoest, Patrick R.,Kang, Zhijun,Fors, Kristina S.,Jung, Stanley,Zhong, Jiaying,Bundesmann, Mark W.,Hou, Xinjun,Lui, Shenping,Kleiman, Robin J.,Vanase-Frawley, Michelle,Schmidt, Anne W.,Menniti, Frank,Schmidt, Christopher J.,Hoffman, William E.,Hajos, Mihaly,McDowell, Laura,Oconnor, Rebecca E.,MacDougall-Murphy, Mary,Fonseca, Kari R.,Becker, Stacey L.,Nelson, Frederick R.,Liras, Spiros
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p. 9055 - 9068
(2013/01/15)
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- COMPOUNDS FOR THE TREATMENT OF METABOLIC DISORDERS
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The present invention is directed to therapeutic compounds which have activity as agonists of GPR119 and are useful for the treatment of metabolic disorders including type II diabetes (I).
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Page/Page column 27
(2010/10/03)
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- NEW ACETYL COENZYME A CARBOXYLASE (ACC) INHIBITORS AND USES IN TREATMENTS OF OBESITY AND DIABETES MELLITUS - 087
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The present invention relates to Acetyl Coenzyme A Carboxylase (ACC) inhibitors according to formula (I), or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, E, L, Z and n are as defined herein, to processes for preparing such compounds, to pharmaceutical compositions containing them, to the use of such inhibitors and to methods for th eir therapeutic use, particularly in the treatments of obesity and diabetes mellitus.
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Page/Page column 258
(2009/07/25)
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- AZETIDINYL G-PROTEIN COUPLED RECEPTOR AGONISTS
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Compounds of formula (I): or pharmaceutically acceptable salts thereof, are agonists of GPR119 and are useful for the treatment of diabetes and as peripheral regulators of satiety, e.g. for the treatment of obesity and metabolic syndrome.
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Page/Page column 14-15
(2009/05/28)
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- AZETIDINYL G-PROTEIN COUPLED RECEPTOR AGONISTS
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Compounds of formula (I) or pharmaceutically acceptable salts thereof, are agonists of GPR119 and are useful for the treatment of diabetes and as peripheral regulators of satiety, e.g. for the treatment of obesity and metabolic syndrome.
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Page/Page column 18
(2009/05/28)
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- OXAZOLIDINONES CONTAINING AZETIDINE AS ANTIBACTERIAL AGENTS
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 and R2 are independently H, F, OH, C1-2alkyl, CF3, OC1-2alkyl, optionally substituted
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Page/Page column 16-17; 41-42
(2010/11/25)
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- Heterocycle-substituted 3-alkyl azetidine derivatives
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Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).
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Page/Page column 49
(2010/11/27)
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- AZETIDINE DERIVATIVES AS G-PROTEIN COUPLED RECEPTOR (GPR119 ) AGONISTS
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Compounds of formula (I) or pharmaceutically acceptable salts thereof, are agonists of GPR119 and are useful for the treatment of diabetes and as peripheral regulators of satiety, e.g. for the treatment of obesity and metabolic syndrome.
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Page/Page column 16; 8; 17-18
(2008/06/13)
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- CB1 MODULATOR COMPOUNDS
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Novel compounds of structural formula (I) are disclosed. As modulators of the Cannabinoid-1 (CB1) receptor, these compounds are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. As such, compounds of the present invention are useful as in the treatment, prevention and suppression of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders (e.g., multiple sclerosis, Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis), cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, and nicotine. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith.
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Page/Page column 125-126
(2008/06/13)
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- SUBSTITUTED 3-ALKYL AND 3-ALKENYL AZETIDINE DERIVATIVES
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Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson’s disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.
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- Pharmaceutically active pyrrolidine derivatives
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The present invention is related to pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including premature labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of CR6R7, NOR6, NNR6R7; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO22—, —SO2NH—, —CH2—,B is either a group —(C═O)—NR8R9 or represents a heterocyclic residue having the formula (a) wherein Q is NR10, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
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- Pharmaceutically active pyrrolidine derivatives as bax inhibitors
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The present invention is related to new substituted pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of neurodegenerative disorders, diseases associated with polygultamine tracts, epilepsy, ischemia, infertility, cardiovascular disorders renal hypoxia, hepatitis and AIDS. Said pyrrolidine derivatives display a modulatory and most notably a down-regulating-up to an inhibitory-activity with respect to the cellular death agonist Bax and/or the activation pathways leading to Bax and allows therefore to block the release of cytochrome (c). The present invention is furthermore related to novel pharmaceutically activity substituted pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of O, S, CRR, NOR, NNRR; A is selected from the group consisting of —(C═O)—, —(C═O)—O—, —C(═NH)—, —(C═O)—NH—, —(C═S)—NH, —SO2-, —SO2NH—; —CH2-; B is either a group —(C═O)—NRR or represents a heterocyclic residue having the formula (II) wherein Q is NR, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
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- Cyclic amine sulfonamides as linkers in the design and synthesis of novel human β3 adrenergic receptor agonists
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Piperidine, pyrrolidine, and azetidine sulfonamides were examined as linkers in designing novel human β3 adrenergic receptor (β3-AR) agonists. The azetidine derivative 37, and piperidine derivatives 7, 8, and 13 were found to be potent β3-AR agonists and have good selectivity against β1- and β2-AR.
- Sum, Fuk-Wah,Wong, Victoria,Han, Stella,Largis, Elwood,Mulvey, Ruth,Tillett, Jeff
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p. 2191 - 2194
(2007/10/03)
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- Cathepsin cysteine protease inhibitors
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This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of Cathepsins K and L. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
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- Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L
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Compounds containing a 1-cyanopyrrolidinyl ring were identified as potent and reversible inhibitors of cathepsins K and L. The original lead compound 1 inhibits cathepsins K and L with IC50 values of 0.37 and 0.45 μM, respectively. Modification of compound 1 by replacement of the quinoline moiety led to the synthesis of N-(1-cyano-3-pyrrolidinyl)benzenesulfonamide (2). Compound 2 was found to be a potent inhibitor of cathepsins K and L with a Ki value of 50 nM for cathepsin K. Replacement of the 1-cyanopyrrolidine of compound 2 by a 1-cyanoazetidine increased the potency of the inhibitor by 10-fold. This increase in potency is probably due to an enhanced chemical reactivity of the compound toward the thiolate of the active site of the enzyme. This is demonstrated when the assay is performed in the presence of glutathione at pH 7.0 which favors the formation of a GSH thiolate anion. Under these assay conditions, there is a loss of potency in the 1-cyanoazetidine series due to the formation of an inactive complex between the GSH thiolate and the 1-cyanoazetidine inhibitors. 1-Cyanopyrrolidinyl inhibitors exhibited time-dependent inhibition which allowed us to determine the association and dissociation rate constants with human cathepsin K. The kinetic data obtained showed that the increase of potency observed between different 1-cyanopyrrolidinyl inhibitors is due to an increase of kon values and that the association of the compound with the enzyme fits an apparent one-step mechanism. 13C NMR experiments performed with the enzyme papain showed that compound 2 forms a covalent isothiourea ester adduct with the enzyme. As predicted by the kinetic analysis, the addition of the irreversible inhibitor E64 to the enzyme-cyanopyrrolidinyl complex totally abolished the signal of the isothiourea bond as observed by 13C NMR, thereby demonstrating that the formation of the covalent bond with the active site cysteine residue is reversible. Finally, compound 2 inhibits bone resorption in an in vitro assay involving rabbit osteoclasts and bovine bone with an IC50 value of 0.7 μM. 1-Cyanopyrrolidine represents a new class of nonpeptidic compounds that inhibit cathepsin K and L activity and proteolysis of bone collagen.
- Falgueyret,Oballa,Okamoto,Wesolowski,Aubin,Rydzewski,Prasit,Riendeau,Rodan,Percival
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-
- Synthesis and structure-activity relationship of novel pyridyl ethers for the nicotinic acetylcholine receptor
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The preparation of novel pyridyl ethers as ligands for the nicotinic acetylcholine receptor (nAChR) is described. Variations of the ring size of the azacycle and substitution on the pyridine had dramatic effects on receptor binding affinity with IC50S at the α4β2 nAChR ranging from 22 to >10,000 nM. The most potent molecule was (R)-2-chloro-3-(4-cyanophenyl)-5-((3-pyrrolidinyl)oxy)pyridine 27f with an IC50 of 22 nM. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Lee, Jung,Davis, Coralie B.,Rivero, Ralph A.,Reitz, Allen B.,Shank, Richard P.
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p. 1063 - 1066
(2007/10/03)
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- Studies directed toward the design of orally active renin inhibitors. 2. Development of the efficacious, bioavailable renin inhibitor (2S)-2-benzyl- 3-[[(1-methylpiperazin-4-yl)sulfonyl]propionyl]-3-thiazol-4-yl-L-alanine amide of (2S,3R,4S)-2-amino-1-cyc
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Employing a set of empirical guidelines for the design of well-absorbed renin inhibitors, we have followed two strategies to improve potency while maintaining bioavailability. One process involved incorporation of an extended N-terminal residue bearing a
- Rosenberg,Spina,Condon,Polakowski,Yao,Kovar,Stein,Cohen,Barlow,Klinghofer,Egan,Tricarico,Perun,Baker,Kleinert
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p. 460 - 467
(2007/10/02)
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