116650-34-1Relevant articles and documents
INDOLE AHR INHIBITORS AND USES THEREOF
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, (2018/11/22)
The present invention provides compounds useful as inhibitors of AHR, compositions thereof, and methods of using the same.
A 3-amino -1, 2, 3, 4-tetrahydrocarbazoles a method for the resolution of
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Paragraph 0047-0049, (2017/04/11)
The invention relates to a resolution method for 3-amino-1, 2, 3, 4-tetrahydrocarbazole. The method adopts L-tartaric acid or D-tartaric acid as the resolving agent, and takes the mixed solvent of an alcohol solvent and water as the resolving solvent. By regulating the volume ratio of the alcohol solvent and water in the resolving solvent, the 3-amino-1, 2, 3, 4-tetrahydrocarbazole is resolved to obtain R-3-amino-1, 2, 3, 4-tetrahydrocarbazole and S-3-amino-1, 2, 3, 4-tetrahydrocarbazole respectively. The method adopts the cheap L-tartaric acid as the resolving agent to reduce the production cost. Meanwhile, different alcohol-water ratios of one resolving agent realize the unexpected effect of resolution of two enantiomers, the complicated process of needing two chiral resolving agents to obtain two enantiomers in production can be further omitted, and raw materials are saved at the same time. Through further crystallization purification, the resolved salts then react with lye to remove the tartaric acid radical, and the e.e.% of the respectively obtained single enantiomer R-3-amino-1, 2, 3, 4-tetrahydrocarbazole and S-3-amino-1, 2, 3, 4-tetrahydrocarbazole are both greater than 99%.
Cutting short the asymmetric synthesis of the ramatroban precursor by employing ω-transaminases
Busto, Eduardo,Simon, Robert C.,Grischek, Barbara,Gotor-Fernandez, Vicente,Kroutil, Wolfgang
supporting information, p. 1937 - 1942 (2014/07/07)
Starting from an adequate ketone precursor previous reports required three steps for the preparation of (R)-2,3,4,9-tetrahydro-1H-carbazol-3-amine, a key intermediate for the synthesis of the antiallergic drug ramatroban. A single biocatalytic step was sufficient to prepare the target amine with >97% ee (HPLC) via reductive amination of the corresponding ketone using an ω-transaminase as biocatalyst. Since the ketone was barely soluble under the reaction conditions employed, it was provided as a solid and still the reaction went to completion within 4 h at 50 mM substrate concentration. Although 2-propylamine is regarded as an ideal amine donor, it turned out to be detrimental for the specific ketone precursor leading to the formation of various side products. These could be avoided by using (R)-1-phenylethylamine as the best suited amine donor. An alternative work-up was developed via freeze-drying of the reaction mixture, enabling the isolation of the desired (R)-amine in excellent yield (96%) and enantiopure form on a preparative scale (500 mg). No purification steps (e.g., column chromatography, crystallisation) were required.
Asymmetric chemoenzymatic synthesis of ramatroban using lipases and oxidoreductases
Busto, Eduardo,Gotor-Fernandez, Vicente,Gotor, Vicente
scheme or table, p. 4842 - 4848 (2012/07/31)
A chemoenzymatic asymmetric route for the preparation of enantiopure (R)-ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1H-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1H-carbazol-3(2H)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (S)-2,3,4,9-tetrahydro-1H-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (R)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms.
N,N-Dimethyl-[9-(arylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amines as novel, potent and selective 5-HT6 receptor antagonists
Nirogi, Ramakrishna V. S.,Konda, Jagadishu Babu,Kambhampati, Ramasastry,Shinde, Anil,Bandyala, Thrinath Reddy,Gudla, Parandhama,Kandukuri, Kiran Kumar,Jayarajan, Pradeep,Kandikere, Vishwottam,Dubey, P. K.
, p. 6980 - 6985,6 (2020/09/02)
The design, synthesis and SAR of novel tetrahydrocarbazole derivatives having 5-HT6 receptor antagonist activity is presented. The racemic compound 15e was found to possess desirable pharmacokinetic properties, adequate brain penetration and activity in animal models of cognition.
The catalytic asymmetric Fischer indolization
Mueller, Steffen,Webber, Matthew J.,List, Benjamin
, p. 18534 - 18537 (2012/01/31)
The first catalytic asymmetric Fischer indolization is reported. In the presence of a 5 mol % loading of a novel spirocyclic chiral phosphoric acid, 4-substituted cyclohexanone-derived phenylhydrazones undergo a highly enantioselective indolization. Efficient catalyst turnover was achieved by the addition of a weakly acidic cation exchange resin, which removes the generated ammonia. The reaction can be conducted under mild conditions and gives various 3-substituted tetrahydrocarbazoles in generally high yields.
SYNTHESIS OF (2-AMINO)-TETRAHYDROCARBAZOLE-PROPANOIC ACID
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Page/Page column 13, (2010/08/04)
The present invention provides a new approach to the synthesis of 2-amino-tetrahydrocarbazole-propanoic acid, a key intermediate for the synthesis of Ramatroban. More specifically, a synthesis of 2-amino-tetrahydrocarbazole- propanoic acid which includes oxidizing an aminocyclohexanol to form an aminocyclohexanone, condensing the aminocyclohexanone to form a tetrahydrocarbazole, deprotecting the tetrahydrocarbazole to yield a racemic mixture of a tetrahydrocarbazole, resolving the racemic mixture to obtain a yield mixture with an enantiomeric excess of one enantiomer over another, alkylating the excess enantiomer to yield an alkyl ester, and hydrolyzing the alkyl ester to yield 2-amino-tetrahydrocarbazole-propanoic acid.
NOVEL DIPEPTIDYL PEPTIDASE IV INHIBITORS; PROCESSES FOR THEIR PREPARATION AND COMPOSITIONS THEREOF
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Page/Page column 28, (2010/02/11)
The present invention relates to novel dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula (I), and their analogs, isomers, pharmaceutical compositions and therapeutic uses, methods of making the same.
Fluorescence Studies with Tryptophan Analogues: Excited State Interactions Involving the Side Chain Amino Group
Eftink, Maurice R.,Jia, Yiwei,Hu, Dana,Ghiron, Camillo, A.
, p. 5713 - 5723 (2007/10/02)
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.
Microenvironmental effects on the solvent quenching rate in constrained tryptophan derivatives
Yu, Hong-Tao,Vela, Marco A.,Fronczek, Frank R.,McLaughlin, Mark L.,Barkley, Mary D.
, p. 348 - 357 (2007/10/02)
Solvent quenching is one of several environmentally sensitive nonradiative decay pathways available to the indole chromophore. It is characterized by 2-3-fold deuterium isotope effects and strong temperature dependence with frequency factors of 1015-1017 s-1 and activation energies of 11-13 kcal/mol in aqueous solution. The effects of ionization state, proximity of the amino group to the indole ring, and N-methylation of indole nitrogen on the solvent quenching rate were examined in four constrained tryptophan derivatives: 1,2,3,4-tetrahydro-2-carboline, 3-amino-1,2,3,4-tetrahydrocarbazole, 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, and 9-methyl-1,2,3,4-tetrahydro-2-carboline-3-carboxylic acid. The constrained derivatives had at most two ground-state conformations, as determined by X-ray crystallography, molecular mechanics calculations, and 1H NMR. Fluorescence lifetimes were assigned to ground-state conformations based on relative populations of conformers and amplitudes of fluorescence decays. Solvent quenching rates were determined from the temperature dependence of the fluorescence lifetime. The solvent quenching rate is decreased by protonation of the amino group in all compounds. It is slower in the carboline derivatives, where the amino group is two bonds away from the indole ring, than in the tetrahydrocarbazole derivatives, where the amino group is three bonds away. In the tetrahydrocarbazoles, the solvent quenching rate is slower in the conformer with the ammonium in the pseudoaxial position closer to the indole ring than in the conformer with the ammonium in the pseudoequatorial position pointing away from the ring. These results suggest that the water quenching rate of tryptophans on protein or peptide surfaces is modulated by proximal ammonium groups.
