N-(4-Arylpiperazinoalkyl)acetamide derivatives of 1,3- and 3,7-dimethyl-1H-purine-2,6(3H,7H)-diones and their 5-HT6, 5-HT7, and D2 receptors affinity

Paweł Żmudzki 1 , Grzegorz Satała 2 , Grażyna Chłoń-Rzepa 1 , Andrzej J. Bojarski 2 , Piotr Popik 3 ,  and Paweł Zajdel 1
  • 1 Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna, 30-688 Kraków, Poland
  • 2 Institute of Pharmacology, Department of Medicinal Chemistry, Polish Academy of Sciences, 12 Smętna, 31-343 Kraków, Poland
  • 3 Institute of Pharmacology, Department of Behavioral Neuroscience and Drug Development, Polish Academy of Sciences, 12 Smętna, 31-343 Kraków, Poland
Paweł Żmudzki, Grzegorz Satała, Grażyna Chłoń-Rzepa, Andrzej J. Bojarski, Piotr Popik and Paweł Zajdel

Abstract

A series of N-(arylpiperazinyl)acetamide derivatives of 1,3- and 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione was synthesized and biologically evaluated in in vitro competition binding experiments for serotonin 5-HT6, 5-HT7, and dopamine D2 receptors. The structure-affinity relationships for this group of compounds allowed for determination of structural features responsible for receptor affinity. Among the investigated derivatives, compounds 5 and 12 with (2,3-dichlorophenyl)piperazine moiety were classified as potent dual 5-HT6/D2 receptors ligands, whereas compound 4, with 4-(benzo[d]isothiazol-3-yl)piperazine moiety, and compounds 8 and 15, with (2,3-dichlorophenyl)piperazine moiety, were classified as potent D2 receptor ligands.

Introduction

Compounds with affinity for serotoninergic (5-HT6, 5-HT7) and dopaminergic type 2 receptors (D2Rs) exhibit potential for the treatment of diverse central nervous system disorders, e.g., depression [1, 2], schizophrenia [3], as well as dementia [4] and Alzheimer disease [5]. Importantly, derivatives with mixed receptor binding profile, often called serotonin/dopamine modulators, may attenuate both negative, positive symptoms of schizophrenia, as well as improve cognitive deficits [6, 7].

A vast group of compounds with mixed serotonin/dopamine receptor binding profile belongs to a class of long-chain arylpiperazines (LCAPs). Typically, in such derivatives, the arylpiperazine moiety is connected via an alkyl linker to the terminal fragment. For several years, we have been interested in developing of LCAPs with different xanthine moieties playing a role of a cyclic amide core in the terminal fragment. In our previous paper, we have described a series of derivatives possessing 8-alkoxy-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione core, which behaved as 5-HT1A receptors agonists [8].

The aim of our study was to investigate structure-affinity relationships for the 5-HT6, 5-HT7, and D2 receptors in a group of LCAPs with xanthine moieties in the terminal fragment and an additional amide bond in the linker. For this purpose, we have designed a series of new N-(arylpiperazinylalkyl)acetamide derivatives of 1,3- and 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione with a different length polymethylene spacer between the amide moiety and the basic nitrogen atom. Structural modifications in the amine fragment comprised introduction of 1-(2,3-dichlorophenyl)piperazine and 1-(benzo[d]isothiazol-3-yl)piperazine, as substructures related to aripiprazole and ziprasidone (Figure 1), respectively. To further examine an impact of replacement of sulfur atom with oxygen atom on affinity, the analogues with 1-(benzo[d]isoxazol-3-yl)piperazine moiety were also synthesized.

Figure 1
Figure 1

Aripiprazole, ziprasidone, and a general structure of 8-alkoxy-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives [8].

Citation: Heterocyclic Communications 21, 1; 10.1515/hc-2014-0200

Results and discussion

The designed compounds were synthesized in reaction of appropriate xanthinylacetic acids, obtained according to the methods previously reported by Maślankiewicz et al. [9], and arylpiperazinoalkylamines, using 1,1′-carbonyldiimidazole (CDI) as activating agent (Schemes 1 and 2).

In the first step, 1,3- or 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione was alkylated by treatment with ethyl 2-chloroacetate in the presence of anhydrous K2CO3 and TEBA (N,N,N-triethylbenzylammonium chloride) in acetone, yielding ethyl 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetate [9] and 2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetate [9], respectively. The esters were subsequently hydrolyzed with 10% solution of NaOH in a water-acetone mixture (2:1), and the resulting acids were isolated after acidification of the reaction mixture. The final products were obtained by acylation of the appropriate arylpiperazino-(4-(benzo[d]isothiazol-3-yl)piperazino-, benzo[d]isoxazol-3-yl)piperazinyl-, or 4-(2,3-dichlorophenyl)piperazino-) derivative of alkylamine with 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetic acid (I) [9] or 2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (II) [9] at room temperature in DMF, using CDI as activating agent. The structures of the newly synthesized compounds 115 were confirmed by analysis of 1H NMR and 13C NMR spectra, LC/MS, and elemental analysis. The investigated compounds were pharmacologically tested as free bases.

The newly synthesized N-(arylpiperazinylalkyl)acetamide derivatives of 1,3- and 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione were tested in competition binding experiments for 5-HT6, 5-HT7, and D2 receptors. Compounds displayed high to low affinity for the tested receptors, ranging from 14 nm to 100 μm for 5-HT6Rs, from 100 nm to 4789 nm for 5-HT7Rs, and 1–2090 nm for D2Rs (Tables 1 and 2).

Table 1

Binding affinities of the synthesized N-(arylpiperazinoalkyl)acetamide derivatives of 1,3-dimethyl-1H-purine-2,6(3H,7H)-dione for 5-HT6, 5-HT7, and D2 receptors. article image

CompoundnRKi (nm)a
5-HT65-HT7D2
12Benzo[d]isothiazol-3-yl1873999273
22Benzo[d]isoxazol-3-yl230210081474
322,3-Dichlorophenyl8273056542
43Benzo[d]isothiazol-3-yl2081102
532,3-Dichlorophenyl142247
64Benzo[d]isothiazol-3-yl114410037
74Benzo[d]isoxazol-3-yl1329121219
842,3-Dichlorophenyl26326816
Aripiprazoleb90260.8
Ziprasidone2010.8

aKi values (SEM±26) based on three independent binding experiments.

bFrom reference [10].

Table 2

Binding affinities of the synthesized N-(arylpiperazinoalkyl)acetamide derivatives of 3,7-dimethyl-1H- purine-2,6(3H,7H)-dione for 5-HT6, 5-HT7, and D2 receptors. article image

CompoundnRKi (nm)a
5-HT65-HT7D2
92Benzo[d]isothiazol-3-yl48782176401
102Benzo[d]isoxazol-3-yl>100 00011022090
1122,3-Dichlorophenyl10664789104
1232,3-Dichlorophenyl223812
134Benzo[d]isothiazol-3-yl39317835
144Benzo[d]isoxazol-3-yl626125339
1542,3-Dichlorophenyl851831
Aripiprazoleb90260.8
Ziprasidone2010.8

aKi values (SEM±26) based on three independent binding experiments.

bFrom reference [10].

The affinity for 5-HT6 and D2 receptors depended on the type of the xanthine core: 1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives displayed higher affinity for 5-HT6 and D2 receptors than their 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione counterparts, e.g., compound 8 vs. compound 15 (Ki(D2) = 85 and 1 nm, respectively). Interestingly, a type of the xanthine core did not significantly influence affinity for 5-HT7Rs.

The impact of the length of the polymethylene spacer between the amide moiety and the basic nitrogen atom was evident: compounds with trimethylene spacer displayed the highest affinity for 5-HT6 and D2 receptors. Compounds 4 and 5 displayed over 9- and 59-fold higher affinity for 5-HT6 receptors than their lower homologues, compounds 1 and 3, respectively, and over 5- and 18-fold higher affinity than their higher homologues, compounds 6 and 8. Although a dimethylene group spacer was the least preferential for 5-HT7Rs, trimethylene, and tetramethylene analogues display comparable affinity for these sites.

Further analysis of the affinity data suggested that replacement of carbostyryl fragment in aripiprazole with xanthinylacetamide moiety increased affinity of 2,3-dichlorophenylpiperazines for 5-HT6Rs (compounds 5 and 12 vs. aripiprazole). At the same time, this modification significantly decreased affinity for 5-HT7Rs. As a consequence, compounds 5 and 12 were classified as potent 5-HT6/D2 receptor ligands. The same modification of ziprasidone structure significantly increased the affinity for 5-HT6 and 5-HT7 receptors, while this effect was much smaller in case of D2 receptors (4 vs. ziprasidone).

Structure-activity relationship studies in the arylpiperazine function suggested that highly lipophilic 1-(2,3-dichlorophenyl)piperazine moiety guaranteed high affinity for 5-HT6 and D2Rs. Compounds with 1-(benzo[d]isothiazol-3-yl)piperazine moiety displayed lower affinity for these receptors. Further substitution of the sulfur atom in 1-(benzo[d]isothiazol-3-yl)piperazine with oxygen atom, which decreased the lipophilicity of the fragment, also caused further loss of affinity. This can be easily observed with direct structural analogues 15 vs. 13 vs. 14, containing 4-(2,3-dichlorophenyl)piperazino, 4-(benzo[d]isothiazol-3-yl)piperazino, and 4-(benzo[d]isoxazol-3-yl)piperazino moieties, respectively. Simultaneously, an influence of arylpiperazine moiety on the affinity for 5-HT7 receptors suggested that generally less lipophilic substituents were preferred, but this influence was much weaker than for 5-HT6 and D2 receptors, e.g., compound 15 had comparable affinity for 5-HT7Rs to those of compounds 13 and 14.

Conclusions

We have designed and synthesized a series of 15 new N-(arylpiperazinylalkyl)acetamide derivatives of 1,3- and 3,7-dimethyl-1H-purine-2,6(3H,7H)-diones. The study allowed for identification of potent 5-HT6/D2 receptor ligands (compounds 5 and 12) and D2 receptor agents (compounds 4, 8, and 15). Structure-affinity relationships studies showed that the 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione core, a polymethylene spacer containing three methylene groups, and 2,3-dichlorophenypiperazine were the optimal elements for high affinity for 5-HT6 and D2 receptors.

Experimental

Melting points (mp) were determined with a Büchi Melting Point B-545 apparatus and are uncorrected. 1H NMR and 13C NMR spectra were taken with a Varian Mercury-VX (300 MHz) spectrometer in DMSO-d6 solutions, using signals of solvent’s residual 1H and 13C atoms as internal standards (δ = 2.49 and 39.7 ppm, respectively). LC/MS analyses were performed on Waters Acquity TQD apparatus with eλ DAD detector. For mass spectrometry, ESI+ (electrospray positive) ionization mode was used. The progress of the reactions and the purity of compounds were routinely checked by TLC using Merck Kieselgel 60 F254 sheets and eluting with dichloromethane/methanol, 90:10. Spots were detected by UV irradiation. All final compounds had purity over 95%. Elemental analyses were taken with Elementar Vario EL III apparatus. All in vitro radioligand binding assays were carried out using methods published by Zajdel et al. [10].

General procedure for preparation of N-(arylpiperazino)acetamide derivatives of 1,3- and 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione 1–15

A mixture of 1 equiv (0.0004 mol) of 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetic acid (I) or 2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (II) with 1.5 equiv of CDI in DFM was stirred in room temperature for 1 h. Afterward, 1 equiv of appropriate amine was added, and stirring was continued for 48 h. Then the mixture was concentrated under reduced pressure and crude product was purified by silica gel chromatography eluting with dichloromethane/methanol (95:5).

N-[2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl]-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (1):

This compound was obtained from I in 59% yield; mp 218–220°C; Rf = 0.31; 1H NMR: δ 2.53 (t, 3J = 6.2 Hz, 2H), 2.63–2.66 (m, 4H), 3.27 (s, 3H), 3.33 (t, 3J = 6.2 Hz, 2H), 3.45–3.47 (m, 4H), 3.48 (s, 3H), 4.87 (s, 2H), 7.28 (ddd, 3J = 8.1 Hz, 3J = 7.1 Hz, 4J = 1.2 Hz, 1H), 7.39 (ddd, 3J = 8.1 Hz, 3J = 7.1 Hz, 4J = 1.2 Hz, 1H), 7.56–7.58 (m, 1H), 7.69 (s, 1H), 7.70–7.76 (m, 1H), 7.80 (dt, 3J = 8.1 Hz, 4J = 1.0 Hz, 1H); 13C NMR: δ 27.8, 29.7, 36.2, 48.9, 49.6, 52.6, 56.6, 106.9, 120.5, 123.7, 124.0, 127.7, 127.8, 142.8, 148.5, 151.6, 152.4, 155.4, 163.7, 166.1. Anal. Calcd for C22H26N8SO3: C, 54.76; H, 5.43; N, 23.22. Found: C, 54.89; H, 5.25; N, 23.12. LC/MS: calcd m/z 483.19, found m/z 483.32.

N-[2-(4-(Benzo[d]isoxazol-3-yl)piperazino)ethyl]-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (2):

This compound was obtained from I in 61% yield; mp 163–165°C; Rf = 0.31; 1H NMR: δ 2.55 (t, 3J = 6.0 Hz, 2H), 2.60–2.68 (m, 4H), 3.37 (s, 3H), 3.38–3.44 (m, 2H), 3.50–3.56 (m, 4H), 3.57 (s, 3H), 4.90 (s, 2H), 7.12–7.25 (m, 2H), 7.40–7.54 (m, 2H), 7.66 (d, 3J = 8.0 Hz), 7.72 (s, 1H); 13C NMR: δ 28.1, 29.9, 36.4, 48.2, 49.9, 52.1, 56.4, 106.7, 110.5, 116.0, 122.0, 122.4, 129.6, 142.3, 148.9, 151.5, 155.6, 161.1, 164.0, 165.6. Anal. Calcd for C22H26N8O4: C, 56.64; H, 5.62; N, 24.02. Found: C, 56.54; H, 5.29; N, 24.10. LC/MS: calcd m/z 467.21, found m/z 467.37.

N-[2-(4-(2,3-Dichlorophenyl)piperazino)ethyl]-2-(1,3-dimethyl-2,6- dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (3):

This compound was obtained from I in 77% yield mp 222–223°C; Rf = 0.28; 1H NMR: δ 2.44 (t, 3J = 6.3 Hz, 2H), 2.49–2.59 (m, 4H), 2.82–2.96 (m, 4H), 3.21 (s, 3H), 3.24–3.28 (m, 2H), 3.41 (s, 3H), 4.81 (s, 2H), 6.72–6.87 (m, 1H), 6.96–7.07 (m, 2H), 7.60–7.70 (m, 2H); 13C NMR: δ 27.7, 29.6, 36.2, 48.8, 50.7, 52.8, 56.5, 106.9, 118.4, 124.6, 127.2, 127.4, 133.8, 142.8, 148.4, 150.6, 151.6, 155.2, 166.2. Anal. Calcd for C21H25N7O3Cl2: C, 51.02; H, 5.10; N, 19.83. Found: C, 51.20; H, 4.85; N, 19.91. LC/MS: calcd m/z 494.15, found m/z 494.29.

N-[3-(4-(Benzo[d]isothiazol-3-yl)piperazino)propyl]-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (4):

This compound was obtained from I in 58% yield; mp 104–106°C; Rf = 0.40; 1H NMR: δ 1.69–1.79 (m, 2H), 2.52–2.59 (m, 2H), 2.69–2.72 (m, 4H), 3.33–3.42 (m, 2H), 3.36 (s, 3H), 3.53–3.58 (m, 4H), 3.57 (s, 3H), 4.86 (s, 2H), 7.35 (ddd, 3J = 8.4 Hz, 3J = 6.9 Hz, 4J = 1.0 Hz, 1H), 7.46 (ddd, 3J = 8.5 Hz, 3J = 6.9 Hz, 4J = 1.0 Hz, 1H), 7.66–7.69 (m, 1H), 7.70 (s, 1H), 7.80 (dt, 3J = 8.0 Hz, 4J = 0.9 Hz, 1H), 7.87–7.90 (m, 1H); 13C NMR: δ 25.1, 28.0, 29.8, 39.4, 49.8, 50.1, 53.0, 56.9, 106.8, 120.6, 123.8, 124.0, 127.6, 127.9, 142.4, 148.7, 151.5, 152.7, 155.5, 163.7, 165.4. Anal. Calcd for C23H28N8SO3: C, 55.56; H, 5.68; N, 22.56. Found: C, 55.32; H, 5.55; N, 22.51. LC/MS: calcd m/z 497.21, found m/z 497.35.

N-[3-(4-(2,3-Dichlorophenyl)piperazino)propyl]-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (5):

This compound was obtained from I in 61% yield; mp 184–185°C; Rf = 0.25; 1H NMR: δ 1.73 (quin, 3J = 6.4 Hz, 2H), 2.52 (t, 3J = 6.5 Hz, 2H), 2.28–2.77 (m, 4H), 2.99–3.21 (m, 4H), 3.34–3.40 (m, 2H), 3.38 (s, 3H), 3.58 (s, 3H), 4.87 (s, 2H), 6.98 (dd, 3J = 6.7 Hz, 4J = 3.1 Hz, 1H), 7.09–7.18 (m, 2H), 7.73 (s, 1H), 7.77–7.87 (m, 1H); 13C NMR: δ 25.1, 28.0, 29.8, 39.4, 49.8, 51.3, 53.3, 56.7, 106.7, 118.6, 124.7, 127.4, 127.5, 134.0, 142.4, 148.9, 151.0, 151.5, 155.6, 165.3. Anal. Calcd for C22H27N7O3Cl2: C, 51.97; H, 5.35; N, 19.29. Found: C, 51.81; H, 5.12; N, 19.19. LC/MS: calcd m/z 508.16, found m/z 508.32.

N-[4-(4-(Benzo[d]isothiazol-3-yl)piperazino)butyl]-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (6):

This compound was obtained from I in 77% yield; mp 108–109°C; Rf = 0.28; 1H NMR: δ 1.44–1.47 (m, 4H), 2.35 (t, 3J = 7.2 Hz, 2H), 2.58–2.62 (m, 4H), 3.23 (t, 3J = 6.2 Hz, 2H), 3.24 (s, 3H), 3.43–3.46 (m, 4H), 3.45 (s, 3H), 4.82 (s, 2H), 7.25 (ddd, 3J = 8.3 Hz, 3J = 6.8 Hz, 4J = 1.2 Hz, 1H), 7.37 (ddd, 3J = 8.0 Hz, 3J = 7.0 Hz, 4J = 1.2 Hz, 1H), 7.50–7.52 (m, 1H), 7.67 (s, 1H), 7.68–7.69 (m, 1H), 7.78 (dd, 3J = 6.8 Hz, 4J = 1.2 Hz, 1H); 13C NMR: δ 23.5, 26.8, 27.8, 29.6, 39.3, 48.8, 49.6, 52.7, 57.9, 106.9, 120.4, 123.7, 124.0, 127.6, 127.7, 142.9, 148.5, 151.6, 152.4, 155.3, 163.3, 166.0. Anal. Calcd for C24H30N8SO3: C, 56.45; H, 5.92; N, 21.94. Found: C, 56.55; H, 5.87; N, 21.81. LC/MS: calcd m/z 511.22, found m/z 511.37.

N-[4-(4-(Benzo[d]isoxazol-3-yl)piperazino)butyl]-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (7):

This compound was obtained from I in 94% yield; mp 146–147°C; Rf = 0.38; 1H NMR: δ 1.50–1.58 (m, 4H), 2.40 (t, 3J = 6.9 Hz, 2H), 2.60–2.63 (m, 4H), 3.24–3.30 (m, 2H), 3.37 (s, 3H), 3.55–3.58 (m, 4H), 3.57 (s, 3H), 4.86 (s, 2H), 7.20 (ddd, 3J = 8.1 Hz, 3J = 6.4 Hz, 4J = 1.7 Hz, 1H), 7.37 (t, 3J = 5.4 Hz, 1H), 7.40–7.50 (m, 2H), 7.66–7.69 (m, 1H), 7.72 (s, 1H); 13C NMR: δ 23.9, 27.1, 28.1, 29.9, 39.7, 48.1, 50.1, 52.4, 57.9, 106.7, 110.5, 116.1, 122.1, 122.3, 129.5, 142.5, 149.0, 151.4, 155.8, 161.2, 163.9, 165.5. Anal. Calcd for C24H30N8O4: C, 58.29; H, 6.11; N, 22.66. Found: C, 58.48; H, 6.05; N, 22.55. LC/MS: calcd m/z 495.25, found m/z 495.42.

N-[4-(4-(2,3-Dichlorophenyl)piperazino)butyl]-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (8):

This compound was obtained from I in 50% yield; mp 167–169°C; Rf = 0.14; 1H NMR: δ 1.54–1.58 (m, 4H), 2.44 (t, 3J = 6.7 Hz, 2H), 2.55–2.73 (m, 4H), 3.00–3.15 (m, 4H), 3.27 (q, 3J = 5.4 Hz, 2H), 3.39 (s, 3H), 3.59 (s, 3H), 4.86 (s, 2H), 6.96 (dd, 3J = 6.5 Hz, 4J = 3.2 Hz, 1H), 7.07–7.20 (m, 2H), 7.30–7.45 (m, 1H), 7.73 (s, 1H); 13C NMR: δ 24.0, 27.1, 28.1, 29.9, 39.7, 50.1, 51.1, 53.2, 57.8, 106.6, 118.6, 124.7, 127.4, 127.5, 134.0, 142.4, 149.1, 151.1, 151.4, 155.8, 165.3. Anal. Calcd for C23H29N7O3Cl2: C, 52.88; H, 5.60; N, 18.77. Found: C, 53.01; H, 5.38; N, 18.73. LC/MS: calcd m/z 522.18, found m/z 522.34.

N-[2-(4-(Benzo[d]isothiazol-3-yl)piperazino)ethyl]-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide (9):

This compound was obtained from II in 69% yield; mp 235–237°C; Rf = 0.33; 1H NMR: δ 2.54 (t, 3J = 6.2 Hz, 2H), 2.64–2.67 (m, 4H), 3.34 (t, 3J = 6.2 Hz, 2H), 3.43–3.46 (m, 4H), 3.47 (s, 3H), 3.87 (s, 3H), 4.59 (s, 2H), 7.28 (ddd, 3J = 8.1 Hz, 3J = 7.0 Hz, 4J = 1.0 Hz, 1H), 7.39 (ddd, 3J = 8.1 Hz, 3J = 7.0 Hz, 4J = 1.0 Hz, 1H), 7.50–7.52 (m, 2H), 7.73 (dt, 3J = 8.1 Hz, 4J = 1.0 Hz, 1H), 7.80 (dt, 3J = 8.2 Hz, 4J = 1.0 Hz, 1H); 13C NMR: δ 29.7, 33.5, 35.8, 43.3, 49.6, 52.6, 56.7, 107.5, 120.5, 123.8, 124.1, 127.7, 127.8, 142.0, 148.9, 151.4, 152.4, 154.8, 163.7, 167.7. Anal. Calcd for C22H26N8SO3: C, 54.76; H, 5.43; N, 23.22. Found: C, 54.73; H, 5.22; N, 23.38. LC/MS: calcd m/z 483.19, found m/z 483.32.

N-[2-(4-(Benzo[d]isoxazol-3-yl)piperazino)ethyl]-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide (10):

This compound was obtained from II in 41% yield; mp 208–210°C; Rf = 0.33; 1H NMR: δ 2.60 (t, 3J = 6.0 Hz, 2H), 2.67–2.70 (m, 4H), 3.44 (q, 3J = 5.6 Hz, 2H), 3.53–3.56 (m, 4H), 3.57 (s, 3H), 3.96 (s, 3H), 4.70 (s, 2H), 6.35–6.45 (m, 1H), 7.22 (ddd, 3J = 8.1 Hz, 3J = 6.3 Hz, 4J = 1.5 Hz, 1H), 7.41–7.54 (m, 3H), 7.66–7.69 (m, 1H); 13C NMR: δ 29.8, 33.6, 35.9, 43.6, 48.2, 52.1, 56.4, 107.5, 110.5, 116.1, 122.1, 122.4, 129.6, 141.8, 149.2, 151.4, 154.8, 161.2, 164.0, 167.2. Anal. Calcd for C22H26N8O4: C, 56.64; H, 5.62; N, 24.02. Found: C, 56.58; H, 5.71; N, 23.92. LC/MS: calcd m/z 467.21, found m/z 467.37.

N-[2-(4-(2,3-Dichlorophenyl)piperazino)ethyl]-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide (11):

This compound was obtained from II in 58% yield; mp 245–247°C; Rf = 0.28; 1H NMR: δ 2.50 (t, 3J = 6.3 Hz, 2H), 2.54–2.64 (m, 4H), 2.87–3.01 (m, 4H), 3.28–3.32 (m, 2H), 3.45 (s, 3H), 3.85 (s, 3H), 4.55 (s, 2H), 6.85 (dd, 3J = 5.4 Hz, 4J = 4.1 Hz, 1H), 6.97–7.10 (m, 2H), 7.51–7.53 (m, 2H); 13C NMR: δ 29.6, 33.4, 36.0, 43.2, 50.8, 52.9, 56.6, 107.5, 118.5, 124.7, 127.3, 127.4, 133.9, 142.0, 148.7, 150.7, 151.4, 154.8, 167.7. Anal. Calcd for C21H25N7O3Cl2: C, 51.02; H, 5.10; N, 19.83. Found: C, 51.12; H, 5.19; N, 19.69. LC/MS: calcd m/z 494.15, found m/z 494.29.

N-[3-(4-(2,3-Dichlorophenyl)piperazino)propyl]-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide (12):

This compound was obtained from II in 75% yield; mp 222–224°C; Rf = 0.30; 1H NMR: δ 1.68 (quin, 3J = 6.9 Hz, 2H), 2.46 (t, 3J = 7.0 Hz, 2H), 2.54–2.72 (m, 4H), 2.92–3.09 (m, 4H), 3.27 (t, 3J = 6.4 Hz, 2H), 3.48 (s, 3H), 3.89 (s, 3H), 4.56 (s, 2H), 6.88 (dd, 3J = 6.2 Hz, 4J = 3.3 Hz, 1H), 7.05–7.10 (m, 2H), 7.51–7.53 (m, 2H); 13C NMR: δ 25.3, 29.7, 33.5, 38.2, 43.3, 50.9, 53.0, 56.1, 107.5, 118.5, 124.7, 127.3, 127.5, 133.9, 141.9, 148.9, 150.7, 151.5, 154.8, 167.6. Anal. Calcd for C22H27N7O3Cl2: C, 51.97; H, 5.35; N, 19.29. Found: C, 52.05; H, 5.21; N, 19.11. LC/MS: calcd m/z 508.16, found m/z 508.32.

N-[4-(4-(Benzo[d]isothiazol-3-yl)piperazino)butyl]-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide (13):

This compound was obtained from II in 57% yield; mp 183–185°C; Rf = 0.24; 1H NMR: δ 1.58–1.64 (m, 4H), 2.45–2.49 (m, 2H), 2.68–2.71 (m, 4H), 3.29–3.35 (m, 2H), 3.56 (s, 3H), 3.56–3.59 (m, 4H), 3.95 (s, 3H), 4.65 (s, 2H), 6.45–6.49 (m, 1H), 7.33–7.36 (m, 1H), 7.45 (ddd, 3J = 8.1 Hz, 3J = 7.0 Hz, 4J = 1.7 Hz, 1H), 7.50 (s, 1H), 7.78–7.81 (m, 1H), 7.86–7.90 (m, 1H); 13C NMR: δ 24.1, 27.2, 29.8, 33.6, 39.5, 43.6, 49.9, 52.9, 57.9, 107.5, 120.5, 123.8, 123.9, 127.5, 127.9, 141.7, 149.1, 151.4, 152.7, 154.8, 163.8, 167.1. Anal. Calcd for C24H30N8SO3: C, 56.45; H, 5.92; N, 21.94. Found: C, 56.63; H, 5.99; N, 21.83. LC/MS: calcd m/z 511.22, found m/z 511.37.

N-[4-(4-(Benzo[d]isoxazol-3-yl)piperazino)butyl]-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide (14):

This compound was obtained from II in 60% yield; mp 163–165°C; Rf = 0.34; 1H NMR: δ 1.57–1.51 (m, 4H), 2.44 (t, 3J = 6.4 Hz, 2H), 2.63–2.67 (m, 4H), 3.28–3.34 (m, 2H), 3.55 (s, 3H), 3.58–3.60 (m, 4H), 3.94 (s, 3H), 4.64 (s, 2H), 6.45 (t, 3J = 5.3 Hz, 1H), 7.20 (ddd, 3J = 8.1 Hz, 3J = 6.4 Hz, 4J = 1.7 Hz, 1H), 7.40–7.48 (m, 2H), 7.50 (s, 1H), 7.67 (d, 3J = 8.0 Hz, 1H); 13C NMR: δ 24.0, 27.2, 29.8, 33.6, 39.5, 43.6, 48.1, 52.4, 57.9, 107.5, 110.4, 116.1, 122.1, 122.3, 129.5, 141.7, 149.1, 151.5, 154.8, 161.2, 163.9, 167.2. Anal. Calcd for C24H30N8O4: C, 58.29; H, 6.11; N, 22.66. Found: C, 58.14; H, 6.11; N, 22.71. LC/MS: calcd m/z 495.25, found m/z 495.42.

N-[4-(4-(2,3-Dichlorophenyl)piperazino)butyl]-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamide (15):

This compound was obtained from II in 18% yield; mp 214–216°C; Rf = 0.16; 1H NMR: δ 1.48–1.55 (m, 4H), 2.42 (t, 3J = 7.2 Hz, 2H), 2.55–2.75 (m, 4H), 2.94–3.11 (m, 4H), 3.21 (t, 3J = 6.2 Hz, 2H), 3.49 (s, 3H), 3.90 (s, 3H), 4.58 (s, 2H), 6.91 (dd, 3J = 6.2 Hz, 4J = 3.3 Hz, 1H), 7.03–7.13 (m, 2H), 7.52–7.55 (m, 2H); 13C NMR: δ 23.6, 27.0, 29.7, 33.5, 39.1, 43.2, 50.7, 53.0, 57.8, 107.5, 118.6, 124.7, 127.3, 127.5, 133.9, 141.9, 148.9, 150.8, 151.49, 154.9, 167.5. Anal. Calcd for C23H29N7O3Cl2: C, 52.88; H, 5.60; N, 18.77. Found: C, 52.95; H, 5.44; N, 18.62. LC/MS: calcd m/z 522.18, found m/z 522.34.

Acknowledgments

This study was supported by the project ‘Prokog,’ UDAPOIG.01.03.01-12-063/09-00, co-financed by the European Union from the European Fund of Regional Development (EFRD).

References

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    López-Rodríguez, M. L.; Porras, E.; Morcillo, M. J.; Benhamú, B.; Soto, L. J.; Lavandera, J. L.; Ramos, J. A.; Olivella, M.; Campillo, M.; Pardo, L. Optimization of the pharmacophore model for 5-HT7R antagonism. Design and synthesis of new naphtholactam and naphthosultam derivatives. J. Med. Chem. 2003, 46, 5638–5350.

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    Carr, G. V.; Schechter, L. E.; Lucki, I. Antidepressant and anxiolytic effects of selective 5-HT6 receptor agonists in rats. Psychopharmacology 2011, 213, 499–507.

  • [3]

    Richtand, N. M.; Welge, J. A.; Logue, A. D.; Keck Jr., P. E.; Strakowski, S. M.; McNamara, R. K. Role of serotonin and dopamine receptor binding in antipsychotic efficacy. Neuropsychopharmacology 2007, 32, 1715–1726.

  • [4]

    Codony, X.; Vela, J. M.; Ramírez, M. J. 5-HT6 receptor and cognition. Curr. Opin. Pharm. 2011, 11, 94–100.

    • Crossref
  • [5]

    Benhamú, B.; Mrtín-Fontecha, M.; Vázquez-Villa, H.; Pardo, L.; López-Rodríguez, M. L. Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer’s disease. J. Med. Chem. 2014, 57, 7160–7181.

  • [6]

    Gacsály, I.; Nagy, K.; Pallagi, K.; Lévay, G.; Hársing Jr., L. G.; Móricz, K.; Kertész, Sz.; Varga, P.; Haller, J.; Gigler, G.; et al. Egis-11150: a candidate antipsychotic compound with procognitive efficacy in rodents. Neuropharmacology 2013, 64, 254–263.

  • [7]

    Zajdel, P.; Partyka, A.; Marciniec, K.; Bojarski, A. J.; Pawłowski, M.; Wesołowska, A. Quinoline- and isoquinoline-sulfonamide analogs of aripiprazole: novel antipsychotic agents? Future Med. Chem. 2014, 6, 57–75.

  • [8]

    Chłoń-Rzepa, G.; Żmudzki, P.; Zajdel, P.; Bojarski, A. J.; Duszyńska, B.; Nikiforuk, A.; Tatarczyńska, E.; Pawłowski, M. 7-Arylpiperazinylalkyl and 7-tetrahydroisoquinolinylalkyl derivatives of 8-alkoxy-purine-2,6-dione and some of their purine-2,6,8-trione analogs as 5-HT1A, 5-HT2A and 5-HT7 serotonin receptor ligands. Bioorg. Med. Chem. 2007, 15, 5239–5250.

  • [9]

    Maślankiewicz, A.; Syrek, B.; Nocuń, M.; Pluta, K. Synthesis of N,N’-dimethyl-7H-xanthine-N″-acetic acids. Acta Pol. Pharm. 1979, 36, 539–543.

  • [10]

    Zajdel, P.; Marciniec, K.; Maślankiewicz, A.; Grychowska, K.; Satała, G.; Duszyńska, B.; Lenda, T.; Siwek, A.; Nowak, G.; Partyka, A.; et al. Antidepressant and antipsychotic activity of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT1A/5-HT2A/5-HT7 and dopamine D2/D3 receptors. Eur. J. Med. Chem. 2013, 60, 42–50.

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  • [1]

    López-Rodríguez, M. L.; Porras, E.; Morcillo, M. J.; Benhamú, B.; Soto, L. J.; Lavandera, J. L.; Ramos, J. A.; Olivella, M.; Campillo, M.; Pardo, L. Optimization of the pharmacophore model for 5-HT7R antagonism. Design and synthesis of new naphtholactam and naphthosultam derivatives. J. Med. Chem. 2003, 46, 5638–5350.

  • [2]

    Carr, G. V.; Schechter, L. E.; Lucki, I. Antidepressant and anxiolytic effects of selective 5-HT6 receptor agonists in rats. Psychopharmacology 2011, 213, 499–507.

  • [3]

    Richtand, N. M.; Welge, J. A.; Logue, A. D.; Keck Jr., P. E.; Strakowski, S. M.; McNamara, R. K. Role of serotonin and dopamine receptor binding in antipsychotic efficacy. Neuropsychopharmacology 2007, 32, 1715–1726.

  • [4]

    Codony, X.; Vela, J. M.; Ramírez, M. J. 5-HT6 receptor and cognition. Curr. Opin. Pharm. 2011, 11, 94–100.

    • Crossref
  • [5]

    Benhamú, B.; Mrtín-Fontecha, M.; Vázquez-Villa, H.; Pardo, L.; López-Rodríguez, M. L. Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer’s disease. J. Med. Chem. 2014, 57, 7160–7181.

  • [6]

    Gacsály, I.; Nagy, K.; Pallagi, K.; Lévay, G.; Hársing Jr., L. G.; Móricz, K.; Kertész, Sz.; Varga, P.; Haller, J.; Gigler, G.; et al. Egis-11150: a candidate antipsychotic compound with procognitive efficacy in rodents. Neuropharmacology 2013, 64, 254–263.

  • [7]

    Zajdel, P.; Partyka, A.; Marciniec, K.; Bojarski, A. J.; Pawłowski, M.; Wesołowska, A. Quinoline- and isoquinoline-sulfonamide analogs of aripiprazole: novel antipsychotic agents? Future Med. Chem. 2014, 6, 57–75.

  • [8]

    Chłoń-Rzepa, G.; Żmudzki, P.; Zajdel, P.; Bojarski, A. J.; Duszyńska, B.; Nikiforuk, A.; Tatarczyńska, E.; Pawłowski, M. 7-Arylpiperazinylalkyl and 7-tetrahydroisoquinolinylalkyl derivatives of 8-alkoxy-purine-2,6-dione and some of their purine-2,6,8-trione analogs as 5-HT1A, 5-HT2A and 5-HT7 serotonin receptor ligands. Bioorg. Med. Chem. 2007, 15, 5239–5250.

  • [9]

    Maślankiewicz, A.; Syrek, B.; Nocuń, M.; Pluta, K. Synthesis of N,N’-dimethyl-7H-xanthine-N″-acetic acids. Acta Pol. Pharm. 1979, 36, 539–543.

  • [10]

    Zajdel, P.; Marciniec, K.; Maślankiewicz, A.; Grychowska, K.; Satała, G.; Duszyńska, B.; Lenda, T.; Siwek, A.; Nowak, G.; Partyka, A.; et al. Antidepressant and antipsychotic activity of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT1A/5-HT2A/5-HT7 and dopamine D2/D3 receptors. Eur. J. Med. Chem. 2013, 60, 42–50.

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