Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Radioligand Binding Assay for 5-HT1A and SERT
2.2.2. In Vivo Studies
2.2.3. Metabolic Stability Evaluation
3. Materials and Methods
3.1. General Remarks
3.2. Synthesis of Compounds
3.2.1. Procedure for the Synthesis of 2-(4-Bromobutyl)-4-aryl-pyrido[1,2-c]pyrimidine-1,3-diones (4a–i) and 2-(4-bromobutyl)-4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine-1,3-diones (5a–i)
3.2.2. General Procedure for the Synthesis of Derivatives of 4-Aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine-1,3-dione (7a–i)
4-Phenyl-2-{4-[4-(6-fluoro-1,2-benzoxazol-3-yl)-1-piperidyl]butyl}-pyrido[1,2-c]pyrimidine-1,3-dione 6a
4-(2-Methylphenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-pyrido[1,2-c]pyrimidine-1,3-dione 6b
4-(2-Methoxphenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-pyrido[1,2-c]pyrimidine-1,3-dione 6c
4-(2-Chlorophenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-pyrido[1,2-c]pyrimidine-1,3-dione 6d
4-(2-Fluorophenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-pyrido[1,2-c]pyrimidine-1,3-dione 6e
4-(4-Methylphenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-pyrido[1,2-c]pyrimidine-1,3-dione 6f
4-(4-Methoxyphenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-pyrido[1,2-c]pyrimidine-1,3-dione 6g
4-(4-Chlorophenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-pyrido[1,2-c]pyrimidine-1,3-dione 6h
4-(4-Fluorophenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-pyrido[1,2-c]pyrimidine-1,3-dione 6i
4-Phenyl-2-{4-[4-(6-fluoro-1,2-benzoxazol-3-yl)-1-piperidyl]butyl}-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 7a
4-(2-Methylphenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 7b
4-(2-Methoxphenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 7c
4-(2-Chlorophenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 7d
4-(2-Fluorophenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 7e
4-(4-Methylphenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 7f
4-(4-Methoxyphenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 7g
4-(4-Chlorophenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 7h
4-(4-Fluorophenyl)-2-{4-[4-(6-fluoro-1,2-benzoxazol)-1-piperidyl]butyl}-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 7i
3.3. Biological Tests
3.3.1. In Vitro Tests
5-HT1A Binding Assay
SERT Binding Assay
5-HT2A, 5-HT6, 5-HT7 and D2 Binding Assay
3.3.2. In Vivo Tests
Body Temperature in Mice
Forced Swim Test in Mice
Metabolic Stability
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Ki [nM] | |||||
---|---|---|---|---|---|
Compound | R | R1 | 5-HT1A | SERT | cLogP |
6a | –H | –H | 23.0 ± 1.0 | 32.0 ± 3.6 | 4.32 |
6b | –CH3 | –H | 30.0 ± 3.5 | >5000 | 4.81 |
6c | –OCH3 | –H | 7.0 ± 1.0 | >5000 | 4.30 |
6d | –Cl | –H | 11.0 ± 1.4 | 373.0 ± 32.0 | 4.98 |
6e | –F | –H | 15.0 ± 0.6 | >1000 | 4.52 |
6f | –H | –CH3 | 74.0 ± 4.0 | 772.0 ± 36.0 | 4.81 |
6g | –H | –OCH3 | 10.0 ± 1.1 | 730.0 ± 79.0 | 4.98 |
6h | –H | –Cl | 21.0 ± 1.5 | 310.0 ± 1.0 | 4.98 |
6i | –H | –F | 17.0 ± 2.0 | 342.0 ± 28.8 | 4.55 |
7a | –H | –H | 27.0 ± 2.0 | 520.0 ± 58.8 | 5.02 |
7b | –CH3 | –H | 35.0 ± 3.5 | >1000 | 5.51 |
7c | –OCH3 | –H | 62.0 ± 6.0 | 878.0 ± 88.0 | 5.00 |
7d | –Cl | –H | 71.0 ± 6.9 | 310.0 ± 34.5 | 5.68 |
7e | –F | –H | 36.0 ± 4.1 | >1000 | 5.22 |
7f | –H | –CH3 | 52.0 ± 2.5 | 1773.0 ± 180.0 | 5.90 |
7g | –H | –OCH3 | 5.0 ± 0.5 | 48.0 ± 2.4 | 5.00 |
7h | –H | –Cl | 25.0 ± 3.0 | 290.0 ± 22.7 | 5.68 |
7i | –H | –F | 9.5 ± 1.1 | 311.0 ± 35.0 | 5.22 |
Reference compound | |||||
Serotonin | 3.6 ± 0.4 | ||||
Methiotepin | 4.8 ± 0.5 | ||||
Imipramine | 17.0 ± 1.3 |
Ki [nM] | ||||||||
---|---|---|---|---|---|---|---|---|
Compound | R1 | R2 | 5-HT1A | SERT | 5-HT2A | 5-HT6 | 5-HT7 | D2 |
6a | –H | –H | 23.0 ± 1.0 | 32.0 ± 3.6 | 17 ± 3 | 376 ± 58 | 62 ± 5 | 7 ± 2 |
6d | –Cl | –H | 11.0 ± 1.4 | 373.0 ± 32.0 | 20 ± 4 | 709 ± 135 | 109 ± 14 | 9 ± 2 |
7g | –H | –OCH3 | 5.0 ± 0.5 | 48.0 ± 2.4 | 16 ± 2 | 400 ± 32 | 94 ± 11 | 10 ± 1 |
7i | –H | –F | 9.5 ± 1.1 | 311.0 ± 35.0 | 44 ± 6 | 740 ± 183 | 161 ± 27 | 17 ±2 |
Reference Compound | ||||||||
Olanzapine [37] | 4.6 ± 0.9 | 7 ± 1 | n.d. | n.d. | ||||
Mianserin [37] | 2.8 ± 0.5 | n.d. | n.d. | n.d. | ||||
Clozapine [37] | n.d. | n.d. | 18 ± 2 | n.d. | ||||
Haloperidol [37] | n.d. | n.d. | n.d. | 4.5 ± 0.7 | ||||
Apomorphine [37] | n.d. | n.d. | n.d. | 42 ± 6 | ||||
Chlorpromazine [37] | n.d. | n.d. | n.d. | 1.8 ± 0.3 |
Treatment | Dose (mg/kg) | Δt ± SEM (°C) | |||
---|---|---|---|---|---|
30 min | 60 min | 90 min | 120 min | ||
Vehicle | - | −0.2 ± 0.2 | −0.0 ± 0.2 | −0.1 ± 0.1 | −0.0 ± 0.1 |
6a | 5 | −2.0 ± 0.2 b | −3.2 ± 0.5 b | −3.1 ± 0.5 b | −2.8 ± 0.5 b |
2.5 | −1.6 ± 0.2 b | −2.5 ± 0.3 b | −2.4 ± 0.3 b | −2.0 ± 0.2 b | |
1.25 | −1.7 ± 0.3 b | −1.7 ± 0.3 b | −1.6 ± 0.2 b | −1.6 ± 0.3 b | |
0.6 | −1.0 ± 0.2 b | −1.2 ± 0.1 b | −0.9 ± 0.1 a | −0.8 ± 0.2 a | |
p < 0.0001 | p < 0.0001 | p < 0.0001 | p < 0.0001 | ||
Vehicle | - | −0.0 ± 0.2 | 0.0 ± 0.1 | −0.1 ± 0.1 | −0.1 ± 0.1 |
7g | 5 | −2.1 ± 0.1 b | −3.4 ± 0.3 b | −3.9 ± 0.5 b | −4.2 ± 0.8 b |
2.5 | −2.2 ± 0.2 b | −2.8 ± 0.3 b | −2.9 ± 0.3 b | −3.0 ± 0.4 b | |
1.25 | −1.5 ± 0.3 b | −1.7 ± 0.3 b | −1.3 ± 0.4 b | −1.0 ± 0.3 | |
p < 0.0001 | p < 0.0001 | p < 0.0001 | p < 0.0001 | ||
Vehicle | - | 0.2 ± 0.1 | 0.1 ± 0.2 | 0.1 ± 0.2 | 0.1 ± 0.2 |
WAY-100635 | 0.1 | 0.1 ± 0.2 | 0.1 ± 0.2 | −0.1 ± 0.2 | −0.2 ± 0.1 |
8-OH-DPAT | 5 | −1.7 ± 0.2 b | −1.1 ± 0.2 b | −0.1 ± 0.1 | 0.3 ± 0.3 |
p < 0.0001 | p < 0.005 | ns | ns |
Treatment and Dose (mg/kg) | Δt ± SEM (°C) | |
---|---|---|
30 min | 60 min | |
Vehicle | 0.0 ± 0.1 | 0.0 ± 0.0 |
Vehicle + 6a (0.6) | −1.0 ± 0.2 c | −1.2 ± 0.1 c |
WAY-100635 + 6a | −0.5 ± 0.2 b,d | −0.4 ± 0.2 a,e |
p < 0.0001 | p < 0.0001 | |
Vehicle | −0.3 ± 0.1 | −0.2 ± 0.1 |
Vehicle + 7g (1.25) | −1.5 ± 0.3 c | −1.7 ± 0.3 c |
WAY-100635 + 7g | −1.2 ± 0.2 b | −0.7 ± 0.3 d |
p < 0.0001 | p < 0.0005 | |
Vehicle | 0.1 ± 0.1 | −0.0 ± 0.1 |
WAY-100635 | 0.3 ± 0.3 | 0.2 ± 0.3 |
ns | ns |
Compound | Average t1/2 [min] (n = 2) | SD [min] | RSD% |
---|---|---|---|
6a | 3.61 | 0.43 | 11.18 |
6d | 3.20 | 0.09 | 2.81 |
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Król, M.; Ślifirski, G.; Kleps, J.; Ulenberg, S.; Belka, M.; Bączek, T.; Siwek, A.; Stachowicz, K.; Szewczyk, B.; Nowak, G.; et al. Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands. Int. J. Mol. Sci. 2021, 22, 2329. https://doi.org/10.3390/ijms22052329
Król M, Ślifirski G, Kleps J, Ulenberg S, Belka M, Bączek T, Siwek A, Stachowicz K, Szewczyk B, Nowak G, et al. Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands. International Journal of Molecular Sciences. 2021; 22(5):2329. https://doi.org/10.3390/ijms22052329
Chicago/Turabian StyleKról, Marek, Grzegorz Ślifirski, Jerzy Kleps, Szymon Ulenberg, Mariusz Belka, Tomasz Bączek, Agata Siwek, Katarzyna Stachowicz, Bernadeta Szewczyk, Gabriel Nowak, and et al. 2021. "Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands" International Journal of Molecular Sciences 22, no. 5: 2329. https://doi.org/10.3390/ijms22052329