- Synthesis of new bridged tetrahydro-β-carbolines and spiro-fused quinuclidines
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Two series of chemically related, conformationally restricted ring systems were synthesized. Bridged tetrahydro-β-carbolines, designed as selective 5-HT receptor ligands, were formed via Pictet-Spengler condensation of cyclic tryptamine precursors. Oxidation of the indole 2-position of the precursors followed by condensation with aldehydes produced spiro-cyclic quinuclidines, containing important muscarine receptor pharmacophores.
- Burm, Brigitte E.A,Gremmen, Christiaan,Wanner, Martin J,Koomen, Gerrit-Jan
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- Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect
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A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT1A/D2/5-HT2A/5-HT6/5-HT7 receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT1A receptors (e.g., 4c Ki = 2.3 nM, 4l Ki = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT1A receptor) exhibited promising affinities for the 5-HT1A/SERT/D2/5-HT6/5-HT7 receptors and showed an antidepressant-like activity in the FST model.
- Wróbel, Martyna Z.,Chodkowski, Andrzej,Herold, Franciszek,Marciniak, Monika,Dawidowski, Maciej,Siwek, Agata,Starowicz, Gabriela,Stachowicz, Katarzyna,Szewczyk, Bernadeta,Nowak, Gabriel,Belka, Mariusz,B?czek, Tomasz,Sata?a, Grzegorz,Bojarski, Andrzej J.,Tur?o, Jadwiga
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- Substituted heterocyclic compounds and application of same to medicines
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The invention relates to substituted heterocyclic compounds and application of the same to medicines and specifically provides the novel substituted heterocyclic compounds or stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and preparation methods thereof. The invention also relates to pharmaceutical compositions containing the compounds and application of the compounds or pharmaceutical compositions to treatment of diseases related to 5-HT6 receptors, especially Alzheimer's disease.
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- Substituted heterocyclic compounds and its application on the medicament (by machine translation)
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The invention relates to substituted heterocyclic compounds and its application on the medicament, in particular to a novel class of substituted heterocyclic compounds or its isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, and their method of preparation. The invention also relates to the compounds of the invention pharmaceutical composition, and said compound or pharmaceutical compositions for the treatment5-HT6receptor-related diseases, in particular Alzheimer's disease in the use thereof. (by machine translation)
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- PHARMACEUTICAL COMPOUND
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Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises the following formula: wherein X2, X4, X10, and X11 may be the same or different and each is independently selected from C and N; X1, X3, X5, X6, X7, X8, and X9 may be the same or different and each is independently selected from C, N and O; each bond having a dotted line may independently be a double bond or a single bond, provided that valencies at each atom are maintained; the dotted lines joining X4 with the carbon atoms either side of X2 are single bonds, and are only present when X2 is absent, X3 is absent and X4 is C, and when these bonds are present the ring carbons on each side of X2 are not directly bonded to each other; each R1 may be present or absent and may be the same or different and is selected from H and a substituted or unsubstituted organic group, provided that the number of R1 groups present is such that the valency of X1 is maintained; each R12, R13, R13', R14, R15 and R15 may be present or absent and may be the same or different and each is independently selected from H and a substituted or unsubstituted organic group, provided that the number of such R groups present is such that the valency of the ring carbon atoms is maintained; R16 may be present or absent and is selected from H and a substituted or unsubstituted organic group, provided that the number of R16 groups present is such that the valency of X2 is maintained; each R17 may be present or absent and may be the same or different and is independently selected from H and a substituted or unsubstituted organic group, provided that the number of R17 groups present is such that the valency of X3 is maintained; each R2, R3, R4, and R5 may be present or absent and may be the same or different and is selected from H and a substituted or unsubstituted organic group, provided that the number of such R groups present is such that the valencies of X6, X7, X8, and X9 are maintained; each R7, R8 and R9 may be present or absent and may be the same or different and is selected from H and a substituted or unsubstituted organic group, provided that the number of such R groups present is such that the valencies of X10, X11, and X5 are maintained; and R6 is selected from H and a substituted or unsubstituted organic group, preferably H and a substituted or unsubstituted C1-C6 alkyl group; and wherein any R group may form a ring with any other R group on an adjacent and/or proximal atom.
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Page/Page column 142-143
(2015/06/18)
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- Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype
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A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values ～ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs.
- Santos, Sofia A.,Lukens, Amanda K.,Coelho, Lis,Nogueira, Fátima,Wirth, Dyann F.,Mazitschek, Ralph,Moreira, Rui,Paulo, Alexandra
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p. 320 - 333
(2015/09/01)
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- Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents. Part 1
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A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated. The chemical structures of the newly prepared compounds were confirmed by 1H NMR, 13C NMR and ESI-HRMS spectra data. All tested compounds proved to be potent 5-HT1A receptor and serotonin transporter protein (SERT) ligands. Among them, compounds 15, 18, 19 and 30 showed significant affinity for 5-HT1A and SERT. Computer docking simulations carried out for compounds 15, 31 and 32 to models of 5-HT1A receptor and SERT confirm the results of biological tests. Due to high affinity for the 5-HT1A receptor and moderate affinity for SERT, compounds 31, 32, 35, and 37 were evaluated for their affinity for D2L, 5-HT6, 5-HT 7 and 5-HT2A receptors. In vivo tests, in turn, resulted in determining the functional activity of compounds 15, 18, 19 and 30 to the 5-HT1A receptor. The results of these tests indicate that all of the ligands possess properties characteristic of 5-HT1A receptor agonists.
- Wróbel, Martyna Z.,Chodkowski, Andrzej,Herold, Franciszek,Gomó?ka, Anna,Kleps, Jerzy,Mazurek, Aleksander P.,Pluciński, Franciszek,Mazurek, Andrzej,Nowak, Gabriel,Siwek, Agata,Stachowicz, Katarzyna,S?awin?ska, Anna,Wolak, Ma?gorzata,Szewczyk, Bernadeta,Sata?a, Grzegorz,Bojarski, Andrzej J.,Tur?o, Jadwiga
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p. 484 - 500
(2013/07/25)
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- DIPHENYLBUTYPIPERIDINE AUTOPHAGY INDUCERS
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Autophagy inducing compounds, methods of their preparation and use, and kits containg said compounds are disclosed herein.
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Page/Page column 7; 87-90
(2011/12/02)
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- Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity, Part 1
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A series of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine containing the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy derivative were synthesized. They were characterized (i) in vitro by binding to 5-HT1A receptors and 5-HT transporter proteins in rat brain cortex membranes and (ii) in vivo in the mouse by induced hypothermia and forced swimming models for antagonist/agonist activity against the 5-HT1A autoreceptors and postsynaptic 5-HT1A receptors, respectively. Structure activity relationship evaluation indicated that the presence of the 3-(4-piperidyl)-1H-indole residue and ortho- or para-substituents with -F or -CH3 groups in the aryl ring as well as an unsubstituted aryl in the 4-aryl-pyrido[1,2-c]pyrimidine moiety promoted low Ki values for both receptors. In contrast, the presence of a 5-methoxy-3-(4-piperidyl)-1H-indole residue as well as -Cl or -OCH3 substituents at the para position markedly reduced the receptor affinity.
- Herold, Franciszek,Chodkowski, Andrzej,Izbicki, Lukasz,Krol, Marek,Kleps, Jerzy,Turlo, Jadwiga,Nowak, Gabriel,Stachowicz, Katarzyna,Dybala, Malgorzata,Siwek, Agata
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experimental part
p. 1710 - 1717
(2009/05/26)
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- Polystyrene sulfonyl chloride: A highly orthogonal linker resin for the synthesis of nitrogen-containing heterocycles
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One linker, broad application: A simple sulfonamide linker for primary and secondary amines was used for the construction of small libraries of privileged indole and quinolone structures on a solid phase. After the synthesis, the products can be liberated ion a traceless manner under electron transfer conditions or according to a "safety catch" principle.
- Mentel, Matthias,Schmidt, Axel M.,Gorray, Michael,Eilbracht, Peter,Breinbauer, Rolf
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supporting information; experimental part
p. 5841 - 5844
(2009/12/08)
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- 3-PIPERIDIN-4-YL-INDOLE ORL-1 RECEPTOR MODULATORS
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The present invention is directed to novel 3-piperidin-4-yl-indole derivatives of formula (I) and forms thereof, wherein X, R1, R2, R3, R4 and R5 are as herein defined, pharmaceutical compositions thereof and use as ORL-1 receptor modulators for treating, preventing or ameliorating ORL-1 receptor mediated disorders and conditions.
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Page/Page column 49
(2008/06/13)
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- Synthesis and structure-activity relationships of novel histamine H 1 antagonists: Indolylpiperidinyl benzoic acid derivatives
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A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H1 antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT2 receptor. Extensive optimization was carried out within this series and a number of histamine H1 antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48, 51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
- Fonquerna, Silvia,Miralpeix, Montse,Pagès, Lluís,Puig, Carles,Cardús, Arantxa,Antón, Francisca,Cárdenas, álvaro,Vilella, Dolors,Aparici, Mónica,Calaf, Elena,Prieto, José,Gras, Jordi,Huerta, Josep M.,Warrellow, Graham,Beleta, Jorge,Ryder, Hamish
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p. 6326 - 6337
(2007/10/03)
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- 4-SUBSTITUTED 1-AMINOCYCLOHEXANE DERIVATIVES FOR UTILIZATION AS ORL1-RECEPTOR AND MU-OPIATE RECEPTOR LIGANDS
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The invention relates to 4-substituted 1-aminocyclohexane derivatives of general formula (I), to a method for the production thereof, to medicaments containing said compounds and to the utilization of 4-substituted 1-aminocyclohexane derivatives for the production of medicaments.
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Page/Page column 30
(2008/06/13)
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- INDOLYLPIPERIDINE DERIVATIVES AS ANTIHISTAMINIC AND ANTIALLERGIC AGENTS
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The invention relates to indolyl piperidinyl derivatives of formula (I) wherein: A1 represents an alkylene, alkyleneoxy, alkylenethio, alkanoylene or hydroxyalkylene group; A2 represents an alkylene, alkyleneoxy, alkylenethio, alkanoylene or an alkyleneoxyalkylene group; W1 represents a phenylene, furanylene or pyridinylene group which is unsubstituted or substituted by one or more halogen atoms, alkoxy groups and/or alkyl groups; W2 represents a 3-10 membered monocyclic or bicyclic group containing from 1 to 3 heteroatoms said group being unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups and/or oxo groups; R1 represents a hydrogen or halogen atom or an alkyl, alkoxy or methylamino group; and R2 represents a carboxyl group; and pharmaceutically acceptable salts thereof; to processes for their preparation; to pharmaceutical compositions containing them; and to their medical use as antihistaminic and antiallergic agents.
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- NEW INDOLYLPIPERIDINE DERIVATIVES AS POTENT ANTIHISTAMINIC AND ANTIALLERGIC AGENTS
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This invention is directed to new potent and selective antagonists of H1 histamine receptors having the general formula (I) to processes for their preparation; to pharmaceutical compositions comprising them; and to their use in therapy as antiallergic agents.
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- Indolylpiperidine derivatives as antihistaminic and antiallergic agents
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Indolylpiperidine compounds of formula (I) wherein: A1 represents an alkylene, alkyleneoxy, alkylenethio, alkanoyl or hydroxyalkylene group; A2 represents a single bond, an alkylene or alkenylene group; W represents a single bond or a phenylene or furanylene group which is unsubstituted or substituted by one or more halogen atoms, alkoxy groups and/or alkyl groups; R1 represents a hydrogen atom or an alkyl, alkenyl, alkynyl, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl alkoxy-alkoxyalkyl, phenylalkyl group wherein the phenyl ring is unsubstituted or substituted by one or more halogen atoms or alkyl, alkoxy or arylalkoxy groups, or a cycloalkylalkyl group wherein the cycloalkyl group is unsubstituted or substituted by one or more halogen atoms, alkyl groups or alkoxy groups; R2 represents a hydrogen or halogen atom or an alkyl or alkoxy group; and R3 represents a carboxyl group or a tetrazolyl group; and pharmaceutically acceptable salts thereof, process for their preparation and medicinal use.
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- Dipeptides which promote release of growth hormone
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Compounds of formula (I) are growth hormone releasing peptide mimetics which are useful for the treatment and prevention of osteoporosis. STR1
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- 4-(Indolyl-3)-1-(benzimidazolonylalkyl)-piperidines, a novel group of potential antiallergy compounds
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A group of indolyl-benzimidazolone-piperidines is described and the structure-activity with reference to the passive cutaneous anaphylaxis (PCA) in rats is discussed. Compound 7b, 4-(indolyl-3)-1-(benzimidazolonyl-propyl)-piperidine, which has the highest potency in this test, was studied in more detail with regard to antihistaminic and secretory cell stabilization properties.
- Freter,Fuchs,Barsumian,Oliver
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p. 272 - 276
(2007/10/02)
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