SYNTHESIS OF 1-BENZYL-3-[4-(ARYL-1-PIPERAZINYL) CARBONYL]-1H-INDOLES: NOVEL LIGANDS WITH POTENTIAL D4 DOPAMINERGIC ACTIVITY

J. Chil. Chem. Soc., 56, Nº 4 (2011) SYNTHESIS OF 1-BENZYL-3-[4-(ARYL-1-PIPERAZINYL) CARBONYL]-1H-INDOLES. NOVEL LIGANDS WITH POTENTIAL D4 DOPAMINERGIC ACTIVITY HERNÁN PESSOA-MAHANA1*, IGNACIO CUEVAS M.1, C. DAVID PESSOA-MAHANA2. RAMIRO ARAYAMATURANA1, IRIUX ALMODOVAR FAJARDO, AND CLAUDIO SAITZ BARRÍA1 Department of Organic and Physical Chemistry , Faculty of Chemical and Pharmaceutical Sciences, University of Chile. Casilla 233. Santiago 1. Chile. 2 Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile. Casilla 306. Santiago 22 . Chile. (Received: December 26, 2010 - Accepted: November 24, 2011) 1 ABSTRACT The synthesis of a series of functionalized 1-Benzyl-3-[4-Aryl-1-piperazingl]carbonyl-1H-Indoles 6(a-f), as a potential new class of bioactive ligands at D4 receptors is reported. The synthetic strategy took place through a five steps sequence to provide indole amides 6(a-f) in 75-92% yield. Keywords : Indole, Arylpiperazines, dopaminergic activity. INTRODUCTION The indole ring system is present in many biologically active medicinal agents and natural products1-3. The first synthesis of substituted indoles was conducted by Fischer and Jourdan as early as 1883, and since then the bicyclic heteroaromatic core has been the target of many synthetic approaches and reactivity studies.4-7 Indoles are also prominent structural elements in the neurotransmitter serotonin, the antiinflammatory drug indomethacin and other molecules showing promise in the treatment of cardiovascular disease, erectile dysfunction, cancer and neurological conditions such as the Alzheimer’s disease8-10. Interesting investigations on the role of dopaminergic system in the ethiology of neurological and psychiatric disorders such as Parkinson´s disease and schizophrenia have been carried out in the last years11. In the course of these studies, and in an attempt to improve the activity of 3-(4-phenylpiperazin1-yl-methyl) indole (I) on D4 receptors (Fig.1). Troschütz12 and Gmeiner13 have synthesized a series of new phenylpiperazinylmethyl indole derivatives. The 2-arylpiperazinylindolecarboxylates (II) displayed high affinity and great selectivity for the human dopamine D4 receptor over the other dopamine receptor subtypes. For instance the Ki value for compound (II), R=H was 1.9 nM (D4) over (D1,D2 and D3 > 2000 nM). Considering the above results, and given our interest in the synthesis of neurobioactive indoles, we carry out the preparation of a new series of indolepiperazines (III) based on the incorporation of an amide function between the arylpiperazine14 and the indole framework. Selectivity studies respect to D4 binding affinity15, recognize the preference of compounds type (I) bearing substituents with a large negative region (COOEt, CN, CHO, CH=NOH), which are naturally not well tolerated by the other D-receptors. In such sense, this new structural function may reinforce the stability of the ligand-receptor D4-complex, acting both as a hydrogen bond acceptor and providing the negative region required for D4 receptor selectivity as well. To the best of our knowledge, these are the first examples of indoles amide connected to arylpiperazines, which will be pharmacologically evaluated in a near future. In this article we report the synthesis in good yield of a series of 1-benzyl-3-[4-Aryl-1-piperazingl]carbonyl-1H-Indoles, with potential biological interest in D4 dopaminergic receptors. 866 X= CH ; R= 2-OMe, 3-OMe, 4-F, 4-NO2, H. X= N ; R =H. RESULT AND DISCUSSION The N-benzyl-3-(4-aryl-1-piperazingl)carbonyl-1(H)-indoles (I) were obtained as follows: commercially available, indole (1) was subjected to a Vilsmeier-Haack formilation to provide 1H-Indole-3-carbaldehyde (2) in 85% yield. The aldehyde function was clearly detected in IR by its strong absorption band at 1634 cm-1 in accord with their aromatic and highly polar character, the 1H-NMR displayed a singlet signal at δ: 9.9 ppm. With the purpose to avoid secondary reactions such as N-oxidation, we decided to protect the indolic N-H, using benzyl bromide in dry DMF at 5 °C, the reaction gave the N-Benzyl derivative (3) as a crystalline solid in 75 % yield (Scheme 1). The electron-withdrawing effect of the formyl group on the indole ring, enhanced the acidity of the NH, facilitating the proton abstraction and N- substitution. Scheme 1. Preparation of 1-Benzyl-1H- indole-3-carbaldehyde(3). Oxidation of (3) with KMnO4 in acetone-water (1:1) mixture, aforded the indole carboxylic acid derivative (4), (Scheme 2) which exhibited in IR the characteristic O-H absorption at 3420-2550cm-1, along with a strong signal at 1655 cm-1 for the carboxylic function. At this point, it is interesting to comment that a first approach considered the preparation of 3-acyl halide indole (4-a), which would react in a second step with appropriate series of arylpiperazines. e-mail: J. Chil. Chem. Soc., 56, Nº 4 (2011) However, this reaction was unsuccessful giving a red-dark syrup displaying many products on thin layer chromatography, even under different experimental conditions. A probable explanation may arise of a policondensation reaction between the indolic rings under the acidic medium. The mass spectrum analysis for indoles 6(a-f) showed the presence of a fragment (m/z) at 233.95 which can be explained assuming an α-cleavage fragmentation pattern of an amide. The major fragment in this series involved a fragment (m/z) at 90.97 which may arise from a N-debenzylation cleavage to yield the base peaks (100%). Finally, the N-debenzylation reaction of the indoles 6 (a-f) will be carried out after the biological proofs, taking into account a possible favorable π- π interaction of the N-benzylic aromatic ring with aromatic aminoacidic residues with the receptor. CONCLUSION In conclusion new arylpiperazine indole derivatives have been synthesized in good yield, the utilized strategy provides an efficient method for the preparation of potentially bioactive ligands. Further efforts focused on the synthesis of new indole derivatives with potential biological relevance, along with neurobiological screening of the synthesized compounds are in progress. EXPERIMENTAL SECTION Thus, we decided to utilize the reaction of (4) with N,N´dicyclohexylcarbodiimide (DCC). Treatment of (4) with DCC in anhydrous CH2Cl2, gave the indole intermediate (5) in quantitative yield (Scheme 2), the 1 H NMR signals at δ: 0.8-2.0 ppm for twenty protons, indicated the presence of the cyclohexyl rings. The signals at δ: 3.51 ppm (m, 1H, CHNH), and δ: 4.304.37 ppm (m,1H, CHN=) suported the methine protons. Scheme 2. Synthesis dicyclohexyl-isourea. of 2-(1-Benzyl-1H-indole-3-carbonyl)-1,3- Finally, the indole (5) was cleanly converted to the corresponding 1-benzyl-3-[4-aryl-1-piperazingl]carbonyl-1H-indoles 6(a-f) in good yield 6592 % by reaction with a series of commercially available arylpiperazines. Formation of series 6(a-f) was mainly supported i (...truncated)