Journal of the Korean Chemical Society (대한화학회지)

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

A Synthesis of Novel Sulfur-Linked Fused Thienotriazolopyrimidine Derivatives

  • Received : 2014.06.16
  • Accepted : 2014.07.09
  • Published : 2014.08.20
Download PDF
⟨ Previous Next ⟩

Abstract

Keywords

INTRODUCTION

Interleukin-6 (IL-6) binds to its receptor (IL-6R, a ligandbinding 80 kDa glycoprotein chain) and induces the homodimerization of a signal transducing glycoprotein 130 (gp130), leading to the activation of the Janus kinase (Jak)/signal transducer and signal activator of transcription-3 (STAT3).1 STAT3 is also frequently over-expressed or persistently activated in most tumors and cancer, and activated STAT3 was found to suppress tumor-immune surveillance.2 Therefore, the blockade of STAT3 activation pathway stimulated by IL-6 could be an attractive therapeutic target for discovery of new drugs and is currently under intense investigation.3

In the other hand, thienotriazolopyrimidines have recently attracted much interest because of their pharmacological and therapeutic properties including anticancer, anti-inflammatory, urea transport protein (UT-B) inhibitor, Shiga toxin trafficking inhibitor 1, and xanthine oxidase inhibitor 2, as shown in Figure 14. Furthermore, sulfur-linked triazoles (3-thio-1,2,4-triazoles) have been reported to possess a wide range of biological activities such as antifungal agent, diacylglycerol acyltransferase 1 (DGAT1) inhibitor 3, carbonic anhydrase inhibition, somatostatin sst2/sst5 agonists, and dopamine D3 receptor antagonist 4.5 We have synthesized over the years thienopyrimidine and thienotriazolopyrimidine derivatives of promising biological activity.6 From a programme to discover novel inhibitors using thienopyrimidine derivatives, some of sulfur-linked thienotriazolopyrimidine compounds were recently found to possess potent IL-6/STAT3 inhibition.7 This result encouraged us to prepare new sulfur-linked tetracyclic thienotriazolopyrimidines in attempt to improve the IL-6/STAT3 inhibitory activity.

Figure 1.Thienotriazolopyrimidines 1, 2 and sulfur-linked triazoles 3, 4.

 

EXPERIMENTAL

Chemistry

Melting points were determined in capillary tubes on Büchi apparatus and are uncorrected. Each compound of the reactions was checked on thin-layer chromatography of Merck Kieselgel 60F254 and purified by column chromatography Merck silica gel (70–230 mesh). The 1H NMR spectra were recorded on Unity Inova 400NB FT NMR spectrometer (400 MHz) with Me4Si as internal standard and chemical shifts are given in ppm (δ). Mass spectra were recorded on a HP 59580 B spectrometer. Elemental analyses were performed on a Carlo Erba 1106 elemental analyzer.

General Procedure for the Preparation of 7 and 8

Thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione (5) or thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione (6)6(f) (5 mmol) and methyl iodide (10 mmol) were stirred in ethanol (20 mL) containing sodium acetate (20 mmol) for 8 h at room temperature. The reaction mix-ture was diluted with water, and the solid was filtered, dried and recrystallized from ethanol to give 7 and 8, respectively.

3-(Methylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimidine (7)

Yield 82％; mp 222–223 ℃; 1H NMR (DMSO-d6): δ 9.60 (s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 7.78 (d, 1H, J = 5.6 Hz), 2.71 (s, 3H); MS (ESI): (m/z) 222.4 (M+). Anal. Calcd. For C8H6N4S2: C, 43.23; H, 2.72; N, 25.20. Found: C, 43.40; H, 2.63; N, 25.08.

3-(Methylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c] pyrimidine (8)

Yield 88％; mp 155–157 ℃; 1H NMR (DMSO-d6): δ 9.61 (s, 1H), 8.31 (d, 1H, J = 5.6 Hz), 7.72 (d, 1H, J = 5.6 Hz), 2.70 (s, 3H); MS (ESI): (m/z) 222.6 (M+). Anal. Calcd. For C8H6N4S2: C, 43.23; H, 2.72; N, 25.20. Found: C, 43.11.; H, 2.69; N, 25.31.

General Procedure for the Preparation of 9 and 10

A mixture of 7 or 8 (5 mmol) and hydrazine hydrate (40 mmol) in ethanol (30 mL) was refluxed for 3 h. After cooling and evaporation, the solid formed was filtered, dried and recrystallized from ethanol to give 9 and 10, respectively.

3-Hydrazinylthieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimidine (9)

Yield 78％; mp 260–262 ℃; 1H NMR (DMSO-d6): δ 8.48 (s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.33 (d, 1H, J = 5.6 Hz); MS (ESI): (m/z) 206.5 (M+). Anal. Calcd. For C7H6N6S: C, 40.77; H, 2.93; N, 40.75. Found: C, 40.88; H, 2.89; N, 40.56.

3-Hydrazinylthieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimidine (10)

Yield 75％; mp 264–266 ℃; 1H NMR (DMSO-d6): δ 8.39 (s, 1H), 7.75 (d, 1H, J = 5.6 Hz), 7.55 (d, 1H, J = 5.6 Hz); MS (ESI): (m/z) 206.1 (M+). Anal. Calcd. For C7H6N6S: C, 40.77; H, 2.93; N, 40.75. Found: C, 40.68; H, 2.83; N, 40.68.

General Procedure for the Preparation of 11 and 12

A mixture of 9 or 10 (3 mmol) and carbon disulfide (30 mmol) in ethanolic potassium hydroxide (10％, 20 mL) was refluxed for 6 h. After cooling and evaporation of solvent, the residue was dissolved in water and acidified by adding 10％ HCl. The solid formed was filtered, dried and recrystallized from ethanol to give 11 and 12, respectively.

[1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[3,2-e] pyrimidine-9(8H)-thione (11)

Yield 80％; mp 256–258 ℃; 1H NMR (DMSO-d6): δ 13.5 (s, 1H), 9.45 (s, 1H), 8.10 (d, 1H, J = 5.6 Hz), 7.56 (d, 1H, J = 5.6 Hz); MS (ESI): (m/z) 248.1 (M+). Anal. Calcd. For C8H4N6S2: C, 38.70; H, 1.62; N, 33.85. Found: C, 38.88; H, 1.69; N, 33.69.

[1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[2,3-e]pyrimidine-9(8H)-thione (12)

Yield 80％; mp 279–281 ℃; 1H NMR (DMSO-d6): δ 14.0 (s, 1H), 8.90 (s, 1H), 8.30 (d, 1H, J = 5.6 Hz), 7.51 (d, 1H, J = 5.6 Hz); MS (ESI): (m/z) 248.5 (M+). Anal. Calcd. For C8H4N6S2: C, 38.70; H, 1.62; N, 33.85. Found: C, 38.80; H, 1.55; N, 33.70.

General Procedure for the Preparation of 13a–f and 14a–f

Sodium acetate (2 mmol) was added to a solution of 11 or 12 (1.2 mmol) in ethanol (20 mL) with stirring at room temperature. After 5 min, an α-bromocarboxylic acid (1.2 mmol) was slowly added in small portions and the resulting solution was heated at reflux for 6 h. After cooling, the solid was filtered, washed with water and recrystallized from ethanol or ethyl acetate to give products, respectively.

2-([1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[3,2-e]pyrimidin-9-ylthio)-2-phenylacetic acid (13a)

Yield 71％; mp 223–224 ℃; 1H NMR (DMSO-d6): δ 9.50 (s, 1H), 8.01 (d, 1H, J = 5.6 Hz), 7.73 (d, 1H, J = 5.6 Hz), 7.38 (m, 2H), 7.25–7.18 (m, 3H), 5.55 (s, 1H); MS (ESI): (m/z) 382.2 (M+). Anal. Calcd. For C16H10N6O2S2: C, 50.25; H, 2.64; N, 21.98. Found: C, 50.38; H, 2.59; N, 22.10.

2-([1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[3,2-e]pyrimidin-9-ylthio)-2-(2-chlorophenyl)acetic acid (13b)

Yield 78％; mp 246–247 ℃; 1H NMR (DMSO-d6): δ 9.56 (s, 1H), 8.04 (d, 1H, J = 5.6 Hz), 7.75 (d, 1H, J = 5.6 Hz), 7.56 (d, 1H), 7.49 (d, 1H), 7.44–7.38 (m, 2H), 5.72 (s, 1H); MS (ESI): (m/z) 416.9 (M+). Anal. Calcd. For C16H9ClN6O2S2: C, 46.10; H, 2.18; N, 20.16. Found: C, 46.01; H, 2.22; N, 20.30.

2-([1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[3,2-e]pyrimidin-9-ylthio)-2-(3-chlorophenyl)acetic acid (13c)

Yield 77％; mp 243–244 ℃; 1H NMR (DMSO-d6): δ 9.50 (s, 1H), 8.02 (d, 1H, J = 5.6 Hz), 7.72 (d, 1H, J = 5.6 Hz), 7.59 (s, 1H), 7.44 (m, 1H), 7.35–7.27 (m, 2H), 5.88 (s, 1H); MS (ESI): (m/z) 416.3 (M+). Anal. Calcd. For C16H9ClN6O2S2: C, 46.10; H, 2.18; N, 20.16. Found: C, 45.96; H, 2.08; N, 20.05.

2-([1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[3,2-e]pyrimidin-9-ylthio)-2-(4-chlorophenyl)acetic acid (13d)

Yield 86％; mp 240–242 ℃; 1H NMR (DMSO-d6): δ 9.55 (s, 1H), 8.03 (d, 1H, J = 5.6 Hz), 7.76 (d, 1H, J = 5.6 Hz), 7.50 (d, 2H), 7.31 (d, 2H), 5.91 (s, 1H); MS (ESI): (m/z) 416.3 (M+). Anal. Calcd. For C16H9ClN6O2S2: C, 46.10; H, 2.18; N, 20.16. Found: C, 46.19; H, 2.04; N, 20.24.

2-([1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[3,2-e]pyrimidin-9-ylthio)-2-(4-bromophenyl)acetic acid (13e)

Yield 66％; mp 266–267 ℃; 1H NMR (DMSO-d6): δ 9.60 (s, 1H), 8.07 (d, 1H, J = 5.6 Hz), 7.78 (d, 1H, J = 5.6 Hz), 7.58 (d, 2H), 7.50 (d, 2H), 5.77 (s, 1H); MS (ESI): (m/z) 461.8 (M+). Anal. Calcd. For C16H9BrN6O2S2: C, 41.66; H, 1.97; N, 18.22. Found: C, 41.61; H, 2.07; N, 18.39.

2-([1,2,4]triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[3,2-e]pyrimidin-9-ylthio)propanoic acid (13f)

Yield 38%; mp 122–123 ℃; 1H NMR (DMSO-d6): δ 9.56 (s, 1H), 8.05 (d, 1H, J = 5.6 Hz), 7.73 (d, 1H, J = 5.6 Hz), 4.33 (q, 1H), 1.42 (d, 3H); MS (ESI): (m/z) 320.8 (M+). Anal. Calcd. For C11H8N6O2S2: C, 41.24; H, 2.52; N, 26.23. Found: C, 41.10; H, 2.59; N, 26.40.

2-([1,2,4]Triazolo[4'3':1,5][1,2,4]triazolo[4,3-c]thieno-[2,3-e]pyrimidin-9-ylthio)-2-phenylacetic acid (14a)

Yield 73％; mp 202–203 ℃; 1H NMR (DMSO-d6): δ 9.48 (s, 1H), 8.24 (d, 1H, J = 5.6 Hz), 7.66 (d, 1H, J = 5.6 Hz), 7.55 (m, 2H), 7.32–7.20 (m, 3H), 5.37 (s, 1H); MS (ESI): (m/z) 382.6 (M+). Anal. Calcd. For C16H10N6O2S2: C, 50.25; H, 2.64; N, 21.98. Found: C, 50.20; H, 2.56; N, 21.85.

2-([1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[2,3-e]pyrimidin-9-ylthio)-2-(2-chlorophenyl)acetic acid (14b)

Yield 82％; mp 217–218 ℃; 1H NMR (DMSO-d6): δ 9.48 (s, 1H), 8.28 (d, 1H, J = 5.6 Hz), 7.71 (d, 1H, J = 5.6 Hz), 7.67 (d, 1H), 7.58 (d, 1H), 7.35–7.25 (m, 2H), 5.81 (s, 1H); MS (ESI): (m/z) 416.9 (M+). Anal. Calcd. For C16H9ClN6O2S2: C, 46.10; H, 2.18; N, 20.16. Found: C, 46.22; H, 2.21; N, 20.01.

2-([1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[2,3-e]pyrimidin-9-ylthio)-2-(3-chlorophenyl)acetic acid (14c)

Yield 75％; mp 237–239 ℃; 1H NMR (DMSO-d6): δ 9.48 (s, 1H), 8.24 (d, 1H, J = 5.6 Hz), 7.66 (d, 1H, J = 5.6 Hz), 7.58 (s, 1H), 7.44 (m, 1H), 7.30–7.21 (m, 2H), 5.32 (s, 1H); MS (ESI): (m/z) 416.8 (M+). Anal. Calcd. For C16H9ClN6O2S2: C, 46.10; H, 2.18; N, 20.16. Found: C, 46.22; H, 2.10; N, 20.30.

2-([1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[2,3-e]pyrimidin-9-ylthio)-2-(4-chlorophenyl)acetic acid (14d)

Yield 80％; mp 208–210 ℃; 1H NMR (DMSO-d6): δ 9.44 (s, 1H), 8.30 (d, 1H, J = 5.6 Hz), 7.78 (d, 1H, J = 5.6 Hz), 7.58 (d, 2H), 7.38 (d, 2H), 5.62 (s, 1H); MS (ESI): (m/z) 416.5 (M+). Anal. Calcd. For C16H9ClN6O2S2: C, 46.10; H, 2.18; N, 20.16. Found: C, 46.23; H, 2.10; N, 20.04.

2-([1,2,4]Triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[2,32-e]pyrimidin-9-ylthio)-2-(4-bromophenyl)acetic acid (14e)

Yield 72％; mp 243–245 ℃; 1H NMR (DMSO-d6): δ 9.48 (s, 1H), 8.23 (d, 1H, J = 5.6 Hz), 7.74 (d, 1H, J = 5.6 Hz), 7.48 (d, 2H), 7.38 (d, 2H), 5.28 (s, 1H); MS (ESI): (m/z) 461.8 (M+). Anal. Calcd. For C16H9BrN6O2S2: C, 41.66; H, 1.97; N, 18.22. Found: C, 41.50; H, 2.09; N, 18.10.

2-([1,2,4]triazolo[4',3':1,5][1,2,4]triazolo[4,3-c]thieno-[3,2-e]pyrimidin-9-ylthio)propanoic acid (14f)

Yield 40％; mp 102–104 ℃; 1H NMR (DMSO-d6): δ 9.50 (s, 1H), 8.28 (d, 1H, J = 5.6 Hz), 7.70 (d, 1H, J = 5.6 Hz), 4.28 (q, 1H), 1.20 (d, 3H); MS (ESI): (m/z) 320.8 (M+). Anal. Calcd. For C11H8N6O2S2: C, 41.24; H, 2.52; N, 26.23. Found: C, 41.12; H, 2.41; N, 26.34.

 

RESULTS AND DISCUSSION

The required starting materials 5 and 6 were prepared according to the reported procedure.6(f) Treatment of 5 or 6 with methyl iodide in the presence of sodium acetate, and the subsequent reaction of the resultant compounds with hydrazine led to the replacement of thiomethyl group to afford 3-hydrazinothienotriazolopyrimidines 9 and 10 (Scheme 1). This substitution reaction gave better yield compared to the reaction of chlorothienotriazolopyrimidine (prepared using SOCl2/DMF) with hydrazine.6(a) Electrophilic attack of carbon disulfide in the presence of ethanolic KOH on the hydrazines 9 and 10 gave 11 and 12, respectively, via further cyclization and elimination of hydrogen sulfide. The new sulfur-linked tetracyclic compounds, 13 and 14, were prepared in good yield by treatment of 11 or 12 with α-bromophenylacetic acids or α-bromopropanoic acid in refluxing ethanol containing sodium acetate (Table 1). It should be, however, noted that α-bromopropanoic acid is much less reactive to 11 and 12 when compared to α-bromophenylacetic acids (entry 6, 12, Table 1). The structural assignment of 13 and 14 was based upon spectroscopic and microanalytical data. For example, 13a did not show the NH signal near at δ 13–14 in 1H NMR spectrum and characteristic peak at 3210 cm−1 in IR spectrum that have found in the precursor 11, but instead showed 1H signals at δ 7.18–7.38 for aromatic protons and a singlet at δ 5.55 for benzylic proton indicating the formation of desired tetracyclic triazole product containing thiophenylacetic acid. The mass spectrum of 13a showed a molecular ion peak at m/z = 382 (M+) for C16H10N6O2S2, and also showed ions at m/z = 364, 338 and 248 which could be attributed to the loss of H2O and CO2, respectively, and cleavage of sulfur bond from the molecular ion.

Scheme 1.Synthesis of 13 and 14. Reagents and conditions: (i) CH3I, CH3CO2Na, EtOH, rt; (ii) NH2NH2, EtOH, reflux; (iii) CS2, KOH, EtOH, reflux; iv) α-bromocarboxylic acid, CH3CO2Na, EtOH, reflux.

Table 1.aIsolated yields.

 

CONCLUSION

In conclusion, we report the synthesis of new sulfurlinked tetracyclic thienotriazolopyrimidine compounds 13 and 14, respectively, from 5 and 6 through cyclization of hydrazine derivatives 9 or 10 with carbon disulfide, and the subsequent reaction with α-bromophenylacetic acids or α-bromopropanoic acid. Further biological work on IL-6/STAT3 inhibitory activity is under way.

References

  1. Aaronson, D.; Horvath, C. Science 2002, 296, 1653. https://doi.org/10.1126/science.1071545
  2. Yu, H.; Pardoll, D.; Jove, R. S. Nat. Rev. Cancer 2009, 9, 798 https://doi.org/10.1038/nrc2734
  3. Rose-John, S.; Waetzig, G. H.; Schller, J.; Gratzinger, J.; Seegert, D. Expert Opin. Ther. Targets 2007, 11, 613. https://doi.org/10.1517/14728222.11.5.613
  4. (b) Adachi, Y.; Yoshio-Hoshino, N.; Nishimoto, N. Curr. Pharm. Des. 2008, 14, 1217. https://doi.org/10.2174/138161208784246072
  5. (a) Lauria, A.; Abbate, I.; Patella, C.; Martorana, A.; Dattolo, G.; Almerico, A. M. Eur. J. Med. Chem. 2013, 62, 416. https://doi.org/10.1016/j.ejmech.2013.01.019
  6. (b) Rizk, O. H.; Shaaban, O. G.; El-Ashmawy, I. M. Eur. J. Med.Chem. 2012, 55, 85. https://doi.org/10.1016/j.ejmech.2012.07.007
  7. (c) Liu, Y.; Esteva-Font, C.; Yao, C.; Phuan, P. W.; Verkman, A. S.; Anderson, M. O. Bioorg. Med. Chem. Lett. 2013, 23, 3338. https://doi.org/10.1016/j.bmcl.2013.03.089
  8. (d) Guetzoyan, L. J.; Spooner, R. A.; Lord, J. M.; Roberts, L. M.; Clarkson, G. J. Eur. J. Med. Chem. 2010, 45, 275. https://doi.org/10.1016/j.ejmech.2009.10.007
  9. (e) Nagamatsu, T.; Ahmed, S.; Hossion, A. M. L.; Ohno, S. Heterocycles 2007, 73, 777. https://doi.org/10.3987/COM-07-S(U)58
  10. (a) Chen, Q.; Zhu, X.-L.; Jiang, L.-L.; Yang, G.-F. Eur. J. Med. 2008, 43, 595. https://doi.org/10.1016/j.ejmech.2007.04.021
  11. (b) Bali, U.; et al. Bioorg. Med. Chem. Lett. 2012, 22, 824. https://doi.org/10.1016/j.bmcl.2011.12.050
  12. (c) Almajan, G. L.; Innocenti, A.; Puccetti, L.; Manole, G.; Barbuceanu, S.; Saramet, I.; Scozzafava, A.; Supuran, C. T. Bioorg. Med. Chem. Lett. 2005, 15, 2347. https://doi.org/10.1016/j.bmcl.2005.02.088
  13. (d) Contour-Galcera, M. O.; Sidhu, A.; Plas, P.; Roubert, P. Bioorg. Med. Chem. Lett. 2005, 15, 3555. https://doi.org/10.1016/j.bmcl.2005.05.061
  14. (e) Micheli, F.; et al. J. Med. Chem. 2010, 53, 374. https://doi.org/10.1021/jm901319p
  15. (a) Whang, J.; Song, Y.-H. J. Heterocycl. Chem. 2013, 50, 603. https://doi.org/10.1002/jhet.1574
  16. (b) Lee, H. J.; Kim, S. M.; Song, Y.-H. Heterocycl. Commun. 2013, 19, 101.
  17. (c) Whang, J.; Song, Y.-H. Heterocycles 2012, 85, 155. https://doi.org/10.3987/COM-11-12371
  18. (d) Song, Y.-H.; Son, H. Y. J. Heterocycl. Chem. 2011, 48, 597. https://doi.org/10.1002/jhet.549
  19. (e) Song, Y.-H.; Moon, J. Heterocycl. Commun. 2011, 17, 135.
  20. (f) Song, Y.-H.; Son, H. Y. J. Heterocycl. Chem. 2010, 47, 1183. https://doi.org/10.1002/jhet.461
  21. (g) Son, H. Y.; Song, Y.-H. Bull. Korean Chem. Soc. 2010, 31, 2242. https://doi.org/10.5012/bkcs.2010.31.8.2242
  22. (h) Song, Y.-H.; Jo, B. S. J. Heterocycl. Chem. 2009, 46, 1132. https://doi.org/10.1002/jhet.186
  23. (i) Jo, B. S.; Son, H. Y.; Song, Y.-H. Heterocycles 2008, 75, 3091. https://doi.org/10.3987/COM-08-11465
  24. Rho, M. C.; Song, Y.-H.; Lee, S. W.; Park, C. S.; Oh, H. M. Novel Heterocyclic Compounds and Use Thereof. Korean Patent, Appl. 10-2013-0008307, 2013.