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A Synthesis of Novel Pyrazolylthienopyrimidine Derivatives as IL-6/STAT3 Inhibitors
A Synthesis of Novel Pyrazolylthienopyrimidine Derivatives as IL-6/STAT3 Inhibitors
Bulletin of the Korean Chemical Society. 2014. Sep, 35(9): 2859-2862
Copyright © 2014, Korea Chemical Society
  • Received : April 22, 2014
  • Accepted : May 26, 2014
  • Published : September 20, 2014
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Sung Min Kim
Seung Woong Lee
Yang-Heon Song

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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 Me 4 Si 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 3A and 3B . 4-Hydrazinothienopyrimidine 1A or 1B (10 mmol) and the appropriate ( E )-3-(dimethylamino)-1-phenylprop-2-en-1- one 2 (10 mmol) were mixed in ethanol (50 mL) containing HCl (1 eq), and the mixture was heated to 70 ℃ for 6 h. After evaporation of the solvent, the residue was purified by column chromatography using as eluent CH 2 Cl 2 -EtOAc (8:2) to give 3A and 3B , respectively.
4-(5-Phenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Aa) . Yield 65%; mp 54-55 ℃; 1 H NMR (DMSO- d 6 ) δ 8.89 (s, 1H, pyrimidine), 8.62 (d, 1H, J = 5.9 Hz, thiophene), 8.36 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.97 (d, 2H, phenyl), 7.60 (d, 1H, J = 5.9 Hz, thiophene), 7.48 (m, 3H, phenyl), 6.90 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 278.93 (M + ). Anal . Calcd. For C 15 H 10 N 4 S: C, 64.73; H, 3.62; N, 20.13. Found: C, 64.54; H, 3.50; N, 20.27.
4-(5-(4-Ethylphenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ab) . Yield 76%; mp 135-136 ℃; 1 H NMR (DMSO- d 6 ) δ 8.45 (s, 1H, pyrimidine), 7.92 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.70 (d, 2H, phenyl), 7.62 (d, 1H, J = 5.9 Hz, thiophene), 7.47 (d, 1H, J = 5.9 Hz, thiophene), 7.30 (d, 2H, phenyl), 6.79 (d, 1H, J = 1.6 Hz, H-4, pyrazole), 2.63 (q, 2H, CH 2 ), 1.17 (t, 3H, Me); MS (ESI): ( m/z ) 306.95 (M + ). Anal . Calcd. For C 17 H 14 N 4 S: C, 66.64; H, 4.61; N, 18.29. Found: C, 66.48; H, 4.50; N, 18.44.
4-(5-m-Tolyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ac) . Yield 70%; mp 162-163 ℃; 1 H NMR (DMSO- d 6 ) δ 8.50 (s, 1H, pyrimidine), 8.05 (d, 1H, J = 6.0 Hz, thiophene), 7.96 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.72 (s, 1H, phenyl, H 2 '), 7.67 (d, 1H, phenyl, H 6 '), 7.54 (d, 1H, J = 5.9 Hz, thiophene), 7.32 (t, 1H, phenyl, H 5 '), 7.10 (d, 1H, phenyl, H 4 '), 6.89 (d,1H, J = 1.6 Hz, H-4, pyrazole), 2.26 (s, 3H, Me); MS (ESI): ( m/z ) 292.79. (M + ). Anal . Calcd. For C 16 H 12 N 4 S: C, 65.73; H, 4.14; N, 19.16. Found: C, 65.70; H, 4.05; N, 19.02.
4-(5-p-Tolyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ad) . Yield 78%; mp 164-165 ℃; 1 H NMR (DMSO- d 6 ) δ 8.47 (s, 1H, pyrimidine), 8.17 (d, 1H, J = 6.0 Hz, thiophene), 7.88 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.82 (d, 1H, J = 5.9 Hz, thiophene), 7.74 (d, 2H, phenyl), 7.24 (d, 2H), 6.77 (d, 1H, J = 1.6 Hz, H-4, pyrazole), 2.20 (s, 3H, Me); MS (ESI): ( m/z ) 292.66. (M + ). Anal . Calcd. For C 16 H 12 N 4 S: C, 65.73; H, 4.14; N, 19.16. Found: C, 65.57; H, 4.11; N, 19.27.
4-(5-3-Bromophenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ae) . Yield 60%; mp 142-143 ℃; 1 H NMR (DMSO- d 6 ) δ 8.48 (s, 1H, pyrimidine), 7.98 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.90 (d, 1H, J = 5.9 Hz, thiophene), 7.74 (d, 1H, J = 5.9 Hz, thiophene), 7.47 (s, 1H, phenyl, H 2 '), 7.42-7.35 (m, 3H), 6.78 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 358.97. (M + ). Anal . Calcd. For C 15 H 9 BrN 4 S: C, 50.43; H, 2.54; N, 15.68. Found: C, 50.20; H, 2.42; N, 15.88.
4-(5-4-Bromophenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Af) . Yield 66%; mp 85-86 ℃; 1 H NMR (DMSO- d 6 ) δ 8.76 (s, 1H, pyrimidine), 8.10 (d, 1H, J = 5.9 Hz, thiophene), 7.95 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.82 (d, 1H, J = 5.9 Hz, thiophene), 7.54 (d, 2H, phenyl), 7.28 (d, 2H, phenyl), 6.78 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 358.81. (M + ). Anal . Calcd. For C 15 H 9 BrN 4 S: C, 50.43; H, 2.54; N, 15.68. Found: C, 50.31; H, 2.42; N, 15.61.
4-(5-3-Chlorophenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ag) . Yield 63%; mp 168-169 ℃; 1 H NMR (DMSO- d 6 ) δ 8.48 (s, 1H, pyrimidine), 7.98 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.74 (d, 1H, J = 5.9 Hz, thiophene), 7.57 (d, 1H, J = 5.9 Hz, thiophene), 7.47 (s, 1H, phenyl, H2'), 7.45-7.39 (m, 3H), 6.76 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 312.95 (M + ). Anal . Calcd. For C 15 H 9 ClN 4 S: C, 57.60; H, 2.90; N, 17.91. Found: C, 57.69; H, 2.79; N, 17.77.
4-(5-4-Chlorophenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ah) . Yield 65%; mp 172-173 ℃; 1 H NMR (DMSO- d 6 ) δ 8.76 (s, 1H, pyrimidine), 8.09 (d, 1H, J = 5.9 Hz, thiophene), 8.02 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.89 (d, 1H, J = 5.9 Hz, thiophene), 7.49 (d, 2H, phenyl), 7.35 (d, 2H, phenyl), 6.87 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 312.87 (M + ). Anal . Calcd. For C 15 H 9 ClN 4 S: C, 57.60; H, 2.90; N, 17.91. Found: C, 57.44; H, 2.82; N, 18.14.
4-(5-Phenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Ba) . Yield 62%; mp 91-93 ℃; 1 H NMR (DMSO- d 6 ) δ 8.56 (s, 1H, pyrimidine), 8.33 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 8.31 (d, 1H, J = 5.9 Hz, thiophene), 7.80 (d, 2H, phenyl), 7.46 (m, 3H, phenyl), 7.38 (d, 1H, J = 5.9 Hz, thiophene), 6.84 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 278.95 (M + ). Anal . Calcd. For C 15 H 10 N 4 S: C, 64.73; H, 3.62; N, 20.13. Found: C, 64.81; H, 3.52; N, 20.02.
4-(5-(4-Ethylphenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bb) . Yield 72%; mp 177-178 ℃; 1 H NMR (DMSO- d 6 ) δ 8.69 (s, 1H, pyrimidine), 8.06 (d, 1H, J = 5.9 Hz, thiophene), 7.85 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.63 (d, 2H, phenyl), 7.61 (d, 1H, J = 5.9 Hz, thiophene), 7.31 (d, 2H, phenyl), 6.50 (d, 1H, J = 1.6 Hz, H-4, pyrazole), 2.70 (q, 2H, CH 2 ), 1.26 (t, 3H, Me); MS (ESI): ( m/z ) 306.90 (M + ). Anal . Calcd. For C 17 H 14 N 4 S: C, 66.64; H, 4.61; N, 18.29. Found: C, 66.52; H, 4.68; N, 18.18.
4-(5-m-Tolyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bc) . Yield 76%; mp 111-112 ℃; 1 H NMR (DMSO- d 6 ) δ 8.67 (s, 1H, pyrimidine), 8.01 (d, 1H, J = 6.0 Hz, thiophene), 7.95 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.73 (s, 1H, phenyl, H 2 '), 7.60 (d, 1H, phenyl, H 6 '), 7.50 (d, 1H, J = 5.9 Hz, thiophene), 7.28 (t, 1H, phenyl, H 5 '), 7.18 (d, 1H, phenyl, H 4 '), 6.85 (d, 1H, J = 1.6 Hz, H-4, pyrazole), 2.32 (s, 3H, Me); MS (ESI): ( m/z ) 292.92. (M + ). Anal . Calcd. For C 16 H 12 N 4 S: C, 65.73; H, 4.14; N, 19.16. Found: C, 65.61; H, 4.00; N, 19.11.
4-(5-p-Tolyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bd) . Yield 70%; mp 131-132 ℃; 1 H NMR (DMSO- d 6 ) δ 8.47 (s, 1H, pyrimidine), 7.83 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.74 (d, 2H, phenyl), 7.70 (d, 1H, J = 6.0 Hz, thiophene), 7.40 (d, 1H, J = 5.9 Hz, thiophene), 7.28 (d, 2H), 6.75 (d, 1H, J = 1.6 Hz, H-4, pyrazole), 2.20 (s, 3H, Me); MS (ESI): ( m/z ) 292.67. (M + ). Anal . Calcd. For C 16 H 12 N 4 S: C, 65.73; H, 4.14; N, 19.16. Found: C, 65.68; H, 4.22; N, 19.02.
4-(5-3-Bromophenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Be) . Yield 66%; mp 111-113 ℃; 1 H NMR (DMSO- d 6 ) δ 8.55 (s, 1H, pyrimidine), 8.02 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.84 (d, 1H, J = 5.9 Hz, thiophene), 7.78 (d, 1H, J = 5.9 Hz, thiophene), 7.49 (s, 1H, phenyl, H 2 '), 7.40-7.35 (m, 3H), 6.76 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 358.86. (M + ). Anal . Calcd. For C 15 H 9 BrN 4 S: C, 50.43; H, 2.54; N, 15.68. Found: C, 50.57; H, 2.40; N, 15.49.
4-(5-4-Bromophenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bf) . Yield 65%; mp 92-95 ℃; 1 H NMR (DMSO- d 6 ) δ 8.64 (s, 1H, pyrimidine), 8.48 (d, 1H, J = 5.9 Hz, thiophene), 8.02 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.57 (d, 1H, J = 5.9 Hz, thiophene), 7.51 (d, 2H, phenyl), 7.33 (d, 2H, phenyl), 6.74 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 358.48. (M + ). Anal . Calcd. For C 15 H 9 BrN 4 S: C, 50.43; H, 2.54; N, 15.68. Found: C, 50.30; H, 2.48; N, 15.54.
4-(5-3-Chlorophenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bg) . Yield 60%; mp 132-134 ℃; 1 H NMR (DMSO- d 6 ) δ 8.68 (s, 1H, pyrimidine), 7.92 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.82 (d, 1H, J = 5.9 Hz, thiophene), 7.59 (d, 1H, J = 5.9 Hz, thiophene), 7.44 (s, 1H, phenyl, H 2 '), 7.42-7.36 (m, 3H), 6.78 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 312.95 (M + ). Anal . Calcd. For C 15 H 9 ClN 4 S: C, 57.60; H, 2.90; N, 17.91. Found: C, 57.46; H, 2.80; N, 17.82.
4-(5-4-Chlorophenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bh) . Yield 55%; mp 92-94 ℃; 1 H NMR (DMSO- d 6 ) δ 8.66 (s, 1H, pyrimidine), 8.06 (d, 1H, J = 5.9 Hz, thiophene), 7.90 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.60 (d, 1H, J = 5.9 Hz, thiophene), 7.33 (d, 2H, phenyl), 7.21 (d, 2H, phenyl), 6.50 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 312.98 (M + ). Anal . Calcd. For C 15 H 9 ClN 4 S: C, 57.60; H, 2.90; N, 17.91. Found: C, 57.76; H, 2.80; N, 17.80.
4-(5-Phenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (4Aa) . 1H NMR (DMSO- d 6 ) δ 8.96 (s, 1H, pyrimidine), 8.60 (d, 1H, J = 5.9 Hz, thiophene), 7.97-7.94 (m, 3H, phenyl and pyrazole), 7.62 (d, 1H, J = 5.9 Hz, thiophene), 7.50-7.47 (m, 3H, phenyl), 7.10 (d, 1H, J = 2.8 Hz, H-4, pyrazole); MS (ESI): ( m/z ) 278.88 (M + ). Anal . Calcd. For C 15 H 10 N 4 S: C, 64.73; H, 3.62; N, 20.13. Found: C, 64.60; H, 3.55; N, 20.03.
4-((Z)-2-((E)-1-(4-Bromophenyl)-3-(2-(thieno[3,2-d]pyramid- in-4-yl)hydrazinyl)allylidene)hydrazinyl)thieno[3,2-d]pyramid-ine (5Bf) . 1 H NMR (DMSO- d 6 ) δ 10.92 (s, 1H, NH), 8.69-8.67 (m, 2H, pyrimidine), 8.47-8.44 (m, 2H, thiophene), 7.73 (d, 2H, phenyl), 7.60 (d, 2H, phenyl), 7.50- 7.47 (m, 2H, thiophene), 7.12 (m, 1H), 6.14 (m, 1H, phenyl); MS (ESI): ( m/z ) 524.74 (M + ). Anal. Calcd. For C 21 H 15 BrN 8 S2: C, 48.19; H, 2.89; N, 21.41. Found: C, 48.03; H, 2.78; N, 21.23.
Acknowledgements
This work was supported by the Korea Research Foundation (project number 2010-0021038).
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