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A Synthesis of Novel Sulfur-Linked Fused Thienotriazolopyrimidine Derivatives
A Synthesis of Novel Sulfur-Linked Fused Thienotriazolopyrimidine Derivatives
Journal of the Korean Chemical Society. 2014. Aug, 58(4): 423-427
Copyright © 2014, Korea Chemical Society
  • Received : June 16, 2014
  • Accepted : July 09, 2014
  • Published : August 20, 2014
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Yang-Heon Song

Abstract
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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 1 4 . 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 D 3 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.
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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 60F 254 and purified by column chromatography Merck silica gel (70–230 mesh). The 1 H 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(2 H )-thione (5) or thieno[2,3- e ][1,2,4]triazolo[4,3- c ]pyrimidine-3(2 H )-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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 8 H 6 N 4 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 8 H 6 N 4 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 7 H 6 N 6 S: 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 7 H 6 N 6 S: 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 8 H 4 N 6 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 8 H 4 N 6 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 10 N 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 9 ClN 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 9 ClN 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 9 ClN 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 9 BrN 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 11 H 8 N 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 10 N 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 9 ClN 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 9 ClN 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 9 ClN 6 O 2 S 2 : 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 ℃; 1 H NMR (DMSO-d 6 ): 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 C 16 H 9 BrN 6 O 2 S 2 : 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-d 6 ): 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 C 11 H 8 N 6 O 2 S 2 : 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 ( 1 ). This substitution reaction gave better yield compared to the reaction of chlorothienotriazolopyrimidine (prepared using SOCl 2 /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 ( 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, 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 1 H NMR spectrum and characteristic peak at 3210 cm −1 in IR spectrum that have found in the precursor 11 , but instead showed 1 H 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 C 16 H 10 N 6 O 2 S 2 , and also showed ions at m/z = 364, 338 and 248 which could be attributed to the loss of H 2 O and CO 2 , respectively, and cleavage of sulfur bond from the molecular ion.
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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.
Preparation of compounds13a–fand14a–f
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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.
Acknowledgements
This work was supported by the Korea Research Foundation (project number 2010-0021038).
References
Aaronson D. , Horvath C. 2002 Science 296 1653 -    DOI : 10.1126/science.1071545
Yu H. , Pardoll D. , Jove R. S. 2009 Nat. Rev. Cancer 9 798 -    DOI : 10.1038/nrc2734
Rho M. C. , Song Y.-H. , Lee S. W. , Park C. S. , Oh H. M. 2013 Novel Heterocyclic Compounds and Use Thereof.