Abstract

Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration and therefore cause hypoglycemia in type 2 diabetic patients. Over the last years, a number of aryl-imidazoline derivatives have been identified that stimulate insulin secretion in a glucose-dependent manner. In the present study, we have developed three series of substituted N-(thieno[2,3-b]pyridin-3-yl)-guanidine (2a–l), N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3a–l), and N-(1H-indol-3-yl)-guanidine (4a–l) as new class of antidiabetic agents. In vitro glucose-dependent insulinotropic activity of test compounds 2a–l, 3a–l, and 4a–l was evaluated using RIN5F (Rat Insulinoma cell) based assay. All the test compounds showed concentration-dependent insulin secretion, only in presence of glucose load (16.7 mmol). Some of the test compounds (2c, 3c, and 4c) from each series were found to be equipotent to BL 11282 (standard aryl-imidazoline), which indicated that the guanidine group acts as a bioisostere of imidazoline ring system.

Graphical abstract

New class of substituted hetero-aryl guanidine derivatives were prepared as BL 11282 analog and screened in vitro for glucose-dependent insulinotropic activity.

Keywords: Guanidine; Pyrrolo[2,3-b]pyridine; Thieno[2,3-b]pyridine; Indole; Type 2 diabetes; Insulinotropic; Antidiabetic

Article Outline

1. Introduction

2. Chemistry

3. Results and discussion

3.1. In vitro insulin secretion assay results

4. Conclusions

5. Experimental

5.1. Chemistry

5.2. Experimental details

5.2.1. General method for the synthesis of N-(2,5-disubstituted-thieno[2,3-b]pyridin-3-yl)-guanidine (2a–l; Scheme 1)

5.2.1.1. Synthesis of bis-Boc-N-(thieno[2,3-b]pyridin-3-yl)-guanidine (6a)

5.2.1.2. Bis-Boc-N-(5-chloro-thieno[2,3-b]pyridin-3-yl)-guanidine (6b)

5.2.1.3. Bis-Boc-N-(5-chloro-2-methyl-thieno[2,3-b]pyridin-3-yl)-guanidine (6c)

5.2.1.4. Bis-Boc-N-(2-methyl-thieno[2,3-b]pyridin-3-yl)-guanidine (6d)

5.2.1.5. Bis-Boc-N-(2-phenyl-thieno[2,3-b]pyridin-3-yl)-guanidine (6e)

5.2.1.6. Bis-Boc-N-(5-chloro-2-phenyl-thieno[2,3-b]pyridin-3-yl)-guanidine (6f)

5.2.1.7. Bis-Boc-N-(2-cyclohexyl-thieno[2,3-b]pyridin-3-yl)-guanidine (6g)

5.2.1.8. Bis-Boc-N-(5-chloro-2-cyclohexyl-thieno[2,3-b]pyridin-3-yl)-guanidine (6h)

5.2.1.9. Bis-Boc-N-(2-ethyl-thieno[2,3-b]pyridin-3-yl)-guanidine (6i)

5.2.1.10. Bis-Boc-N-(5-chloro-2-ethyl-thieno[2,3-b]pyridin-3-yl)-guanidine (6j)

5.2.1.11. Bis-Boc-N-(2-benzyl-thieno[2,3-b]pyridin-3-yl)-guanidine (6k)

5.2.1.12. Bis-Boc-N-(2-benzyl-5-chloro-thieno[2,3-b]pyridin-3-yl)-guanidine (6l)

5.2.1.13. Synthesis of N-(thieno[2,3-b]pyridin-3-yl)-guanidine (2a)

5.2.1.14. N-(5-Chloro-thieno[2,3-b]pyridin-3-yl)-guanidine (2b)

5.2.1.15. N-(5-Chloro-2-methyl-thieno[2,3-b]pyridin-3-yl)-guanidine (2c)

5.2.1.16. N-(2-Methyl-thieno[2,3-b]pyridin-3-yl)-guanidine (2d)

5.2.1.17. N-(2-Phenyl-thieno[2,3-b]pyridin-3-yl)-guanidine (2e)

5.2.1.18. N-(5-Chloro-2-phenyl-thieno[2,3-b]pyridin-3-yl)-guanidine (2f)

5.2.1.19. N-(2-Cyclohexyl-thieno[2,3-b]pyridin-3-yl)-guanidine (2g)

5.2.1.20. N-(5-Chloro-2-cyclohexyl-thieno[2,3-b]pyridin-3-yl)-guanidine (2h)

5.2.1.21. N-(2-Ethyl-thieno[2,3-b]pyridin-3-yl)-guanidine (2i)

5.2.1.22. N-(5-Chloro-2-ethyl-thieno[2,3-b]pyridin-3-yl)-guanidine (2j)

5.2.1.23. N-(2-Benzyl-thieno[2,3-b]pyridin-3-yl)-guanidine (2k)

5.2.1.24. N-(2-Benzyl-5-chloro-thieno[2,3-b]pyridin-3-yl)-guanidine (2l)

5.2.2. General method for the synthesis of N-(2,5-disubstituted-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3a–l; Scheme 2)

5.2.2.1. Synthesis of 3-nitroso-1H-pyrrolo[2,3-b]pyridine (8a)

5.2.2.2. 5-Chloro-3-nitroso-1H-pyrrolo[2,3-b]pyridine (8b)

5.2.2.3. 5-Chloro-2-methyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine (8c)

5.2.2.4. 2-Methyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine (8d)

5.2.2.5. 3-Nitroso-2-phenyl-1H-pyrrolo[2,3-b]pyridine (8e)

5.2.2.6. 5-Chloro-3-nitroso-2-phenyl-1H-pyrrolo[2,3-b]pyridine (8f)

5.2.2.7. 2-Cyclohexyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine (8g)

5.2.2.8. 5-Chloro-2-cyclohexyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine (8h)

5.2.2.9. 2-Ethyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine (8i)

5.2.2.10. 5-Chloro-2-ethyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine (8j)

5.2.2.11. 2-Benzyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine (8k)

5.2.2.12. 2-Benzyl-5-chloro-3-nitroso-1H-pyrrolo[2,3-b]pyridine (8l)

5.2.2.13. Synthesis of 3-amino-1H-pyrrolo[2,3-b]pyridine (9a)

5.2.2.14. 5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9b)

5.2.2.15. 5-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9c)

5.2.2.16. 2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9d)

5.2.2.17. 2-Phenyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9e)

5.2.2.18. 5-Chloro-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9f)

5.2.2.19. 2-Cyclohexyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9g)

5.2.2.20. 5-Chloro-2-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9h)

5.2.2.21. 2-Ethyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9i)

5.2.2.22. 5-Chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9j)

5.2.2.23. 2-Benzyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9k)

5.2.2.24. 2-Benzyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylamine (9l)

5.2.2.25. Synthesis of bis-Boc-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10a)

5.2.2.26. Bis-Boc-N-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10b)

5.2.2.27. Bis-Boc-N-(5-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10c)

5.2.2.28. Bis-Boc-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10d)

5.2.2.29. Bis-Boc-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10e)

5.2.2.30. Bis-Boc-N-(5-chloro-2-Phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10f)

5.2.2.31. Bis-Boc-N–(2-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10g)

5.2.2.32. Bis-Boc-N-(5-chloro-2-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10h)

5.2.2.33. Bis-Boc-N-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10i)

5.2.2.34. Bis-Boc-N-(5-chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10j)

5.2.2.35. Bis-Boc-N-(2-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10k)

5.2.2.36. Bis-Boc-N-(2-benzyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (10l)

5.2.2.37. Synthesis of N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3a)

5.2.2.38. N-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3b)

5.2.2.39. N-(5-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3c)

5.2.2.40. N-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3d)

5.2.2.41. N-(2-Phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3e)

5.2.2.42. N-(5-Chloro-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3f)

5.2.2.43. N-(2-Cyclohexyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3g)

5.2.2.44. N-(5-Chloro-2-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3h)

5.2.2.45. N-(2-Ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3i)

5.2.2.46. N-(5-Chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3j)

5.2.2.47. N-(2-Benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3k)

5.2.2.48. N-(2-Benzyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3l)

5.2.3. General method for the synthesis of N-(2,5-disubstituted-1H-indol-3-yl)-guanidine (4a–l; Scheme 3)

5.2.3.1. Synthesis of 3-nitro-1H-indole (12a)

5.2.3.2. 5-Chloro-3-nitro-1H-indole (12b)

5.2.3.3. 5-Chloro-2-methyl-3-nitro-1H-indole (12c)

5.2.3.4. 2-Methyl-3-nitro-1H-indole (12d)

5.2.3.5. 3-Nitro-2-phenyl-1H-indole (12e)

5.2.3.6. 5-Chloro-3-nitro-2-phenyl-1H-indole (12f)

5.2.3.7. 2-Cyclohexyl-3-nitro-1H-indole (12g)

5.2.3.8. 5-Chloro-2-cyclohexyl-3-nitro-1H-indole (12h)

5.2.3.9. 2-Ethyl-3-nitro-1H-indole (12i)

5.2.3.10. 5-Chloro-2-ethyl-3-nitro-1H-indole (12j)

5.2.3.11. 2-Benzyl-3-nitro-1H-indole (12k)

5.2.3.12. 2-Benzyl-5-chloro-3-nitro-1H–indole (12l)

5.2.3.13. Synthesis of 3-amino-1H-indole (13a)

5.2.3.14. 5-Chloro-1H-indol-3-ylamine (13b)

5.2.3.15. 5-Chloro-2-methyl-1H-indol-3-ylamine (13c)

5.2.3.16. 2-Methyl-1H-indol-3-ylamine (13d)

5.2.3.17. 2-Phenyl-1H-indol-3-ylamine (13e)

5.2.3.18. 5-Chloro-2-phenyl-1H-indol-3-ylamine (13f)

5.2.3.19. 2-Cyclohexyl-1H-indol-3-ylamine (13g)

5.2.3.20. 5-Chloro-2-cyclohexyl-1H-indol-3-ylamine (13h)

5.2.3.21. 2-Ethyl-1H-indol-3-ylamine (13i)

5.2.3.22. 5-Chloro-2-ethyl-1H-indol-3-ylamine (13j)

5.2.3.23. 2-Benzyl-1H-indol-3-ylamine (13k)

5.2.3.24. 2-Benzyl-5-chloro-1H-indol-3-ylamine (13l)

5.2.3.25. Synthesis of bis-Boc-N-(1H-indol-3-yl)-guanidine (14a)

5.2.3.26. Bis-Boc-N-(5-chloro-1H-indol-3-yl)-guanidine (14b)

5.2.3.27. Bis-Boc-N-(5-chloro-2-methyl-1H-indol-3-yl)-guanidine (14c)

5.2.3.28. Bis-Boc-N-(2-methyl-1H-indol-3-yl)-guanidine (14d)

5.2.3.29. Bis-Boc-N-(2-phenyl-1H-indol-3-yl)-guanidine (14e)

5.2.3.30. Bis-Boc-N-(5-chloro-2-Methyl-1H-indol-3-yl)-guanidine (14f)

5.2.3.31. Bis-Boc-N-(2-cyclohexyl-1H-indol-3-yl)-guanidine (14g)

5.2.3.32. Bis-Boc-N-(5-chloro-2-cyclohexyl-1H-indol-3-yl)-guanidine (14h)

5.2.3.33. Bis-Boc-N-(2-ethyl-1H-indol-3-yl)-guanidine (14i)

5.2.3.34. Bis-Boc-N-(5-chloro-2-ethyl-1H-indol-3-yl)-guanidine (14j)

5.2.3.35. Bis-Boc-N-(2-benzyl-1H-indol-3-yl)-guanidine (14k)

5.2.3.36. Bis-Boc-N-(5-chloro-2-benzyl-1H-indol-3-yl)-guanidine (14l)

5.2.3.37. Synthesis of N-(1H-Indol-3-yl)-guanidine (4a)

5.2.3.38. N-(5-Chloro-1H-indol-3-yl)-guanidine (4b)

5.2.3.39. N-(5-Chloro-2-methyl-1H-indol-3-yl)-guanidine (4c)

5.2.3.40. N-(2-Methyl-1H-indol-3-yl)-guanidine (4d)

5.2.3.41. N-(2-Phenyl-1H-indol-3-yl)-guanidine (4e)

5.2.3.42. N-(5-Chloro-2-phenyl-1H-indol-3-yl)-guanidine (4f)

5.2.3.43. N-(2-Cyclohexyl-1H-indol-3-yl)-guanidine (4g)

5.2.3.44. N-(5-Chloro-2-cyclohexyl-1H-indoyl-3-yl)-guanidine (4h)

5.2.3.45. N-(2-Ethyl-1H-indol-3-yl)-guanidine (4i)

5.2.3.46. N-(5-Chloro-2-ethyl-1H-indol-3-yl)-guanidine (4j)

5.2.3.47. N-(2-Benzyl-1H-indol-3-yl)-guanidine (4k)

5.2.3.48. N-(2-Benzyl-5-chloro-1H-indol-3-yl)-guanidine (4l)

5.3. In vitro glucose-dependent insulin secretion (RIN5F cell assay screening protocol)

Acknowledgements

References

ZRC communication No. 189.