- AROMATIC RING DERIVATIVE AS IMMUNOREGULATION AND PREPARATION METHOD AND APPLICATION OF AROMATIC RING DERIVATIVE
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Relating to a compound represented by formula (I) and a pharmaceutically acceptable salt of the compound, and an application of the compound as an S1P1 agonist.
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Paragraph 0060-0061
(2021/10/15)
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- Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer
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Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.
- Wang, Lei,Fang, Kun,Cheng, Junfei,Li, Yu,Huang, Yahui,Chen, Shuqiang,Dong, Guoqiang,Wu, Shanchao,Sheng, Chunquan
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p. 696 - 713
(2020/02/04)
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- Synthesis method for preparing 2-substituted indole derivative
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The invention relates to a synthesis method for preparing a 2-substituted indole derivative. The method includes the following steps: mixing aromatic amine compounds (I), ketone compounds (II) and a drying agent in an organic solvent; adding a palladium catalyst; and reacting in an aerobic weak acid environment to prepare the indole compounds (III). (I), (II) and (III) are as shown in the specification, wherein R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted phenyl, pyridyl and heterocyclic aryl; (I) can be pyridylamine, pyrimidylamine, pyridazinam or pyrazinamide which may further be substituted or unsubstituted; and the substituents are selected fromone or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, amino; and R2 is selected from C1-C6 alkyl, formate groups or C1-C6 alkylamide groups.
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Paragraph 0071-0074
(2019/05/28)
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- Carboxylic Acid-Promoted Single-Step Indole Construction from Simple Anilines and Ketones via Aerobic Cross-Dehydrogenative Coupling
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The cross-dehydrogenative coupling (CDC) reaction is an efficient strategy for indole synthesis. However, most CDC methods require special substrates, and the presence of inherent groups limits the versatility for further transformation. A carboxylic acid-promoted aerobic catalytic system is developed herein for a single-step synthesis of indoles from simple anilines and ketones. This versatile system is featured by the broad substrate scope and the use of ambient oxygen as an oxidant and is convenient and economical for both laboratory and industry applications. The existence of the labile hydrogen at C-3 and the highly transformable carbonyl at C-2 makes the indoles versatile building blocks for organic synthesis in different contexts. Computational studies based on the density functional theory (DFT) suggest that the rate-determining step is carboxylic acid-assisted condensation of the substrates, rather than the functionalization of aryl C-H. Accordingly, a pathway via imine intermediates is deemed to be the preferred mechanism. In contrast to the general deduction, the in situ formed imine, instead of its enamine isomer, is believed to be involved in the first ligand exchange and later carbopalladation of the α-Me, which shed new light on this indolization mechanism.
- Ren, Long,Nan, Guanglei,Wang, Yongcheng,Xiao, Zhiyan
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p. 14472 - 14488
(2018/11/23)
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- Influence of a Basic Side Chain on the Properties of Hypoxia-Selective Nitro Analogues of the Duocarmycins: Demonstration of Substantial Anticancer Activity in Combination with Irradiation or Chemotherapy
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A new series of nitro analogues of the duocarmycins was prepared and evaluated for hypoxia-selective anticancer activity. The compounds incorporate 13 different amine-containing side chains designed to bind in the minor groove of DNA while spanning a wide range of base strength from pKa 9.64 to 5.24. The most favorable in vitro properties were associated with strongly basic side chains, but the greatest in vivo antitumor activity was found for compounds containing a weakly basic morpholine. This applies to single-agent activity and for activity in combination with irradiation or chemotherapy (gemcitabine or docetaxel). In combination with a single dose of γ irradiation 50 at 42 μmol/kg eliminated detectable clonogens in some SiHa cervical carcinoma xenografts, and in combination with gemcitabine using a well-tolerated multidose schedule, the same compound caused regression of all treated A2780 ovarian tumor xenografts. In the latter experiment, three of seven animals receiving the combination treatment were completely tumor free at day 100.
- Tercel, Moana,Lee, Ho H.,Mehta, Sunali Y.,Youte Tendoung, Jean-Jacques,Bai, Sally Y.,Liyanage, H. D. Sarath,Pruijn, Frederik B.
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p. 5834 - 5856
(2017/07/22)
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- Initial development of a cytotoxic amino-seco-CBI warhead for delivery by prodrug systems
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Abstract Cyclopropabenzaindoles (CBIs) are exquisitely potent cytotoxins which bind and alkylate in the minor groove of DNA. They are not selective for cancer cells, so prodrugs are required. CBIs can be formed at physiological pH by Winstein cyclisation of 1-chloromethyl-3-substituted-5-hydroxy-2,3-dihydrobenzo[e]indoles (5-OH-seco-CBIs). Corresponding 5-NH2-seco-CBIs should also undergo Winstein cyclisation similarly. A key triply orthogonally protected intermediate on the route to 5-NH2-seco-CBIs has been synthesised, via selective monotrifluoroacetylation of naphthalene-1,3-diamine, Boc protection, electrophilic iodination, selective allylation at the trifluoroacetamide and 5-exo radical ring-closure with TEMPO. This intermediate has potential for introduction of peptide prodrug masking units (deactivating the Winstein cyclisation and cytotoxicity), addition of diverse indole-amide side-chains (enhancing non-covalent binding prior to alkylation) and use of different leaving groups (replacing the usual chlorine, allowing tuning of the rate of Winstein cyclisation). This key intermediate was elaborated into a simple model 5-NH2-seco-CBI with a dimethylaminoethoxyindole side-chain. Conversion to a bio-reactive entity and the bioactivity of this system were confirmed through DNA-melting studies (ΔTm = 13°C) and cytotoxicity against LNCaP human prostate cancer cells (IC50 = 18 nM).
- Twum, Elvis A.,Nathubhai, Amit,Wood, Pauline J.,Lloyd, Matthew D.,Thompson, Andrew S.,Threadgill, Michael D.
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supporting information
p. 3481 - 3489
(2015/08/03)
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- IRE-1α INHIBITORS
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PROBLEM TO BE SOLVED: To provide compounds which directly inhibit inositol requiring enzyme 1 (IRE-1α activity) in vitro, prodrugs, and pharmaceutically acceptable salts thereof. SOLUTION: The present invention provides a compound represented by formula (A) [R3 and R4 are H or the like; Q5-Q8, together with the benzene ring to which they are attached, form a benzofused ring, where at least one of Q5-Q8 is a heteroatom selected from N, O, and S. COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 1400; 1401
(2016/10/07)
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- N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor
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On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.
- Bautista-Aguilera, Oscar M.,Samadi, Abdelouahid,Chioua, Mourad,Nikolic, Katarina,Filipic, Slavica,Agbaba, Danica,Soriano, Elena,De Andrés, Lucía,Rodríguez-Franco, María Isabel,Alcaro, Stefano,Ramsay, Rona R.,Ortuso, Francesco,Ya?ez, Matilde,Marco-Contelles, José
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supporting information
p. 10455 - 10463
(2015/02/19)
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- Efficient microwave combinatorial synthesis of novel indolic arylpiperazine derivatives as serotoninergic ligands
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An easy and convenient microwave-assisted synthesis of a small library of indolic arylpiperazine derivatives is described. Parallel and mixed pool combinatorial methods are reported and compared. The described reactions are nucleophilic substitutions of several aromatic piperazines in presence of K2CO3. Good yields and short reaction times are the main aspect of these procedures. Binding assays shed additional light on the influence of the LCAPs on the 5-HT1A, 5-HT2A and 5-HT2C receptors affinity and allowed to disclose three interesting compounds as 5-HT2C, mixed 5-HT2A/5-HT2C and 5-HT1A/5-HT2C ligands (4i, 4l and 4d, respectively), with potential antiepileptic, anxiolytic or atypical antipsychotic agent therapeutical profiles.
- Frecentese, Francesco,Fiorino, Ferdinando,Perissutti, Elisa,Severino, Beatrice,Magli, Elisa,Esposito, Antonella,De Angelis, Francesca,Massarelli, Paola,Nencini, Cristina,Viti, Barbara,Santagada, Vincenzo,Caliendo, Giuseppe
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experimental part
p. 752 - 759
(2010/04/04)
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- Indole derivatives as MCP-1 receptor antagonists
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A compound of Formula I, wherein: R1 is hydrogen, halo, methyl, ethyl or methoxy; R2 is hydrogen, halo, methyl, ethyl or methoxy; R3 is a halo group, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, trifluoromethyl, nitro, cyano, trifluoromethoxy, C(O)R7, or S(O)nR7 where n is 0, 1 or 2 and R7 is an alkyl group; R4 is a halo, trifluoromethyl, methylthio, methoxy, trifluoromethoxy or lower alkyl, lower alkenyl or lower alkynyl or COR8 where R8 is lower alkyl; R6 is hydrogen, halo, lower alkyl, lower alkenyl, lower alkynyl or COR9 where R9 is lower alkyl; provided that when R1 is hydrogen, halo or methoxy, R2 is hydrogen, halo, methyl, ethyl or methoxy, R5 and R6 are both hydrogen, and one of R3 or R4 is not halo or trifluoromethyl; or a pharmaceutically acceptable salt or prodrug thereof. These compounds have useful activity for the treatment of inflammatory disease, specifically in antagonizing an MCP-1 mediated effect in a warm-blooded animal such as a human being.
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- Indole derivatives and their use as MCP-1 antagonist
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A compound of formula (1) wherein R1 is hydrogen, halo or methoxy, R2 is hydrogen, halo, methyl, ethyl or methoxy; R3 is carboxy, tetrazolyl, or —CONHSO2R4where R4is methyl, ethyl, phenyl, 2,5-dimethylisoxazolyl or trifluoromethyl; T is —CH2— or —SO2—; and ring A is 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrid-5-yl; or a pharmaceutically acceptable salt or prodrug thereof, as well as pharmaceutical compositions containing them are described and claimed. These compounds and compositions are useful in the treatment of disease mediated by monocyte chemoattractant protein-1 or RANTES (Regulated Upon Activation, Normal T-cell Expressed and Secreted), such as inflammatory disease.
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Page/Page column 18-19
(2010/02/06)
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- Induction of apoptosis in cancer cells
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The present invention provides compounds that are inducers or inhibitors of apoptosis or apoptosis preceded by cell-cycle arrest. In addition, the present invention provides pharmaceutical compositions and methods for treating mammals with leukemia or other forms of cancer or for treating disease conditions caused by apoptosis of cells.
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- Indole derivatives as mcp-1 receptor antagonists
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A compound of formula (I) wherein: R1 is hydrogen, halo or methoxy; R2 is hydrogen, halo, methyl, ethyl or methoxy; R3 is a halo group or a trifluoromethyl group; R4 is a halo group or a trifluoromethyl group; R5 is hydrogen or halo; R6 is hydrogen or halo; provided that when R5 and R6 are both hydrogen, and one of R3 or R4 is chloro or fluoro, then the other is not chloro or fluoro; or a pharmaceutically acceptable salt or prodrug thereof. These compounds have useful activity for the treatment of inflammatory disease, specifically in antagonising an MCP-1 mediated effect in a warm-blooded animal such as a human being.
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- First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling
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The first cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor is reported. The inhibitor was obtained by rational modification of a high throughput screening lead with the aid of a S. pneumoniae FabH homology model. This homology model was used to design analogues that would have both high affinity for the enzyme and appropriate aqueous solubility to facilitate cocrystallization studies.
- Daines, Robert A.,Pendrak, Israil,Sham, Kelvin,Van Aller, Glenn S.,Konstantinidis, Alex K.,Lonsdale, John T.,Janson, Cheryl A.,Qiu, Xiayang,Brandt, Martin,Khandekar, Sanjay S.,Silverman, Carol,Head, Martha S.
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- Fatty acid synthase inhibitors
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This invention relates to the use of compounds as inhibitors of the fatty acid synthase FabH.
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Page column 6
(2008/06/13)
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- Fatty acid synthase inhibitors
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This invention relates to the use of compounds as inhibitors of the fatty acid synthase FabH.
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- Indole compounds useful for treating bacterial infections
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This invention relates to the use of compounds as inhibitors of the fatty acid synthase FabH useful in treating bacterial infections.
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- Product based on inorganic or organic lamellar particles, containing a melanotic pigment, process for preparing it and its use in cosmetics
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The invention relates to a product in powder form consisting of organic or inorganic particles having a lamellar structure, having a size of less than 50 microns and containing at least one synthetic melanotic pigment formed in situ by oxidation of an indole compound, and to its use for the protection of the human epidermis, in make-up products and for dyeing hair.
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- Process for dyeing keratin fibres with a monohydroxyindole associated with an iodide and hydrogen peroxide
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Process for dyeing keratin fibres consisting in applying on these fibres a composition (A) containing at least one indole colorant of formula: STR1 where R1 =H or C1 -C4 alkyl; R2 and R3, which may be identical or different, denote H, C1 -C4 alkyl, carboxyl or alkoxycarbonyl; or a salt or a precursor of a compound (I), associated, either with iodide ions, or with H2 O2 ; application of composition (A) being preceded or followed by the application of a compound (B) which contains, either H2 O2 at a pH of 2 to 12 when (A) contains iodide ions, or iodide ions at a pH of 2 to 11 when (A) contains H2 O2. This process allows particularly powerful and resistant dyes to be made.
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