- Method for protecting sulfonyl of deamination amine
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The invention discloses a method for removing sulfenyl protection of amine. The method comprises the following steps: dissolving N - sulfonyl-protected amine and a base in a reaction solvent, then adding diphenylphosphine to uniformly mix and maintain 90 °C. When TCL detection reaction is complete, a recrystallization method or an extraction separation method is adopted to obtain the target product. The method disclosed by the invention adopts diphenylphosphine as an extraction reagent, is good in reaction activity, high in selectivity and wide in application range, and can replace the use of a hazardous reagent under the basic heating condition. Prodrug research and development and industrial production are of great significance.
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Paragraph 0042-0044
(2021/11/03)
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- METHODS AND MATERIALS FOR INCREASING OR MAINTAINING NICOTINAMIDE MONONUCLEOTIDE ADENYLYL TRANSFERASE-2 (NMNAT2) POLYPEPTIDE LEVELS
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This document provides methods and materials for increasing or maintaining NMNAT2 polypeptide levels within cells. For example, compounds (e.g., organic compounds) having the ability to increase or maintain NMNAT2 polypeptide levels within cells, formulations containing compounds having the ability to increase or maintain NMNAT2 polypeptide levels within cells, methods for making compounds having the ability to increase or maintain NMNAT2 polypeptide levels within cells, methods for making formulations containing compounds having the ability to increase or maintain NMNAT2 polypeptide levels within cells, methods for increasing or maintain NMNAT2 polypeptide levels within cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in NMNAT2 polypeptide levels are provided (or for preventing said condition).
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Page/Page column 187
(2020/09/08)
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- Biomimetic Oxidative Coupling Cyclization Enabling Rapid Construction of Isochromanoindolenines
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Herein, we report a biomimetic oxidative coupling cyclization strategy for the highly efficient functionalization of tetrahydrocarbolines (THCs). This process enables rapid access to complex isochromanoindolenine scaffolds in moderate to excellent yields.
- Ye, Jinxiang,Lin, Yuqi,Liu, Qing,Xu, Dekang,Wu, Fan,Liu, Bin,Gao, Yu,Chen, Haijun
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supporting information
p. 5457 - 5460
(2018/09/13)
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- Thiapyran[4,3-b] indole compound and preparing method and application thereof
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The invention discloses a thiapyran[4,3-b] indole compound and a preparing method and application thereof. The structure of the compound is shown in the formula 1, wherein the formula 1 is shown in the description, and R1-R5 are not all hydrogen. The compound has excellent activities of inhibiting mycelial growth, protecting detached leaves, protecting living bodies and treating the living bodiesfor rhizoctonia solani, the effects of the compound are even superior to those of positive control drugs, and the compound has an important application value in preventing and/or treating rice sheathblight.
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Paragraph 0049; 0054; 0055
(2018/10/19)
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- TRICYCLIC COMPOUNDS FOR USE IN TREATMENT OF PROLIFERATIVE DISORDERS
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The present invention relates to compounds of Formula (I) as defined herein, and salts, hydrates and solvates thereof. The present invention also relates to pharmaceutical compositions comprising compounds of Formula (I), and to the use of compounds of Formula (I) in the treatment or prevention of PRMT5-mediated disorders, such as cancer.
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Paragraph 00158; 00160
(2018/10/19)
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- Carboline- and phenothiazine-derivated heterocycles as potent SIGMA-1 protein ligands
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Sigma 1 receptors are associated with neurodegenerative and psychiatric disorders. These receptors, via their chaperoning functions that counteract endoplasmic reticulum stress and block neurodegeneration, may serve as a target for a new generation of antidepressants or neuroprotective agents. The involvement of these receptors has also been observed in neuropathic pain and cancer. Only a few ligands, such as Igmesine and Anavex 2-73, have been involved in clinical trials. Thus the development of sigma 1 ligands is of interest to a new generation of drugs. Previous work in our lab underlined the potency of benzannulated bicyclic compounds as interesting ligands. Herein the work was extended to a series of novel tricyclic compounds. Carboline- and phenothiazine-derivated compounds were designed and synthesized. In vitro competition binding assays for sigma 1 and 2 receptors showed that most of them have high affinity for sigma 1 receptor (Ki = 2.5-18 nM), and selectivity toward sigma 2 receptor, without cytotoxic effects on SY5Y cells.
- Donnier-Maréchal, Marion,Larchanché, Paul-Emmanuel,Le Broc, Delphine,Furman, Christophe,Carato, Pascal,Melnyk, Patricia
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p. 198 - 206
(2014/12/11)
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- CARBOLINE COMPOUNDS USABLE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES
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The present invention relates to a compound according to Formula (A) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or polymorph thereof, and its use.
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Page/Page column 24
(2015/01/16)
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- Beta and gamma carboline derivatives as potential anti-Alzheimer agents: A comparison
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Nine novel β2- and 3-carboline derivatives bearing either methyl-, propargyl- or phenethyl-residues at the indole nitrogen were synthesized and tested as potential anti-Alzheimer drugs. Antagonism of recombinantly expressed NMDA receptors, inhibition of cholinesterases, and radical scavenging properties were determined for all compounds. Some were additionally tested in vivo for their ability to reverse scopolamine-induced cognitive impairment in an 8-arm radial maze experiment with rats. For the most promising candidates, the interaction with muscarinic M1receptors was also investigated. With this set of compounds assays the influence of the scaffold itself and the substituents can be investigated separately. 5-Methyl-β3-carboline (6) was the most potent (0.25 1/4mol/100 g b.w.) compound in the in vivo test and might be a good starting point for the development of novel anti-Alzheimer drugs.
- Otto, Robert,Penzis, Robert,Gaube, Friedemann,Winckler, Thomas,Appenroth, Dorothea,Fleck, Christian,Tr?nkle, Christian,Lehmann, Jochen,Enzensperger, Christoph
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- (1 R,2 R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3- b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A potent and highly selective cathepsin k inhibitor for the treatment of osteoarthritis
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Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
- Dossetter, Alexander G.,Beeley, Howard,Bowyer, Jonathan,Cook, Calum R.,Crawford, James J.,Finlayson, Jonathan E.,Heron, Nicola M.,Heyes, Christine,Highton, Adrian J.,Hudson, Julian A.,Jestel, Anja,Kenny, Peter W.,Krapp, Stephan,Martin, Scott,MacFaul, Philip A.,McGuire, Thomas M.,Gutierrez, Pablo Morentin,Morley, Andrew D.,Morris, Jeffrey J.,Page, Ken M.,Ribeiro, Lyn Rosenbrier,Sawney, Helen,Steinbacher, Stefan,Smith, Caroline,Vickers, Madeleine
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supporting information; experimental part
p. 6363 - 6374
(2012/09/25)
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- Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells
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Second-generation Tubastatin A analogues were synthesized and evaluated for their ability to inhibit selectively histone deacetylase 6 (HDAC6). Substitutions to the carboline cap group were well-tolerated with substitution at the 2-position of both β- and γ-carbolines being optimal for HDAC6 activity and selectivity. Some compounds in this series were determined to have subnanomolar activity at HDAC6 with more than 7000 fold selectivity for HDAC6 versus HDAC1. Selected compounds were then evaluated for their ability to augment the immunosuppressive effect of Foxp3+ regulatory T cells. All compounds tested were found to enhance the ability of regulatory T cells to inhibit the mitotic division of effector T cells both in vitro and in vivo, suggesting that further investigation into the use of these compounds for the treatment of autoimmune disorders is warranted.
- Kalin, Jay H.,Butler, Kyle V.,Akimova, Tatiana,Hancock, Wayne W.,Kozikowski, Alan P.
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p. 639 - 651
(2012/03/11)
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- HDAC INHIBITORS AND THERAPEUTIC METHODS USING THE SAME
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Histone deacetylases inhibitors (HDACIs) and compositions containing the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit, like a cancer, a neurodegenerative disorder, a neurological disease, traumatic brain injury, stroke, malaria, an autoimmune disease, autism, and inflammation, also are disclosed.
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Page/Page column 62
(2011/02/24)
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- Synthesis and structure-activity relationships of γ-carboline derivatives as potent and selective cysLT1 antagonists
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A γ-carboline series of cysLT1 receptor antagonists has been prepared. Some of the compounds show good potencies both, in vitro and in vivo, compared to the standard compounds.
- Bonjoch, Josep,Diaba, Faiza,Pages, Lluis,Perez, Daniel,Soca, Lidia,Miralpeix, Montserrat,Vilella, Dolors,Anton, Paquita,Puig, Carles
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scheme or table
p. 4299 - 4302
(2010/04/29)
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- γ-Carbolines: Binding at 5-HT5A serotonin receptors
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Screening of various agents resulted in the identification of 5-methyl-1,2,3,4-tetrahydro-γ-carboline (1; Ki=5,300 nM) as a compound with modest affinity for mouse 5-HT5A receptors. Structure-affinity studies were conducted resulting
- Khorana, Nantaka,Purohit, Anil,Herrick-Davis, Katherine,Teitler, Milt,Glennon, Richard A.
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p. 717 - 722
(2007/10/03)
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- Fluorescence Studies with Tryptophan Analogues: Excited State Interactions Involving the Side Chain Amino Group
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The fluorescence of a large set of tryptophan analogues, including several that are conformationally constrained, was studied.The constrained analogues include tetrahydrocarboline-3-carboxylic acid and 3-amino-3-carboxytetrahydrocarbazole.Steady state and time-resolved fluorescence measurements were made as a function of pH.The fluorescence quantum yields of the constrained analogues are higher than those for the unconstrained counterparts.The emission intensity of the constrained analogues, as well as 4-methyltryptophan, decreases with deprotonation of the side chain α-ammonium groups; this is in contrast to the increase in fluorescence of tryptophan with deprotonation of this group.These results are consistent with the existence of excited state proton transfer to carbon 4 of the indole ring as a quenching mechanism, which is sterically prohibited in the constrained analogues and 4-methyltryptophan.From quantum yield and lifetime data (most decays are nonexponential), the effective rate constant for nonradiative depopulation of the excited state was calculated.For tryptophan analogues having two side chain functional groups, there is a synergistic effect; the presence of two side chain groups causes more quenching than expected from the sum of the individual contributions.For analogues having an α-ammonium group, this synergism appears to be correlated with an induced change in the pKa of this group.Deprotonation of this α-ammonium group also caused a red shift in the emission of these compounds; this appears to be due to electrostatic repulsion between the α-NH3+ group and the excited indole dipole.
- Eftink, Maurice R.,Jia, Yiwei,Hu, Dana,Ghiron, Camillo, A.
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p. 5713 - 5723
(2007/10/02)
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- Antipsychotic Activity of Substituted γ-Carbolines
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Several novel substituted γ-carbolines were synthesized and examined in a series of in vitro and in vivo pharmacological tests to determine potential antipsychotic activity.Most compounds were orally active in blocking the conditioned avoidance response (CAR) in rats but did not antagonize apomorphine-induced stereotyped behavior.Compound 17 (Wy-47,384), a γ-carboline with a 3-(3-pyridinyl)propyl side chain, was selected for development as an atypical antipsychotic agent because of its potent and selective profile in preclinical psychopharmacological tests.It blocked CAR in rats with an AB50 of 14 mg/kg po, showed weak affinity for the D2 receptor site (Ki = 104 nM), and showed differential potency in antagonizing apomorphine-induced stereotyped behavior (ED50 = 11 mg/kg ip) and climbing behavior (ED50 = 4 mg/kg ip).Such activities are suggestive of antipsychotic efficacy combined with a low potential for extrapyramidal side effect (EPS) liability.
- Abou-Gharbia, Magid,Patel, Usha R.,Webb, Michael B.,Moyer, John A.,Andree, Terrance H.,Muth, Eric A.
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p. 1818 - 1823
(2007/10/02)
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