Table of Contents Author Guidelines Submit a Manuscript
Advances in Chemistry
Volume 2015, Article ID 850974, 8 pages
http://dx.doi.org/10.1155/2015/850974
Research Article

Synthesis, Characterization, and Antihypertensive Evaluation of Some Novel 2,2,8,8-Tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-b′]dipyran Derivatives

1Department of Pharmaceutical Chemistry, Krupanidhi College of Pharmacy, Bangalore 35, India
2Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India

Received 24 June 2014; Accepted 3 January 2015

Academic Editor: Georgia Melagraki

Copyright © 2015 Pankaj Dwivedi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A series of 2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-b′]dipyran derivatives 7a–e and 8a–e were synthesized from resorcinol. All the synthesized compounds were characterized by FTIR, mass spectra, and 1H NMR. These compounds were evaluated for antihypertensive activity using Wister Albino Rat model. Direct antihypertensive activity was performed using the instrument BIOPAC System MP-36 Santa Barbara, California, for recording blood pressure response. Among the title compounds, compounds 7b, 7c, and 7d showed potent antihypertensive activity and other compounds were also found to exert low and moderate antihypertensive activity. The relaxant potency in rat aorta and trachea was used for biological characterization of the benzopyrans. Structure-activity relationships study was investigated around position-4 of the benzopyran nucleus.

1. Introduction

Potassium specific channels are assorted group of ion channels and play a fundamental role in the modulation of cell excitability [1, 2]. Potassium channel classifications and their pharmacological activities have been reviewed extensively [3]. The term “potassium channel openers (KCOs)” was introduced to designate a group of novel synthetic molecules which are specified by cromakalim. It led to a new direction in the pharmacology of ion channels by reporting that cromakalim evoked smooth muscle relaxant effects by the opening of K+ channels in cell membranes [4]. It has initiated major research efforts in the search for other such molecules and in the determination of the specific channel(s) involved [5]. KCO properties are demonstrated in a diverse range of synthetic chemical structures and endogenous substances [6].

Cromakalim evoked a contractile response in rabbit aorta bathed in a Ca2+ free solution which is related to the effects on intracellular Ca2+ stores [7]. These findings support those obtained from vascular smooth muscle where contractile responses to noradrenaline depend on intracellular calcium stores which are attenuated by cromakalim [8]. In contrast, the effect of cromakalim on rat pulmonary artery did not appear to involve an action on Ca2+ release from internal stores [9]. A variety of compounds having a benzopyran such as levocromakalim, bimakalim, and Y-27152 generally exhibit potent antihypertensive activity. Benzodipyrans have structural and chemical similarity with the cromakalim [10]. The ATP-sensitive potassium channel (KATP) openers (e.g., chromakalim) were originally developed for the treatment of hypertension due to their potent peripheral vasodilating properties [11]. To find more potent vasodilators, various benzopyran derivatives modified at position-4 were synthesized and structure-activity relationship was examined by evaluation of the extent and duration of the increase in coronary blood flow in anesthetized dogs [12]. Compounds having a 1, 6-dihydro-6-oxopyridazin-3-yl amino group at position-4, in addition to the two methoxymethyl groups at position-2, were found to be more potent and have an improved duration of action [13].

Myocardial preconditioning as KCOs is of great interest as myocardial protecting agents [14]. The first generation (KATP) openers IVI (Figure 1) are potent peripheral vasodilators, but the use of these compounds for the treatment of acute myocardial ischemia is limited due to the possibility of hemodynamic alterations upon systemic administration which can result in under perfusion of the area that is already at risk [15]. It was presumed that clinical utility of these agents for the treatment of hypertension is due to their peripheral vasodilating properties, as they are widely known to open potassium channels in several tissue types. But relevant studies have shown that KATP openers have direct cardioprotective properties independent of their vasodilator effect. Therefore, tissue selective KATP openers are clearly required to explore the potential of these agents [16].

Figure 1: First generation potassium channel openers (KCOs) as antihypertensive agents.

2. Experimental

2.1. General

All the reagents were purchased from Sigma-Aldrich Chemicals (Bangalore, India) and were used without further purification. All solvents were distilled and dried using dry sieves as the usual manner. TLC analysis was carried out on aluminum foil precoated with silica gel 60 F254 (Sigma-Aldrich, Bangalore dealer). Melting points were determined on a Thomas micro-hot stage apparatus and are uncorrected. FTIR spectra were determined as KBr solid discs on a Shimadzu model 470 spectrophotometer. 1H NMR spectra were recorded using a Jeol Eclipse 400 MHz spectrometer using CDCl3 as NMR solvent and are reported in ppm down field from the residual CDCl3. 1H NMR spectrum exhibited different signals at different ppm which were assigned to the different types of protons. The synthetic route leading to the title compounds is summarized in Scheme 1.

Scheme 1: Synthesis of 2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-]dipyran derivatives 7a–e and 8a–e from resorcinol for antihypertensive activity.
2.2. Synthesis
2.2.1. 2,4-Diacetyl Resorcinol (2)

Dry resorcinol 1 (1.0 g, 9.09 mmol) was added to a mixture of zinc chloride (2.467 g, 18.18 mmol) in dried acetic anhydride (1.89 mL, 18.18 mmol) in a round bottom flask quickly with stirring. The reaction mixture was slowly heated on wire gauze and kept at 145–150°C for 15 min. The resulting viscous reaction mixture was allowed to cool at room temperature and ice cold aqueous hydrochloride solution was added to it with constant stirring. An orange-red crystalline compound separated out, which was purified by column chromatography to obtain white color solid compound. Yield 70.58%. mp 175–177°C. IR (KBr) ν (cm−1): 3414.3, 3079.8, 2926.1, 1658.6, 1588.6, 1256.7. 1H NMR (CDCl3, δ ppm): 12.93 (s, Ar, 2H), 8.19 (s, 1H), 6.39 (s, 1H), 2.62 (s, 6H). MS (EIMS, FAB, m/z): 195.4 (M + 1).

2.2.2. 2,2,8,8-Tetramethyl-2,3,7,8-tetrahydro-4H,6H-benzo-[1,2-b:5,4-]-dipyran-4,6-dione (3)

2,4-Diacetyl resorcinol 2 (1.0 g, 5.15 mmol) was mixed with piperidine (0.875 g, 10.3 mmol) and acetone (3.0 mL) in toluene in a round bottom flask which was fixed with Dean Stark apparatus. The resulting reaction mixture was slowly heated at 120–125°C for 24 hr. After completion of reaction, the reaction mixture was distilled off to remove the solvents. It was quenched with ice cold water and extracted with chloroform. Organic layer was separated and dried over sodium sulfate and solvent was evaporated off. The compound was purified by column chromatography over silica gel to get a white color solid product. Yield 51.85%. mp 184–186°C. IR (KBr) ν (cm−1): 2973.4, 2929.7, 1703.1, 1600.9, 1234.2. 1H NMR (CDCl3, δ ppm): 8.46 (s, 1H), 6.38 (s, 1H), 2.69 (s, 4H), 1.45 (s, 12H). MS (EIMS, FAB, m/z): 275.1 (M + 1).

2.2.3. 2,2,8,8-Tetramethyl-2,3,7,8-tetrahydro-4H,6H-benzo-[1,2-b:5,4-]dipyran-4,6-dihydroxy (4)

To a solution containing 500 mg (0.013 mol) of lithium aluminum hydride (LAH) in 25 mL ether, the corresponding chromanone 3 (1.37 g, 0.005 mole) in 30 mL of ether was added drop wise with stirring in a round bottom flask. The resulting reaction mixture was heated to reflux for an hour, allowed to cool, and then filtered. Acetone (20 mL) was added to the resulting filtrate to decompose the excess of lithium aluminum hydride and the reaction was monitored by TLC. Yield 65.43%. mp 183–185°C. IR (KBr) ν (cm−1): 3281.7, 2972.2, 2361.8, 1630.1, 1254. 1H NMR (CDCl3, δ ppm): 8.33 (d, 3H), 6.46 (s, 2H), 2.92 (s, 2H), 1.52 (s, 4H). MS (EIMS, FAB, m/z): 279.7 (M + 1).

2.2.4. 2,2,8,8-Tetramethyl-2H,8H-benzo[1,2-b:5,4-]dipyran (5)

Compound 4 was refluxed with 6 M HCl (10 mL) for 10 min. Then, 50 mL water was added to it and the reaction mixture was further refluxed for 1.0 h, allowed to cool, solvent was evaporated off, and aqueous phase was extracted with methylene chloride. Organic layer was dried over sodium sulfate, concentrated, and purified by column chromatography over silica gel to get a white color solid product. Yield 83.19%. mp 195–197°C. IR (KBr) ν (cm−1): 3042.7, 2977.5, 1562.7, 1212.7. 1H NMR (CDCl3, δ ppm): 6.61 (s, 1H), 6.27 (s, 2H), 6.25 (d, 1H, J = 9.9 Hz), 5.47 (d, 1H, J = 9.9 Hz), 1.42 (s, 12H). MS (EIMS, FAB, m/z): 243.5 (M + 1).

2.2.5. 2,2,8,8-Tetramethyl-2H,8H-benzo-[1,2-b:5,4-]dipyran Oxide (6)

Compound 5 (100 mg, 0.413 mmol) was dissolved in dichloromethane. m-Chloroperbenzoic acid (m-CPBA) (213 mg, 1.239 mmol) was added to resulting reaction mixture. It was allowed to stir at 0°C for 1 h. Solvent was evaporated at low temperature and excess of m-CPBA was decomposed by NaHCO3 solution. The aqueous solution was extracted using dichloromethane and organic layer was separated. It was concentrated and purified by column chromatography over silica gel to get a white color solid product. Yield 37.09%. mp 186–188°C. IR (KBr) ν (cm−1): 3074.3, 2934.5, 1553.5, 1243.3, 1043.4. 1H NMR (CDCl3, δppm): 7.54 (d, 1H, J = 9.6 Hz), 6.32 (d, 1H, J = 7.8 Hz), 6.27 (s, 1H), 2.46 (s, 3H). MS (EIMS, FAB, m/z): 275.1 (M + 1).

2.2.6. 2,2,8,8-Tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-]dipyran Derivatives (7a–e) and 2,2,8,8-Tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-benzo-[1,2-b:5,4-]dipyran Derivatives (8a–e)

Compound 6 (100 mg, 0.364 mmol) was dissolved in 30 mL ethanol in a 100 mL round bottom flask. Benzylamine (0.78 mL, 729 mmol) was added to the above reaction mixture and was allowed to reflux at 80°C for 3 h and reaction was monitored by TLC. After completion of reaction, it was distilled off to remove solvent from the reaction mixture. Then, it was quenched with ice cold water and extracted with dichloromethane. Organic layer was distilled off to get crude product. Further purification was accomplished by column chromatography. Mobile phase: ethyl acetate: hexane = 6:4.

2.3. Antihypertensive Activity
2.3.1. Toxicity Studies to Fix Up LD50

Toxicity studies were carried out according to the OECD guidelines numbers 420 and 421 in order to fix up the dose to carry out the antihypertensive activity [17, 18]. Wister Albino Rats weighing 200–250 g were chosen and oral route is selected for the drug administration. Six groups of animals each containing three animals were initially selected as per the guidelines numbers 420 and 421. Given dose of 70 mg/kg body weight was monitored in the animal for the toxic symptoms as well as mortality [19]. The animals showed high toxicity symptoms such as increased intestinal motility, diarrhoea, tail erection, and irritation to nose, and all the animals were dead after 3.0 h. Hence, we decreased the dose to 50 mg/kg body weight and administered to the next group of animals, monitored for toxic symptoms and mortality. In this dose, animals were safe but showed fewer toxic symptoms and only few were died. Toxicity symptoms were diarrhoea, tail erection, and irritation to the nose. Once again, we decreased the dose and it was fixed to a dose of 20 mg/kg body weight to the next set of animals and observed for the toxic symptoms and mortality. All the animals were safe and no toxic symptoms were seen at this specific dose. Hence, it was concluded that 20 mg/kg body weight dose was safe and recommended dose for further antihypertensive activity [20].

2.3.2. Direct Antihypertensive Activity

Direct antihypertensive activity was carried out using the instrument BIOPAC System MP-36 Santa Barbara California for recording the blood pressure response [21]. The instrument was calibrated before carrying out the experiment and process was thoroughly practiced and understood including handling and surgically cannulating artery for monitoring blood pressure and a vein for drug administration [22, 23].

2.3.3. Preparation of Model

Male albino rats weighing 200–250 g were used for the antihypertensive activity. Rats were anesthetized using urethane hydrochloride (1.25 g/kg). Rats were prepared by shaving the neck and inguinal region using animal hair clippers. Jugular vein was surgically cannulated for the drug administration. Left carotid artery was isolated and exposed by dissection for blood pressure recording using PE-50 tubing [24]. By means of a three-way plastic stop cock and a stainless steel needle at the end of the PE tubing, arterial cannula and venous cannula were attached to a blood-pressure transducer and syringe, respectively [25, 26]. Fluid was filled in the both cannulae with heparinised saline before cannulation. Arterial cannula was connected via the BSL pressure transducer (SS13L) to the BIOPAC Systems, Inc. Criterion for antihypertensive activity was the reduction of systolic arterial pressure by about 10–20 mmHg [27].

2.3.4. Experimental Procedure

Adrenaline (5.0 µg/kg, i.v.) was administered intravenously for the sympathetic system activation to induce hypertension [28, 29]. Venous cannula was flushed with 0.2 mL of normal saline and allowed to return to preinjection level. Test compound 20 mg/kg solution was injected intravenously and allowed to equilibration in the system. Adrenaline (5.0 µg/kg, i.v.) was repeated as described previously. Blood-pressure response was observed and recorded to each procedure [3032]. Antihypertensive activity of the benzodipyran derivatives 7a–e and 8a–c was summarized in Table 1.

Table 1: Antihypertensive activity of the benzodipyran derivatives 7ae and 8ac.

3. Result and Discussion

3.1. Chemistry

4, 6-Diacetyl resorcinol 2 was synthesized using a mixture of zinc chloride in dried acetic anhydride from dry resorcinol 1 by constant stirring. It was kept at high temperature for 30 min and was purified through column chromatography [33, 34]. Compound 3 (2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4H,6H-benzo[1,2-b:5,4-]dipyran-4,6-dione) was synthesized from 4,6-diacetyl resorcinol using acetone and piperidine in a solution in a Dean Stark apparatus using toluene as solvent. The reaction mixture was slowly heated at 120–125°C for 24 h to get the compound 3 [35, 36]. Compound 4 (2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4H,6H-benzo[1,2-b:5,4-]dipyran-4,6-dihydroxy) was synthesized using lithium aluminum hydride (LAH) in ether; the corresponding chromanone in ether and both these solutions were added drop wise with stirring. The resulting reaction mixture was heated to reflux for 1 h [37]. This reaction mixture was taken as such for the synthesis of 2,2,8,8-tetramethyl-2H,8H-benzo[1,2-b:5,4-]dipyran 5 by adding 6 M HCl and allowed to reflux for 1.5 h. After completion of the reaction, solvent was evaporated and the remaining aqueous phase was extracted with methylene chloride [38, 39]. 2,2,8,8-Tetramethyl-2H,8H-benzo[1,2-b:5,4-]dipyran oxide 6 was synthesized from compound 5 by dissolving in dichloromethane and required quantity of m-chloroperbenzoic acid (m-CPBA) was added to it. The resulting reaction mixture was allowed to stir at 0–5°C for 6-7 h [40]. Different benzodipyran derivatives 7a–e and 8a–e were synthesized from different amines such as diethylamine, 3,4-dichlorobenzylamine, dibenzylamine, benzylamine, and N-methyl piperazine. These derivatives were synthesized by the ring opening of epoxide and were identified by different spectroscopic techniques [41]. The synthesized compounds were screened for antihypertensive activity and some of these compounds showed significant antihypertensive activity. Physical and spectral analysis of 2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-]dipyran derivatives 7a–e are summarized in Table 2. Physical and spectral analysis of 2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-]dipyran derivatives 8ae are summarized in Table 3.

Table 2: Physical and spectral analysis of 2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-:5,4-] dipyran derivatives 7ae.
Table 3: Physical and spectral analysis of 2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-benzo[1,2-:5,4-] dipyran 8ae.

4. Conclusion

The present study describes the synthesis and evaluation of the antihypertensive activity of novel 2,2,8,8-tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-]dipyran derivatives 7ae and 8ae. Compounds 7b, 7c, and 7d showed potent antihypertensive activity and can constitute lead compounds. Compounds 7a, 8a, and 8c showed minimal antihypertensive activity while other compounds showed moderate antihypertensive activity.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

The authors would like to thank Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India, for providing continuous support and Krupanidhi College of Pharmacy, Bangalore, for providing necessary facilities for experimental work. The authors are also thankful to SAIF, CDRI, Lucknow, for spectral analysis of the synthesized compounds. The authors are also thankful to Council of Scientific and Industrial Research (CSIR), India, and Department of Science & Technology (DST), India, for providing for financial support.

References

  1. B. Rudy, “Diversity and ubiquity of K+ channels,” Neuroscience, vol. 25, pp. 729–735, 1988. View at Google Scholar
  2. L. Aguilar-Bryan, C. G. Nichols, S. W. Wechsler et al., “Cloning of the β cell high-affinity sulfonylurea receptor: a regulator of insulin secretion,” Science, vol. 268, no. 5209, pp. 423–426, 1995. View at Publisher · View at Google Scholar · View at Scopus
  3. K. S. Atwal, G. J. Grover, S. Z. Ahmed et al., “Cardioselective anti-ischemic ATP-sensitive potassium channel openers,” Journal of Medicinal Chemistry, vol. 36, no. 24, pp. 3971–3974, 1993. View at Publisher · View at Google Scholar · View at Scopus
  4. F. Dreyer, “Peptide toxins and potassium channels,” Reviews of Physiology Biochemistry and Pharmacology, vol. 115, pp. 93–136, 1990. View at Publisher · View at Google Scholar · View at Scopus
  5. I. Baczkó, I. Leprán, and J. G. Papp, “KATP channel modulators increase survival rate during coronary occlusion-reperfusion in anaesthetized rats,” European Journal of Pharmacology, vol. 324, no. 1, pp. 77–83, 1997. View at Publisher · View at Google Scholar · View at Scopus
  6. K. S. Atwal, P. Wang, W. L. Rogers et al., “Small molecule mitochondrial F1F0 ATPase hydrolase inhibitors as cardioprotective agents. Identification of 4-(N-arylimidazole)-substituted benzopyran derivatives as selective hydrolase inhibitors,” Journal of Medicinal Chemistry, vol. 47, no. 5, pp. 1081–1084, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. A. Noma, “ATP-regulated K+ channels in cardiac muscle,” Nature, vol. 305, pp. 147–148, 1983. View at Publisher · View at Google Scholar · View at Scopus
  8. A. D. Wickenden, “K+ channels as therapeutic drug targets,” Pharmacology & Therapeutics, vol. 94, no. 1-2, pp. 157–182, 2002. View at Publisher · View at Google Scholar
  9. S. J. H. Ashcroft and F. M. Ashcroft, “Properties and functions of ATP-sensitive K-channels,” Cellular Signalling, vol. 2, no. 3, pp. 197–214, 1990. View at Publisher · View at Google Scholar · View at Scopus
  10. G. Edwards and A. H. Weston, “The pharmacology of ATP-sensitive potassium channels,” Annual Review of Pharmacology and Toxicology, vol. 33, pp. 597–637, 1993. View at Publisher · View at Google Scholar · View at Scopus
  11. J. Anabuki, M. Hori, H. Ozaki, I. Kato, and H. Karaki, “Mechanisms of pinacidil-induced vasodilatation,” European Journal of Pharmacology, vol. 190, no. 3, pp. 373–379, 1990. View at Publisher · View at Google Scholar · View at Scopus
  12. R. H. Grimm Jr., “Antihypertensive therapy: taking lipids into consideration,” The American Heart Journal, vol. 122, no. 3, pp. 910–918, 1991. View at Publisher · View at Google Scholar · View at Scopus
  13. S. L. Archer, J. Huang, T. Henry, D. Peterson, and E. K. Weir, “A redox-based O2 sensor in rat pulmonary vasculature,” Circulation Research, vol. 73, no. 6, pp. 1100–1112, 1993. View at Publisher · View at Google Scholar · View at Scopus
  14. J. Bellemin-Baurreau, A. Poizot, P. E. Hicks, L. Rochette, and J. Michael Armstrong, “Effects of ATP-dependent K+ channel modulators on an ischemia-reperfusion rabbit isolated heart model with programmed electrical stimulation,” European Journal of Pharmacology, vol. 256, no. 2, pp. 115–124, 1994. View at Publisher · View at Google Scholar · View at Scopus
  15. V. M. Bolotina, “Calcium-activated potassium channels in cultured human endothelial cells are not directly modulated by nitric oxide,” Nature, vol. 368, pp. 850–854, 1994. View at Google Scholar
  16. G. Edwards and A. H. Weston, “The pharmacology of ATP-sensitive potassium channels,” Annual Review of Pharmacology and Toxicology, vol. 33, pp. 597–637, 1993. View at Publisher · View at Google Scholar · View at Scopus
  17. R. Hong, J. Feng, R. Hoen, and G.-Q. Lin, “Synthesis of (±)-3,3′-bis(4-hydroxy-2H-benzopyran): a literature correction,” Tetrahedron, vol. 57, no. 41, pp. 8685–8689, 2001. View at Publisher · View at Google Scholar · View at Scopus
  18. K. Tanaka, H. Kawasaki, K. Kurata, Y. Aikawa, Y. Tsukamoto, and T. Inaba, “T-614, a novel antirheumatic drug, inhibits both the activity and induction of cyclooxygenase-2 (COX-2) in cultured fibroblasts,” Japanese Journal of Pharmacology, vol. 67, no. 4, pp. 305–314, 1995. View at Publisher · View at Google Scholar · View at Scopus
  19. E. Tyrrell, K. H. Tesfa, I. Greenwood, and A. Mann, “The synthesis and biological evaluation of a range of novel functionalised benzopyrans as potential potassium channel activators,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 3, pp. 1237–1240, 2008. View at Publisher · View at Google Scholar · View at Scopus
  20. J. M. Evans, C. S. Fake, T. C. Hamilton, R. H. Poyser, and G. A. Showell, “Synthesis and antihypertensive activity of 6,7-disubstituted trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ols,” Journal of Medicinal Chemistry, vol. 27, no. 9, pp. 1127–1131, 1984. View at Publisher · View at Google Scholar · View at Scopus
  21. G. C. Rovnyak, S. Z. Ahmed, C. Z. Ding et al., “Cardioselective antiischemic ATP-sensitive potassium channel (KATP) openers. 5. Identification of 4-(N-aryl)-substituted benzopyran derivatives with high selectivity,” Journal of Medicinal Chemistry, vol. 40, no. 1, pp. 24–34, 1997. View at Publisher · View at Google Scholar · View at Scopus
  22. H. H. Herman, S. H. Pollock, L. C. Fowler, and S. W. May, “Demonstration of the potent antihypertensive activity of phenyl-2-aminoethyl sulfides,” Journal of Cardiovascular Pharmacology, vol. 11, no. 5, pp. 201–210, 1988. View at Publisher · View at Google Scholar · View at Scopus
  23. J. L. Wang, K. Aston, D. Limburg et al., “The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part III: the three microdose candidates,” Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 23, pp. 7164–7168, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. Y.-M. Lee, M.-H. Yen, Y.-Y. Peng et al., “The antihypertensive and cardioprotective effects of (−)-MJ-451, an ATP-sensitive K+ channel opener,” European Journal of Pharmacology, vol. 397, no. 1, pp. 151–160, 2000. View at Publisher · View at Google Scholar · View at Scopus
  25. N. Kaur, A. Kaur, Y. Bansal, D. I. Shah, G. Bansal, and M. Singh, “Design, synthesis, and evaluation of 5-sulfamoyl benzimidazole derivatives as novel angiotensin II receptor antagonists,” Bioorganic and Medicinal Chemistry, vol. 16, no. 24, pp. 10210–10215, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. S. Prasanna, E. Manivannan, and S. C. Chaturvedi, “Quantitative structure-activity relationship analysis of a series of 2,3-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 14, no. 15, pp. 4005–4011, 2004. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Bali, Y. Bansal, M. Sugumaran et al., “Design, synthesis, and evaluation of novelly substituted benzimidazole compounds as angiotensin II receptor antagonists,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 17, pp. 3962–3965, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. L. Xing, B. C. Hamper, T. R. Fletcher et al., “Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 3, pp. 993–996, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. J. Gierse, M. Nickols, K. Leahy et al., “Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors,” European Journal of Pharmacology, vol. 588, no. 1, pp. 93–98, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. H. J. Finlay, J. Lloyd, M. Nyman et al., “Pyrano-[2,3b]-pyridines as potassium channel antagonists,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 8, pp. 2714–2718, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. B. Becker, M.-H. Antoine, Q.-A. Nguyen et al., “Synthesis and characterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissues,” British Journal of Pharmacology, vol. 134, no. 2, pp. 375–385, 2001. View at Publisher · View at Google Scholar · View at Scopus
  32. Y. H. Joo, J. K. Kim, S.-H. Kang et al., “2,3-Diarylbenzopyran derivatives as a novel class of selective cyclooxygenase-2 inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 3, pp. 413–417, 2003. View at Publisher · View at Google Scholar · View at Scopus
  33. R. Hong, J. Feng, R. Hoen, and G.-Q. Lin, “Synthesis of (±)-3,3′-bis(4-hydroxy-2H-benzopyran): a literature correction,” Tetrahedron, vol. 57, no. 41, pp. 8685–8689, 2001. View at Publisher · View at Google Scholar · View at Scopus
  34. J. Lim, I.-H. Kim, H. H. Kim, K.-S. Ahn, and H. Han, “Enantioselective syntheses of decursinol angelate and decursin,” Tetrahedron Letters, vol. 42, no. 24, pp. 4001–4003, 2001. View at Publisher · View at Google Scholar · View at Scopus
  35. M. C. Breschi, V. Calderone, A. Martelli et al., “New benzopyran-based openers of the mitochondrial ATP-sensitive potassium channel with potent anti-ischemic properties,” Journal of Medicinal Chemistry, vol. 49, no. 26, pp. 7600–7602, 2006. View at Publisher · View at Google Scholar · View at Scopus
  36. T. Takahashi, H. Koga, H. Sato, T. Ishizawa, N. Taka, and J.-I. Imagawa, “Synthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openers,” Bioorganic and Medicinal Chemistry, vol. 6, no. 3, pp. 323–337, 1998. View at Publisher · View at Google Scholar · View at Scopus
  37. H. Cho, S. Katoh, S. Sayama et al., “Synthesis and selective coronary vasodilatory activity of 3,4-dihydro- 2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivatives: novel potassium channel openers,” Journal of Medicinal Chemistry, vol. 39, no. 19, pp. 3797–3805, 1996. View at Publisher · View at Google Scholar · View at Scopus
  38. N. Taka, H. Koga, H. Sato, T. Ishizawa, T. Takahashi, and J.-I. Imagawa, “6-Substituted 2,2-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openers,” Bioorganic and Medicinal Chemistry, vol. 8, no. 6, pp. 1393–1405, 2000. View at Publisher · View at Google Scholar · View at Scopus
  39. R. Thompson, S. Doggrell, and J. O. Hoberg, “Potassium channel activators based on the benzopyran substructure: synthesis and activity of the C-8 substituent,” Bioorganic & Medicinal Chemistry, vol. 11, no. 8, pp. 1663–1668, 2003. View at Publisher · View at Google Scholar · View at Scopus
  40. R. Mannhold, G. Cruciani, H. Weber et al., “6-Substituted benzopyrans as potassium channel activators: synthesis, vasodilator properties, and multivariate analysis,” Journal of Medicinal Chemistry, vol. 42, no. 6, pp. 981–991, 1999. View at Publisher · View at Google Scholar · View at Scopus
  41. J. Renaud, S. F. Bischoff, T. Buhl et al., “Estrogen receptor modulators: identification and structure—activity relationships of potent ERα-selective tetrahydroisoquinoline ligands,” Journal of Medicinal Chemistry, vol. 46, no. 14, pp. 2945–2951, 2003. View at Publisher · View at Google Scholar · View at Scopus