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A Straightforward Route to Enantiopure Pyrrolizidines And

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A Straightforward Route to Enantiopure Pyrrolizidines And Molecules 2001, 6, 784-795 molecules ISSN 1420-3049 http://www.mdpi.org Biologically Active 1-Arylpiperazines. Synthesis of New N-(4- Aryl-1-piperazinyl)alkyl Derivatives of Quinazolidin-4(3H)-one, 2,3-Dihydrophthalazine-1,4-dione and 1,2-Dihydropyridazine- 3,6-dione as Potential Serotonin Receptor Ligands Piotr Kowalski1,*, Teresa Kowalska1, Maria J. Mokrosz2, Andrzej J. Bojarski2 and Sijka Charakchieva-Minol2 1 Institute of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska str., 31-155 Cracow, Poland; 2 Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna str., 31-343 Cracow, Poland * Author to whom correspondence should be addressed; e-mail: [email protected] Received: 26 February 2001; in revised form: 28 August 2001 / Accepted: 28 August 2001 / Published: 31 August 2001 Abstract: The synthesis of a series of new n-propyl and n-butyl chain containing 1-aryl- piperazine derivatives of quinazolidin-4(3H)-one (7) 2-phenyl-2,3-dihydrophthalazine-1,4- dione (8) and 1-phenyl-1,2-dihydropyridazine-3,6-dione (9) as potential serotonin receptor ligands is described. Keywords: Arylpiperazines, lactams, serotonin receptor ligands. Introduction Early studies by Hibert et al. have shown that there are two basic pharmacophore groups common to all five classes of 5-HT1A receptor ligands: a basic nitrogen atom and an aromatic ring with its centre positioned at a distance of 5.2-5.7 Å [1]. Since then several attempts have been made to extend that model, but the large diversity of ligand structures made definition of general interaction modes Molecules 2001, 6 785 impossible. In consequence, a search for other pharmacophore groups was limited to single classes or subgroups of ligands [2-5]. In the case of 1-arylpiperazine derivatives – the biggest and thoroughly investigated class of 5-HT1A receptor ligands [6] – an amide moiety [7] or an amide oxygen atom [8] was suggested as a third interaction point; however, the authors developed those models on the basis of a relatively small group of compounds. Extensive CoMFA investigation of a large set of 1- arylpiperazine derivatives has revealed that in this third interaction region different forces, e.g. steric, electrostatic or lipophilic, may influence the ligand-receptor complex formation [9]. Since the role of the amide fragment in ligand-receptor interactions is still unclear systematic structure affinity relationship studies are necessary. Recently we described the synthesis and pharmacological results concerning new arylpiperazine derivatives with systematic modifications in the amide part, i.e. 1-arylpiperazine derivatives of benzoxazinone 1-4, benzoxazolinone 5 and benzoxazolindione 6 [10]. O O O O N O N O R N O N O O 1 2; R = H 5 6 3; R = Cl 4; R = CH3 a: (CH2)3 NN d: (CH2 )4 NN Cl Cl b: (CH2 )3 NN e: (CH2 )4 NN c: (CH2)3 NN f: (CH2 )4 NN CH3O CH3 O The majority of these compounds have a distinct affinity for 5-HT1A and/or 5-HT2A receptor binding sites. Radioligand binding studies have shown that compounds 1b, 2a-b, 2d-e, 4b and 6e-f have a good (Ki = 1.25 - 40 nM) and compounds 1a, 3a-b and 5a-b a moderate (Ki = 72-110 nM) affinity for 5- HT1A receptors. The 5-HT2A affinity of the obtained compounds was within a range of Ki = 18 - 495 nM. On the other hand Buspirone – {4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-8-azaspiro[4.5]decane- 7,9-dione – approved as the anxiolytic drug, and its two analogues Ipsapirone and Gepirone bind with high affinity and selectivity to 5-HT1A serotonin receptor sites. Therefore, in order to throw more light on ligand – 5-HT1A receptor interactions we designed new model 1-phenylpiperazine and 1-(2- pyrimidinyl)piperazine derivatives with systematic structural changes within the terminal amide part. Molecules 2001, 6 786 O N N (CH2)4 N N N O BUSPIRONE O O N N CH3 N (CH2)4 N N N (CH2)4 N N S N CH3 N O O O IPSAPIRONE GEPIRONE Results and Discussion We present in this paper the synthesis of new N-[3-(4-aryl-1-piperazinyl)propyl] or N-[4-(4-aryl-1- piperazinyl)butyl] derivatives of quinazolidin-4(3H)-one (7a-d), 2-phenyl-2,3-dihydrophthalazine-1,4- dione (8a-d) and 1-phenyl-1,2-dihydropyridazine-3,6-dione (9a-d) (Scheme 1) in which the length of a spacer, arylpiperazine and terminal amide fragment were systematically modified. Preliminary investigation results on affinities of obtained compounds for 5HT1A and 5HT2A receptor sites are also presented. O O O N N N N N N Ph Ph O O 7 8 9 a:(CH2 )3 NN c: (CH2 )4 NN N N b: (CH2 )3 NN d: (CH2 )4 NN N N Scheme 1. Starting materials quinazolidin-4(3H)-one (7), 2-phenyl-2,3-dihydrophtalazine-1,4-dione (8) and 1- phenyl-1,2-dihydropyridazine-3,6-dione (9) were obtained according to procedures described in the literature. Quinazolidin-4(3H)-one (7) was obtained from antranilic acid [11], 2-phenyl-2,3- dihydrophtalazine-1,4-dione (8) from ftalic anhydride [12], while 1-phenyl-1,2-dihydropyridazine-3,6- dione (9) from maleic anhydride [13]. Molecules 2001, 6 787 O O O O (CH2)X (CH2) H N n N n N N + N N N N ; n = 3, ; n = 4 ; n = 3, ; n = 4 7 12 13 14 15 X = Cl X = Br O O O O H 10; Cl(CH2)3Br (CH2)X (CH2) N N n N n N K2CO3/KI/CH3CN + N N N N Ph or 11; Br(CH2)4Br Ph Ph Ph K CO /KI/CH CN O 2 3 3 O O O 8 16; n = 3, 17; n = 4 18; n = 3, 19; n = 4 X = Cl X = Br O O O O H (CH )X (CH2)n N N 2 n N N + N N N N Ph Ph Ph Ph O O O O 9 20; n = 3, 21; n = 4 22; n = 3, 23; n = 4 X = Cl X = Br Scheme 2. Compounds 7a-d, 8a-d, 9a-d were prepared by a two-step procedure. Alkylation of 7-9 with 1- bromo-3-chloropropane (10) or 1,4-dibromobutane (11) in the presence of K2CO3 in acetonitrile led to the formation of halogen intermediates 12, 13, 16, 17, 20 and 21 (Scheme 2). In the reaction, symmetrically disubstituted derivatives 14, 15, 18, 19, 22 and 23, were also formed as byproducts. When in a place of 1-bromo-3-chloropropane (10) 1,3-dibromopropane was used, increased yields of the disubstituted derivatives (14, 18 and 22) have been observed. The yields, melting points, and 1H- NMR signals observed in the regions characteristic of CH2X and CH2NC=O protons as well as absorption of the carbonyl group in IR spectra of obtained compounds 12-23 are collected in Table 1. The presence of the carbonyl group in the compounds 12-15 is confirmed by the absorptions found in the usual carbonyl region at 1658-1680 cm-1. The 1H-NMR spectra of compounds 12-13 display typical signals arising from the methylene hydrogens in the -CH2X and -CH2NC=O fragments, while disubstituted derivatives 14 and 15 gave 1H-NMR spectra in which two equivalent methylene 1 hydrogens have been detected in the -CH2NC=O fragment. The above analysis of the H-NMR and IR spectra indicated that under the applied reaction conditions quinazolidin-4(3H)-one (7) undergoes N- substitution. Application of the same reaction conditions to alkylation of 2-phenyl-2,3- dihydrophthalazine-1,4-dione (8) and 1-phenyl-1,2-dihydropyridazine-3,6-dione (9) results in Molecules 2001, 6 788 formation of the N-substituted derivatives 16-19 and 20-23 respectively, in agreement with both our own and literature reports on the structural determination of substituted lactams [14-21]. Table 1. Reaction yields, physical properties and spectral data of halogen- (12, 13, 16, 17, 20 and 21) and disubstituted derivatives (14, 15, 18, 19, 22 and 23) of quinazolidin-4(3H)-one (7), 2-phenyl-2,3-dihydrophthalazine-1,4-dione (8) and 1-phenyl-1,2-dihydropyridazine-3,6-dione (9). Comp. Yield M.p. Crystallization 1H-NMR, δ (ppm) IR, (cm-1) o No. % [ C] solvent CH2XCH2NC=O C=O 12 51 105-107 methanol 3.61, t, 2H 4.20, t, 2H 1665 13 69 86-88 methanol 3.45, t, 2H 4.05, t, 2H 1658 14 5.3 194-196 methanol - 4.23, t, 4H 1672 15 11 223-225 ethanol - 4.10, t, 4H 1680 16 67 80-82 methanol 3.78, t, 2H 4.52, t, 2H 1656 17 49 65-67 methanol 3.52, t, 2H 4.39, t, 2H 1657 18 6.3 145-147 ethanol - 4.61, t, 4H 1669 19 28 241-243 DMF - 4.49, t, 4H 1657 20 65 70-72 acetone 3.70, t, 2H 4.33, t, 2H 1671 21 53 62-65 methanol 3.46, t, 2H 4.20, t, 2H 1670 22 7.1 202-204 methanol - 4.33, t, 4H 1659 23 13 165-167 ethanol - 4.23, t, 4H 1677 Target compounds 7a-d, 8a-d, 9a-d were obtained upon condensation of intermediates 12, 13, 16, 17, 20 or 21 with 1-phenylpiperazine (24) or 1-(2-pyrimidinyl)piperazine (25), respectively (Scheme 3). 7a - d, 12 or 13 or 16 or K2CO3 + HNN Ar 8a - d, 17 or 20 or 21 CH3CN 9a - d 24; Ar = N 25; Ar = N Scheme 3.
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