Abstract
Two series of sulfonylureas derivatives including 24 compounds (4, 7, 5a–5o, 8a–8h), among them 17 new derivatives, have been synthesized and evaluated for their α-glucosidase inhibitory activity. Compounds 5c, 5h and 8e showed significant in vitro α-glucosidase inhibition with IC50 values of 5.58, 79.85 and 213.36 µm, respectively, comparing with the standard compounds acarbose (IC50 = 268.29 µm) and glipizide (IC50 = 300.47 µm). The preliminary structure-activity relationships (SARs) of the synthesized compounds were also investigated.
1 Introduction
Sulfonylurea derivatives are compounds containing a central S-aryl sulfonylurea unit with p-substituents on the phenyl ring (R1) and substituents at the urea’s N′-terminus (R2) [1] (Figure 1). They exhibit a wide range of biological activity such as antidiabetic [2], diuretic [3], antitubercular [4], antimalerial [5], anticancer [6], anti-inflammatory [7], thromboxane A2 receptor antagonism activity [8]. Especially sulfonylureas are widely used in medicine as potent blood glucose-reducing agents for the treatment of diabetes. Sulfonylureas alter the plasma membrane of cells to increase their responsiveness to insulin action, by increasing the number of insulin receptors [1]. The side effect of these reagents is, however, associated with hypoglycemia, weight gain and cardiovascular risks. The combination of sulfonylureas with α-glucosidase inhibitors, an add-on therapy, have been reported to improve lipid profiles, decrease body weight, prevent macroangiopathy, reduce the hemoglobin A1c and control the glycemic level in type 2 diabetic patients [9], [ 10].
Structures of sulfonylureas and glipizide.
The present study is aimed to develop novel sulfonylurea derivatives with increased α-glucosidase inhibitory activity as well as decreasing the diabetic complications during treatment by sulfonylureas. Two series of sulfonylurea derivatives based on the structure of glipizide (Figure 1), an antidiabetic medicament, have been synthesized. Various phenyl and heterocyclic rings were incorporated into the sulfonylurea scaffold. As a result, 24 derivatives (4, 7, 5a–5o, 8a–8h) were obtained, 17 of which (5a, 5c, 5e, 5g–5k, 5n, 5o, 8a–8h) are new. All of the synthesized compounds were evaluated for α-glucosidase inhibition.
2 Results and discussion
2.1 Chemistry
The synthetic routes of compounds 5a–5o and 8a–8h are shown in Schemes 1 and 2, respectively. The structure of glipizide was modified at N-phenylethylsulfamoyl moiety (R1 substitution), while the cyclohexyl ring at the N-terminus was maintained (Scheme 1). The desired products were synthesized by a general method for the synthesis of sulfonylurea derivatives by treatment of sulfonamides with appropriate isocyanides in the presence of base (Scheme 1) [1]. Compound 1 (4-(2-aminoethyl)benzenesulfoamide) was used as the starting material. N-Boc protection of 1 gave compound 2 which was then reacted with cyclohexyl isocyanate in the presence of K2CO3 to afford 3. Deprotection of 3 with trifluoroacetic acid (TFA) in DCM provided the key intermediate 4. Finally, coupling of 4 with various of carboxylic acids in the presence of ethyl chloroformate and triethylamine (TEA) gave the target compounds 5a–5l. Instead of SOCl2 or (COCl)2 as reagent to activate carboxylic acid, ethyl chloroformate was used to avoid the formation of by-products (Scheme 1). The sulfonylurea derivatives (5a–5l) were obtained in moderate to good yields (66–82%). Compounds 5m, 5n and 5o were prepared by treatment of 2,3-pyridine dicarboxylic anhydride or phthalic anhydride with amine 4. According to the literature, the reactivity of 2,3-pyridine dicarboxylic anhydride toward nitrogen nucleophiles under different conditions affords different products [11]. In our study, treatment of 4 with 2,3-pyridine dicarboxylic anhydride in glacial acetic acid at room temperature gave nicotinic acid derivative 5o. This was compatible with the studies of Ammar YA et al. for the similar reaction [11]. It was reported that refluxing 2,3-pyridine dicarboxylic anhydride with amine in glacial acetic acid for 3 h led to the dicarboxylation of the carboxylic acid group, providing nicotiamide as main product and nicotiimide as as a minor product [11]. However, in our case, nicotiimide 5n was obtained as the main product, even heating the reaction for 7 h.
Synthesis of sulfonylurea derivatives (5a–5o). Reagents and conditions: a) DMF, Boc2O, r.t., 4 h, 95%; b) Cyclohexyl isocyanate, K2CO3, acetone, r.t., 6 h, 96.6%; c) TFA, DCM, r.t., 4 h, 92%; d) ClCO2C2H5, TEA, acetone, 0–5 °C, 1 h; e) 4, TEA, acetone, r.t., 4 h, 69.3–81.1%; f) 4, acetic acid, reflux, 7 h, (5m: 81.5%, 5n: 66.1%); g) 4, acetic acid, r.t., 1 h, 72.5%.
Synthesis of sulfonylurea derivatives 8a–8h. Reagents and conditions: a) i. ClCO2Et, TEA, acetone, 0 °C, 1 h; ii. 1, TEA, acetone, r.t., 3 h, 93.4%; b) K2CO3, acetone, ClCO2C2H5, reflux, 4 h, 89.2%; c) toluene, R2NH2, reflux, 4 h, 68.4–84.2%.
The structures of the synthesized compounds were confirmed by means of MS, 1D (1H, 13C) and 2D (HSQC, HMBC) spectra. The 1H NMR spectra of 2 indicated the additional signal of tert-butyl group at δH = 1.36 ppm (9H, 3 × CH3), together with the corresponding signals of 1. The formation of urea cyclohexyl moiety in compound 3 was confirmed by the appearance of the signals at δH = 1.65–1.18 ppm (C6H11), 10.25 ppm (br s, 1H, SO2NH), and at δC = 150.35 ppm (NHCONH), 48.01–24.10 ppm (C6H11). The lack of the tert-butyl signal in the 1H NMR of compound 4 indicated the removing of the protecting group in the structure of 4. The formation of the amide urea moiety in 4 was further confirmed by the correlation between CONH-C6H11 (δH = 6.62 ppm)/C-8′ (δC = 150.49 ppm), C-1 (δC = 48.06 ppm) and C-2, C-6 (δC = 32.24 ppm) in HMBC spectrum. The presence of additionally aromatic proton signals as well as the signals of amide groups at δH = 8.07–9.83 ppm (CONH) and δC = 165.0–168.2 ppm (CONH) proved the formation of the sulfoamide derivative (5a–5l). Compound 5c showed the signals of an AB substituted aromatic ring at δH = 7.38 ppm (d, J = 8.5 Hz, 2H, 2‴-H, 6‴-H) and δH = 6.79 ppm (d, J = 8.5 Hz, 2H, 3‴-H, 5‴-H). The correlation of H-6‴ (δH = 8.17 ppm)/CONHCH2 (δC = 168.04 ppm) in HMBC spectrum confirmed the formation of amide bond in 5h. The appearance of four additional aromatic protons signals at δH = 7.85–7.81 ppm, and the carbon signals at δC = 167.60 (COOH), 134.40 and 131.43 ppm (C–Ar) confirmed the structure of compound 5m. The aromatic pyridine protons at δH = 8.96–7.77 ppm, together with the carbon signals at δC = 166.03, 165.93 (CONH imide) indicated the formation of the imide ring in 5n. The correlation of δH = 8.05 ppm (4‴-H)/δC = 167.9 ppm (COOH) and δH = 8.66 ppm (6‴-H)/δC = 165.06 ppm (CONH) was observed in HMBC spectrum of 5o, suggesting the location of carboxylic acid and amide moiety at C-3‴ and C-2‴ of pyridine ring, respectively. Furthermore, the formation of the amide bond in compound 5o was confirmed by the correlation of CONH (δH = 8.76) ppm/C=O (δC 165.06 ppm), C-2’’ (δC = 39.83 ppm).
In Scheme 2, various substitutions at N-terminus of the urea moiety (R1) were introduced to provide sulfonylureas mimic glipizide. Compound 5-methylpyrazin-2-carboxylic acid was treated with ethyl chloroformate in the presence of TEA, following by the addition of 1 to yield sulfonamide (6). This compound was subsequently refluxed with ethyl chloroformate in the presence of anhydrous potassium carbonate (K2CO3) to obtain the key intermediate carbamate 7. Finally, sulfonylurea derivatives 8a–8h were synthesized by condensation of 7 with various of amines in toluene. The use of toluene as solvents gave the products in the best yields, comparing with other solvents such as dioxane or DMF. The structures of the products were elucidated by means of 1H and 13C NMR spectroscopy. The 1H NMR spectrum of compound 6 indicated the presence of two singlet signals of pyrazine protons at δH = 9.02 ppm (s, 1H, 3‴-H) and δH = 8.59 ppm (s, 1H, 6‴-H). The appearance of the NH protons at δH = 8.91 ppm (t, J = 6.0 Hz, 1H, CONH), δH = 7.27 ppm (s, 2H, SO2NH2) in the 1H NMR spectrum confirmed the structure the amide product 6. The NMR spectra of 7 exhibited additionally signals at δH = 3.99 ppm (q, J = 7.0 Hz, 2H) and δH = 1.07 ppm (t, J = 7.0 Hz, 3H), and at δC = 151.01, 61.83 and 13.88 ppm, corresponding to the carbamate moiety (NHCOOCH2CH3). The disappearance of the ethyl ester protons and the presence of aromatic protons at δH = 7.01–7.89 ppm in 1H NMR spectra of 8a–8h clearly confirmed the formation of urea derivatives. The carbonyl carbons of the urea groups (NHCONH) were resonated at δC = 156–158 ppm in the 13C NMR spectra of 8a–8h.
2.2 Biological activity
Twenty-two compounds (5a–5o, 8a–8h) were evaluated for their ability to inhibit α-glucosidase. Acarbose and glipizide were used as standard compounds to compare with the synthesized derivatives. Compound 5c (R = 4–OH–C6H4) was the most active compound with an IC50 value of 5.58 µm, 48 and 60 times much better than the standard drug acarbose and glipizide (IC50 of 268.29 and 300.47 µm, respectively). The p-substituted hydroxyl group at trans-cinnamoyl moiety plays an important role of the activity. This is confirmed due to the observation that compound 5d without the OH group (R = –C6H5) did not show α-glucosidase inhibition. Preliminary structure-activity relationships (SARs) presumed that trans-cinnamoyl derivatives are weak intestinal α-glucosidase inhibitors [12]. However, the presence of a hydroxyl group at para position enhanced significantly the inhibition, probably because they may form hydrogen bonds with the polar groups (amide, guanidine, peptide, amino, and carboxyl groups) of amino acid residues in the active site of intestinal α-glucosidase enzyme [12]. Compound 5h (R = 2–OH–3,5–di–I–C6H2) exhibited good activity with an IC50 value of 79.85 µm. Comparing the activity of 5h with 5g (R = 2–I–C6H4, IC50 of 278.88 µm), the installation of OH and disubstituted iodine seems to enhance the activity. Compound 5l, 5i and 5o with heterocyclic substitutions (quinoxaline, isoquinoline and picolinic, respectively) showed moderate activity with IC50 values of 226.03, 322.49 and 312.12 µm, respectively (Table 1, Scheme 1). Compound 8e (R1 = 3–CF3–4–NO2–C6H3) and 8g (R1 = 2–OH–4–NO2–C6H3) exhibited good activity with an IC50 of 213.36 and 269.44 µm, respectively (Table 1, Scheme 2), comparing with acarbose and glipizide (IC50 = 268.29 and 300.47 µm), respectively. The introduction of the nitro group into the aromatic rings of the series products in Scheme 2 seems to enhance the α-glucosidase inhibitory activity. Other compounds were found to be inactive.
α-Glucosidase inhibitory activity of sulfonylurea derivatives.
| Nr | Compound | IC50 (µm) | Nr | Compound | IC50 (µm) |
|---|---|---|---|---|---|
| 1 | 5a | > 350 | 13 | 5n | > 350 |
| 2 | 5b | > 350 | 14 | 5o | 312.12 |
| 3 | 5c | 5.58 | 15 | 8a | > 350 |
| 4 | 5d | > 350 | 16 | 8b | > 350 |
| 5 | 5e | > 350 | 17 | 8c | > 350 |
| 6 | 5f | > 350 | 18 | 8d | > 350 |
| 7 | 5g | 278.88 | 19 | 8e | 213.36 |
| 8 | 5h | 79.85 | 20 | 8f | > 350 |
| 9 | 5i | 322.49 | 21 | 8g | 269.44 |
| 10 | 5k | > 350 | 22 | 8h | > 350 |
| 11 | 5l | 226.03 | 23 | Acarbosea | 268.29 |
| 12 | 5m | > 350 | 24 | Glipizideb | 300.47 |
a, bStandard compounds.
3 Conclusions
In conclusion, 24 sulfonylurea derivatives have been synthesized and evaluated for their α-glucosidase inhibitory activity. Among them, compound 5c, 5h, 5l and 8e exhibited significant α-glucosidase inhibition, comparing with the commercially available acarbose and glipizide. The introduction of 4-hydroxyl-trans-cinnamoyl moiety at N-phenylethylsulfamoyl unit (compound 5c) considerably increased α-glucosidase inhibitory activity. Our newly synthesized sulfonylurea derivatives exhibited promising α-glucosidase inhibition, which would be supported for the “add on therapy” to prevent the complications during the treatment of diabetics by sulfonylurea agents. Comprehensive pharmacological investigation of these compounds should be taken under consideration for further research.
4 Experimental section
4.1 Materials and methods
Reagents were purchased from Aldrich and Merck with analytical grade and used without further purification. Solvents for column chromatography were distilled before using. Melting points (in °C) were determined on a Thermo Mel-temp 3.0 (U.S.A). IR spectra were recorded on an IMPACT 410 Nicolet spectrometer. ESI-MS spectra were measured on 1100Agilent LC/MS ion Trap. NMR spectra (1H, 13C, DEPT, HSQC, and HMBC) were recorded on a Bruker Avance 500 MHz. Thin layer chromatography was performed on a pre-coated silica gel 60 F254 (Merck) and were visualized under UV light (λmax = 254 nm) and stained with a solution of 1% (w/w) vanillin in H2SO4. Column chromatography was performed on silica gel 300–400 mesh (Merck).
4.2 α-Glucosidase inhibition assay
The assay was performed on 96 well-plates (200 µL per well). The test sample was dissolved in 10% DMSO and diluted further to the concentrations of 1024, 256, 64, 16, 4, 1 μg mL−1. Each concentration of the test sample (10 μL) was incubated at T = 37 °C with phosphate buffer 100 mm (pH = 6.8, 40 µL), α-glucosidase 0.4 U mL−1 (25 µL), p-nitrophenyl α-d-glucopyranoside 2.5 mm (25 µL). After 30 min, the reaction was stopped by adding 100 µL of 0.1 m Na2CO3. The enzyme activities were determined by measuring the absorbance at λmax = 405 nm. The control was prepared using the same procedure replacing the tested sample by distilled water, while activity of the reference was tested by replacing the sample with acarbose. Percentage of inhibition was calculated as followed:
4.3 Synthesis of tert-butyl(4-sulfamoylphenethyl)carbamate (2) [13]
4-(2-Aminoethyl)benzenesulfonamide (1) (4.0 g, 0.020 mol) was dissolved in dimethylformamide (DMF) (75 mL). The solution was cooled to 0–5 °C in an ice bath and solution of di-tert-butyl dicarbonate (Boc2O) (4.8 g, 0.022 mol) was added. The ice bath was then removed to allow the reaction to room temperature and kept for 4 h. The reaction solution was then poured into 300 mL water. The white powder was precipitated, filtered and dried to give 2 (5.7 g). Yield: 95.0%, white powder; m.p. 180–182 °C. – 1H NMR (500 MHz, DMSO-d6): δ = 7.73 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.26 (s, 2H), 6.89 (br s, 1H), 3.17 (q, J = 7.0 Hz, 2H), 2.76 (t, J = 7.0 Hz, 2H), 1.36 (s, 9H). – 13C NMR (125 MHz, DMSO-d6): δ = 155.45, 143.59, 141.94, 128.98, 125.56, 77.51, 40.00, 35.05, 28.16.
4.4 Synthesis of tert-butyl-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl}carbamate (3) [14]
Compound 2 (5.1 g, 0.017 mol) and potassium carbonate (4.7 g, 0.034 mol) in acetone (200 mL) was refluxed for 1 h, followed by addition of cyclohexyl isocyanate (2.70 g, 0.022 mol). The reaction mixture was continuously refluxed for 6 h. The solvent was removed under reduced pressure and the residue was added water (100 mL), neutralized with 1% HCl to pH = 5–6. The product was collected by filtration and washed with water. Pure compound 3 was obtained by recrystallization from ethanol/water (6.99 g). Yield: 96.6 %, white powder; m.p. 213–215 °C. – IR (film, KBr): ν = 3336 (NH), 2932 (–CH, alkane), 1691 (C=C, aromatic), 1536 (C=O, amide), 1351 and 1168 (O=S=O), 1296.52 (C–O) cm−1. – 1H NMR (500 MHz, DMSO-d6) δ = 10.25 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 6.88 (t, J = 5.5 Hz, 1H), 6.30 (d, J = 7.5 Hz, 1H), 3.19 (q, J = 7.5 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H), 1.65–1.63 (m, 2H), 1.59–1.56 (m, 2H), 1.49–1.47 (m, 1H), 1.34 (s, 9H), 1.25–1.18 (m, 2H), 1.15–1.04 (m, 4H). – 13C NMR (125 MHz, DMSO-d6): δ = 155.46, 150.35, 145.20, 138.00, 129.14, 127.13, 77.52, 48.01, 40.00, 35.15, 32.21, 28.16, 24.92, 24.10. – MS ((−)-ESI): m/z (%) = 424.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 448.0 (100) [M+Na]+.
4.5 Synthesis of 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (4) [14]
In a 100 mL three-necked flask compound 3 (7.3 g, 0.017 mol) was dissolved in 75 mL DCM. The solution was cooled in an ice bath and trifluoroacetic acid (TFA) (20 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 h, and the solvent was removed under reduced pressure. Cool water (100 mL) was added to the residue and the solid appeared was filtered, washed with distilled water, recrystallized by ethanol/water (20/2) to give the product 4 (5.1 g). Yield: 92.0 %, white solid; m.p. 199–201 °C. – 1H NMR (500 MHz, DMSO-d6): δ = 10.48 (br s, 1H, 7′-H), 7.93 (br s, 2H, NH2), 7.85 (d, J = 8.5 Hz, 2H, 2′-H, 6′-H), 7.48 (d, J = 8.5 Hz, 2H, 3′-H, 5′-H), 6.62 (d, J = 8.0 Hz, 1H, NH), 3.26–3.28 (1H, m, 1-H), 3.11 (m, 2H, 2″-H), 2.96 (m, 2H, 1’’-H), 1.65–1.63 (m, 2H), 1.60–1.57 (m, 2H), 1.49–1.47(m, 1H), 1.24–1.17 (m, 2H,), 1.14–1.01 (m, 2H), 1.09–1.05 (m, 1H). – 13C NMR (125 MHz, DMSO-d6): δ = 150.49 (C-8′), 142.78 (C-4′), 138.88 (C-1′), 129.20 (C-3′, C-5′), 127.47 (C-2′, C-6′), 48.06 (C-1), 40.00 (C-2″), 32.74 (C-1’’), 32.24 (C-2, C-6), 24.94 (C-4), 24.15 (C-3, C-5). – MS ((+)-ESI): m/z (%) = 325.9 (100) [M+H]+. – MS ((−)-ESI): m/z (%) = 323.9 (100) [M−H]−.
4.6 General procedure for the preparation of sulfonylureas 5a–5l
Appropriate carboxylic acid, (0.01 mol) was dissolved in anhydrous acetone (50 mL) and triethylamine (1.42 mL, 0.01 mol). After 15 min at 0 °C, ethyl chloroformate (0.97 mL, 0.01 mol) was added dropwise and the reaction was kept for 60 min, followed by addition of 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (4) (3.25 g, 0.01 mol) and triethylamine (1.42 mL, 0.01 mol) in anhydrous acetone (20 mL). The resulting mixture was stirred for 4 h at room temperature. Acetone was removed under reduced pressure, and the residue was acidified with 5% HCl to pH ≈ 5. White solid product was collected and washed with water and dried at 65 °C.
4.6.1 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-2-hydroxynicotinamide (5a)
Yield: 72.0%, white powder; m.p. 170–172 °C. – IR (film, KBr): ν = 3267 (NH), 3114 (OH), 2931.86, (–CH, alkane), 1669 (C=C, aromatic), 1543 (C=O, amide), 1424 (C=N), 1308 and 1147 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 12.43 (br s, 1H), 10.27 (br s, 1H), 9.83 (t, J = 5.5 Hz, 1H), 8.32 (dd, J = 2.5, 7.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.68 (br s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 6.46 (t, J = 6.5 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 3.58 (q, J = 7.0 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H), 1.65–1.06 (10H, m). – 13C NMR (125 MHz, DMSO-d6): δ = 163.25, 162.20, 150.53, 145.08, 143.83, 139.31, 138.25, 129.14, 127.24, 120.23, 106.17, 48.02, 40.00, 35.05, 32.22, 24.94, 24.12. – MS ((+)-ESI): m/z (%) = 446.9 (60) [M+H]+. – MS ((−)-ESI): m/z (%) = 444.9 (40) [M−H]−.
4.6.2 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}benzamide (5b) [15]
Yield: 81.1%, white powder; m.p. 189–191 °C. – IR (film, KBr): ν = 3344 (NH), 2934 (–CH, alkane), 1654 (C=C, aromatic, 1536 (C=O, amide), 1343.91 and 1164.09 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 10.27 (br s, 1H), 8.56 (t, J = 5.5 Hz, 1H), 7.82–7.78 (m, 4H), 7.53–7.42 (m, 5H), 6.30 (d, J = 7.5 Hz, 1H), 3.53 (q, J = 6.5 Hz, 2H), 2.95 (t, J = 7 Hz, 2H), 1.65–1.06 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 166.25, 150.43, 145.31, 138.11, 134.5, 131.07, 129.20, 128.23, 127.26, 127.07, 48.03, 40.24, 34.81, 32.24, 24.95, 24.15. – MS ((−)-ESI): m/z (%) = 427.7 (100) [M−H]−. − MS ((+)-ESI): m/z (%) = 428.7 (70) [M+H]+.
4.6.3 (E)-N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl}-3-(4-hydroxyphenyl)acrylamide (5c)
Yield: 76.3%, white powder; m.p. 144–145 °C. – IR (film, KBr): ν = 3313 (OH), 2931.14 (NH), 2854 (–CH, alkane), 1653, (C=C, aromatic, 1535 (C=O, amide), 1341 and 1159 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 10.28 (br s, 1H, SO2NH), 9.80 (s, 1H, OH), 8.07 (t, J = 6 Hz, 1H, CONH), 7.82 (d, J = 8.5 Hz, 2H, 2′-H, 6′-H), 7.46 (d, J = 8.5 Hz, 2H, 3′-H, 5′-H), 7.38 (d, J = 8.5 Hz, 2H, 2‴-H, 6‴-H), 7.32 (d, J = 15.5 Hz, 1H, 7‴-H), 6.79 (d, J = 8.5 Hz, 2H, 3‴-H, 5‴-H), 6.37 (d, J = 15.5 Hz, 1H, 8‴-H), 6.32 (d, J = 8.0 Hz, 1H, CONH), 3.45 (q, J = 7.0 Hz, 2H, 2″-H), 2.88 (t, J = 7.0 Hz, 2H, 1″-H), 1.66–1.64 (m, 2H), 1.60–1.57 (m, 2H), 1.50–1.47 (m, 1H), 1.25–1.17 (m, 2H), 1.15–1.06 (m, 4H). – 13C NMR (125 MHz, DMSO-d6): 165.43 (CONH), 158.78 (C-4‴), 150.45 (C-8′), 145.27 (C-4′), 138.73 (C-7‴), 138.13 (C-1′), 129.16 (2C, C-2‴, C-6‴), 129.14 (2C, C-3’’, C-5’’), 127.22 (2C, C-2′, C-6′), 125.84, 118.49, 115.68 (2C, C-3‴, C-5‴), 48.03 (C-1), 40.00 (C-2″), 34.92 (C-1″), 32.23 (C-2, C-6), 24.93, 24.11 (C-3, C-5). – MS ((+)-ESI): m/z (%) = 472.3 [M+H]+.
4.6.4 N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl}cinnamamide (5d) [16]
Yield: 74.1%, white powder; m.p. 163–164 °C. – IR (film, KBr): ν = 3345 (NH), 2935 (–CH, alkane), 1654 (C=C, aromatic), 1540 (C=O, amide), 1341 and 1162 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 7.91 (d, J = 8.5 Hz, 2H), 7.56–7.55 (m, 3H), 7.49 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 16.5 Hz, 1H), 7.42–7.37(m, 3H), 6.57 (d, J = 16.00 Hz, 1H), 3.61 (t, J = 7.0 Hz, 2H), 3.46–3.41(m, 1H), 3.00 (t, J = 7.0 Hz, 2H), 1.79–1.15 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 164.94, 150.44, 145.18, 138.59, 138.16, 134.84, 129.36, 129.13, 128.85, 127.44, 127.22, 122.06, 48.01, 40.00, 34.83, 32.21, 24.92, 24.10. – MS ((−)-ESI): m/z (%) = 454.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 455.9 (40) [M+H]+, 478.1 (100) [M+Na]+.
4.6.5 4 Amino-N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl}benzamide (5e)
Yield: 76.3%, white powder; m.p. 165–166 °C. – IR (film, KBr): ν = 3440 (NH2), 3336 (NH), 2931 (–CH, alkane), 1688 (C=C, aromatic), 1533 (C=O, amide), 1335 and 1158 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 10.27 (s, 1H), 8.09 (t, J = 5.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 6.52 (d, J = 8.5 Hz, 2H), 6.31 (d, J = 7.5 Hz, 1H), 5.56 (br s, 2H), 3.46 (q, J = 7.0 Hz, 2H), 2.90 (t, J = 7.0 Hz, 2H), 1.65–1.06 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 166.25, 151.50, 150.37, 145.55, 137.98, 129.12, 128.57, 127.20, 121.19, 112.48, 48.02, 40.00, 35.12, 32.22, 24.93, 24.11. – MS ((−)-ESI): m/z (%) = 443.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 445.0 (60) [M+H]+, 467.0 (100) [M+Na]+.
4.6.6 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-4-methoxybenzamide (5f) [16]
Yield: 69.9%, white powder; m.p. 209–211 °C. – IR (film, KBr): ν = 3301(NH), 3454 (CH3), 2940 (–CH, alkane), 1684 (C=C, aromatic), 1529 (C=O, amide), 1256 (C–O), 1340.43 and 1167.70 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 8.42 (t, J = 5.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 6.31 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 3.51 (q, J = 7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H), 1.66–1.07 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 165.78, 161.48, 150.42, 145.42, 138.07, 129.20, 128.89, 127.24, 126.71, 113.44, 55.30, 48.07, 40.20, 34.92, 32.24, 24.95, 24.14. – MS ((−)-ESI): m/z (%) = 458.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 459.9 (50) [M+H]+.
4.6.7 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-2-iodobenzamide (5g)
Yield: 78.1%, white powder; m.p. 160–162 °C. – IR (film, KBr): ν = 3306 (NH), 2934 (–CH, alkane), 1681 (C=C, aromatic), 1534 (C=O, amide), 1335 and 1164 (O=S=O), 1244 (C–I) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 10.26 (s, 1H), 8.44 (t, J = 5.5 Hz, 1H), 7.85–7.79 (m, 3H), 7.50 (m, 1H), 7.42–7.39 (m, 2H), 7.21 (dd, J = 1.5 Hz, 8.0 Hz, 1H), 7.15–7.13 (m, 1H), 6.30 (br s, 1H), 3.50 (q, J = 7.0 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H), 1.66–1.07 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 168.79, 150.53, 144.97, 143.03, 138.95, 130.54, 129.23, 129.08, 127.83, 127.79, 127.15, 93.24, 47.99, 41.08, 34.48, 32.23, 24.90, 24.09. – MS ((−)-ESI): m/z (%) = 553.9 (30) [M−H]−. – MS ((+)-ESI): m/z (%) = 555.9 (70) [M+H]+.
4.6.8 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-2-hydroxy-3,5-diiodobenzamide (5h)
Yield: 69.3%, white powder; m.p. 178–180 °C. – IR (film, KBr): ν = 3745 (OH phenol), 3297 (NH), 2929 (–CH, alkane), 1682 (C=C, aromatic), 1537 (C=O, amide), 1329 and 1161 (O=S=O), 1274, 1252 (C–I) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 13.95 (s, 1H), 10.27 (s, 1H, SO2NH), 9.27 (s, 1H, CONH), 8.17 (d, J = 2.0 Hz, 1H, 6‴-H), 8.15 (s, 1H, 4‴-H), 7.82 (d, J = 8.5 Hz, 2H, 2′-H, 6′-H), 7.47 (d, J = 8.5 Hz, 2H, 3′-H, 5′-H), 6.31 (d, J = 7.5 Hz, 1H, CONH), 3.56 (q, J = 7.0 Hz, 2H, 2″-H), 2.96 (q, J = 7.0 Hz, 2H, 1’’-H), 1.64–1.62 (m, 2H), 1.58–1.56 (m, 2H),1.49–1.46 (m, 1H), 1.24–1.17 (m, 2H), 1.14–1.06 (m, 3H). – 13C NMR (125 MHz, DMSO-d6): δ = 168.04 (CONH), 159.87 (C-2‴), 150.33 (CONH), 149.31 (C-6‴), 144.77 (C-4′), 138.22 (C-1′), 135.11 (C-4‴), 129.16 (C-3′, C-5′), 127.27 (C-2′, C-6′), 88.82 (C-3‴), 81.12 (C-5‴), 48.00 (C-1), 40.28 (C-2″), 34.21 (C-1″), 32.18 (C-2, C-6), 24.92 (C-4), 24.08 (C-3, C-5). – MS ((−)-ESI): m/z (%) = 695.8 (15) [M−H]−. – MS ((+)-ESI): m/z (%) = 697.7 (15) [M+H]+.
4.6.9 N-{4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl}isoquinoline-1-carboxamide (5i)
Yield: 72.0%, white powder; m.p. 123–124 °C. – IR (film, KBr): ν = 3351 (NH), 2931 (–CH, alkane), 1662 (C=C, aromatic), 1531 (C=O, amide), 1341 and 1161(O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 8.93 (t, J = 5.5 Hz, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 5.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.79 (t, J = 8.5 Hz, 1H), 7.68 (t, J = 8.5 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.30 (d, J = 6.5 Hz, 1H), 3.65 (q, J = 7.0 Hz, 3H), 3.00 (t, J = 7 Hz, 2H), 1.64–1.05 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 166.15, 151.38, 140.81, 136.49, 130.62, 129.17, 128.28, 127.18, 127.03, 126.54, 125.40, 123.18, 48.06, 40.00, 34.82, 32.33, 25.00, 24.19. – MS ((−)-ESI): m/z (%) = 479.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 481.0 (40) [M+H]+.
4.6.10 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}-3-methylpicolinamide (5k)
Yield: 74.0%, white powder; m.p. 120–121 °C. – IR (film, KBr): ν = 3345 (NH), 2938 (–CH, alkane), 1673 (C=C, aromatic), 1534 (C=O, amide), 1354 and 1163 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 8.68 (t, J = 6.0 Hz, 1H), 8.41 (d, J = 4.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.42 (dd, J = 4.5, 8.0 Hz, 1H), 6.32 (d, J = 7.5 Hz, 1H), 3.55 (q, J = 7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H), 2.46 (s, 3H), 1.65–1.16 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 166.00 (CONH), 150.36, 149.24, 145.69, 145.20, 140.03, 138.07, 133.05, 129.13, 127.16, 125.28, 48.00, 40.00, 34.81, 32.19, 24.90, 24.07, 19.09. – MS ((−)-ESI): m/z (%) = 443.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 444.9 (60) [M+H]+.
4.6.11 N-{4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}quinoxaline-2-carboxamide (5l) [17]
Yield: 76.1%, white powder; m.p. 197–199 °C. – IR (film, KBr): ν = 3324 (NH), 2942 (–CH, alkane), 1687 (C=C, aromatic), 1530 (C=O, amide), 1338 and 1163 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.44 (s, 1H), 9.16 (t, J = 5.5 Hz, 1H), 8.18 (dd, J = 3.5, 6.0 Hz, 2H), 7.98 (m, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 6.26 (d, J = 5.5 Hz, 1H), 3.65 (q, J = 7.5 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 1.63–1.15 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 163.14, 144.30, 143.63, 142.94, 139.77, 131.85, 131.26, 129.38, 129.07, 127.20, 48.02, 40.00, 34.77, 32.31, 24.98, 24.16. – MS ((−)-ESI): m/z (%) = 480.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 481.9 (70) [M+H]+.
4.7 General procedure for the preparation of sulfonylureas 5m, 5n, 5o
Phthalic anhydride or 2,3-pyridinedicarboxylic anhydride (0.01 mol) in glacial acetic acid (30 mL) was added 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (4) (0.01 mol). The reaction mixture was refluxed for 7 h and the reaction was cooled to room temperature. The white solid was filtered and washed with water, recrystallized in ethanol/water to obtain pure product 5m or 5n.
2,3-pyridinedicarboxylic anhydride (0.01 mol) in glacial acetic acid (30 mL) was added 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (4) (0.01 mol). The reaction mixture was stirred at room temperature for 1 h. The white solid was filtered and washed with water, recrystallized in ethanol/water to obtain 5o.
4.7.1 2-((4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl)carbamoyl)benzoic acid (5m) [18]
Yield: 81.5%, white powder; m.p. 161–163 °C. – IR (film, KBr): ν = 3071 (OH), 3349 (NH), 2935 (-CH, alkane), 1718 (C=O, acid), 1655 (C=C, aromatic), 1536 (C=O, amide), 1342 and 1122 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 10.24 (s, 1H), 7.85–7.81 (m, 4H), 7.78 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 8.0 Hz, 1H), 3.85 (t, J = 7.0 Hz, 2H), 3.46 (q, J = 7.0 Hz, 1H), 3.03 (t, J = 7.0 Hz, 2H), 1.64–1.05 (m, 10H). – 13C NMR (125 MHz, DMSO-d6): δ = 168.55, 167.60, 150.35, 144.02, 138.36, 134.40, 131.43, 131.11, 129.22, 127.49, 123.01, 48.03, 40.00, 38.25, 33.25, 34.51, 24.94, 24.13. – MS ((−)-ESI): m/z (%) = 471.9 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 474.0 (100) [M+H]+.
4.7.2 N-(Cyclohexylcarbamoyl)-4-{2-(5,7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6yl)-ethyl}benzenesulfonamide (5n)
Yield: 66.1%, white powder; m.p. 224–226 °C. – IR (film, KBr): ν = 3309 (NH), 2918 (–CH, alkane), 1709 (C=C, aromatic), 1531 (C=O, amide), 1341and 1163 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6, 25 °C, TMS): δ = 10.27 (t, J = 3.5 Hz, 1H, SO2NH), 8.96 (d, J = 5.0 Hz, 1H,), 8.27 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.77 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 6.28 (d, J = 7.5 Hz, 1H, CONH), 3.88 (t, J = 7.5 Hz, 2H), 3.03 (t, J = 7.5 Hz, 3H), 1.65–1.62(m, 2H), 1.8–1.56 (m, 1H), 1.49–1.46 (m, 1H), 1.23–1.18 (m, 2H), 1.10–1.06 (m, 3H). – 13C NMR (125 MHz, DMSO-d6, 25 °C, TMS): δ = 166.03, 165.93, 154.08, 151.31, 150.47, 143.90, 138.50, 131.22, 129.21, 127.83, 127.32, 127.08, 48.03, 40.00, 38.37, 32.21, 24.94, 24.12. – MS ((−)-ESI): m/z (%) = 455.0 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 456.9 (40) [M+H]+.
4.7.3 3-({4-[N-(Cyclohexylcarbamoyl)sulfamoyl]phenethyl}carbamoyl)picolinic acid (5o)
Yield: 72.5%, white powder; m.p. 174–176 °C. – IR (film, KBr): ν = 3742 (OH), 3324 (NH), 2936 (–CH, alkane), 1721 (C=O, acid), 1653 (C=C, aromatic), 1540 (C=O, amide), 1338 and 1163 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 8.76 (t, J = 5.5 Hz, 1H, CONH), 8.66 (dd, J = 1.5, 5.0 Hz, 1H, 6‴-H), 8.05 (dd, J = 1.5, 8.0 Hz, 1H, 4‴-H), 7.82 (d, J = 8.5 Hz, 2H, 2′-H, 6′-H), 7.60 (dd, J = 4.5, 7.5 Hz, 1H, 5‴-H), 7.49 (d, J = 8.5 Hz, 2H, 3′-H, 5′-H), 6.36 (d, J = 7.5 Hz, 1H, CONH), 3.54–3.50 (m, 3H, 1-H, 2″-H), 2.95 (t, J = 7.5 Hz, 2H, 1″-H), 1.65–1.62 (m, 2H), 1.58–1.56 (m, 2H), 1.13–1.16 (m, 2H), 1.23–1.17 (m, 2H), 1.09–1.07 (m, 2H). – 13C NMR (125 MHz, DMSO-d6): δ = 167.90 (COOH), 165.06 (C-7‴), 150.42 (C-2‴), 150.17 (C-3‴), 149.57 (C-6‴), 145.14 (C-4′), 138.13 (C-1′), 136.77 (C-4‴), 129.11 (C-2′, C-6′), 127.22 (C-3′,C-5′), 125.14 (C-5‴), 48.02 (C-1), 39.83 (C-2″, 34.55 (C-1″), 32.20 (C-2, C-6), 24.92 (C-4), 24.08 (C-3, C-5). – MS ((−)-ESI): m/z (%) = 473.0 (20) [M−H]−. – MS ((+)-ESI): m/z (%) = 474.8 (70) [M+H]+.
4.8 Synthesis of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazin carboxamide (6) [19]
To a stirred solution of 5-methyl-pyrazin-2-carboxylic acid (0.01 mol) in anhydrous acetone (50 mL) and triethylamine (1.42 mL, 0.01 mol) at 0 °C, ethyl chloroformate (0.97 mL, 0.01 mol) was added dropwise and the reaction was further stirred for 60 min. A solution of 4-(2-aminoethyl)-benzenesulfonamide (2.0 g, 0.01 mol) and triethylamine (1.42 mL, 0.01 mol) in anhydrous acetone was then added. The resulting mixture was stirred for 3 h at room temperature. Acetone was then removed, and the residue was acidified with 5% HCl to pH ≈ 5. The white solid was collected and washed with distilled water. Pure product (6) was obtained by recrystallization from ethanol (2.99 g).
Yield: 93.4%, brown powder; m.p. 237–239 °C. – IR (film, KBr): ν = 3309 (NH), 1695 (C=C, aromatic), 1528 (C=O, amide), 1340 and 1158 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.02 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H, CONH), 8.59 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.27 (s, 2H, SO2NH2), 3.57 (q, J = 7.0 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H), 2.58 (s, 3H, CH3). – 13C NMR (125 MHz, DMSO-d6): δ = 162.99 (CONH); 156.85 (CONH), 143.54, 142.83, 142.36, 142.04, 129.08, 126.55, 125.68, 40.0, 34.65, 21.31(CH3). – MS ((−)-ESI): m/z (%) = 319 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 321 (100) [M+H]+.
4.9 Synthesis of ethyl-({4-[2-(5-methylpyrazine-2-carboxamido)ethyl]phenyl}sulfonyl)-carbamate (7)
N-(4-sulfamoylphenethyl) carboxamide derivatives (6) (0.01 mol) were mixed with a solution of ethyl chloroformate (1.23 mL, 0.013 mol), anhydrous potassium carbonate (2.0 g, 014 mmol) in dry acetone (300 mL). The reaction was refluxed for 4 h and the solvent was removed under reduced pressure. The residue was suspended in water (100 mL), neutralized with 1% HCl. The white solid was filtered and washed with distilled water to obtain 3.5 g of the desired product 7. Yield: 89.2%, brown powder; m.p. 159–161 °C. – IR (film, KBr): ν = 3349 (NH), 1743 (C=O, carbamate), 1660 (C=C, aromatic), 1518 (C=O, amide), 1340 and 1160 (O=S=O), 1229 (C–O, carbamate) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.01 (d, J = 1.5 Hz, 1H, 3‴-H), 8.92 (t, J = 6.0 Hz, 1H, CONH), 8.58 (s, 1H, 6‴-H), 7.80 (d, J = 8.5 Hz, 2H, 2′-H, 6′-H), 7.48 (d, J = 8.5 Hz, 2H, 3′-H, 5′-H), 3.99 (q, J = 7.0 Hz, 2H, COOCH2CH3), 3.59 (q, J = 7.0 Hz, 2H, 2″-H), 2.98 (t, J = 7.0 Hz, 2H, 1″-H), 2.57 (s, 3H, CH3), 1.07 (t, J = 7.0 Hz, 3H, COOCH2CH3). – 13C NMR (125 MHz, DMSO-d6): δ = 162.96 (CONH), 156.77 (C-5‴), 151.01 (NHCOOCH2CH3), 145.65 (C-4′), 142.75 (C-3’’’), 142.33 (C-6‴), 142.01 (C-2‴), 137.09 (C-1′), 129.32 (2C, C-3′, C-5′), 127.43 (2C, C-6′, C-2′), 61.83 (COOCH2CH3), 40.0 (C-2″), 34.65 (C-1″), 21.25 (CH3-5‴), 13.88 (COOCH2CH3).
4.10 General procedure for the preparation of sulfonylurea derivatives (8a–h)
Carbamate derivatives (7) (0.01 mol) and amines (0.011 mol) in toluene was refluxed for 4 h. The reaction was then allowed to cool to room temperature. The solid was filtered, washed with water and recrystallized in ethanol.
4.10.1 5-Methyl-N-{4-[N-(phenethylcarbamoyl)sulfamoyl]phenethyl}pyrazine-2-carboxamide (8a)
Yield: 74.9%, white powder; m.p. 191–193 °C. – IR (film, KBr): ν = 3347 (NH), 1674 (C = C, aromatic), 1536 (C=O, amide), 1341 and 1167 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.01 (d, J = 1.0 Hz, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 1.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.26–7.10 (m, 5H), 3.58 (q, J = 7.0 Hz, 2H), 3.16 (q, J = 7.0 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 2.56 (s, 3H). – 13C NMR (125 MHz, DMSO-d6): δ = 162.98, 156.78, 142.78, 142.34, 142.03, 139.21, 137.27, 128.60, 128.58, 128.25, 126.98, 126.0, 40.81, 35.33, 34.70, 33.12, 21.27. – MS ((+)-ESI): m/z (%) = 467.9 (100) [M+H]+. – MS ((−)-ESI): m/z (%) = 465.9 (100) [M−H]−.
4.10.2 5-Methyl-N-(4-{N-[(2,3,4-trifluorophenyl)carbamoyl]sulfamoyl}phenethyl)pyrazine-2-carboxamide (8b)
Yield: 84.2%, white powder; m.p. 179–180 °C. – IR (film, KBr): ν = 3327 (NH), 1651 (C=C, aromatic), 1529 (C=O, amide), 1348 and 1160 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 10.98 (s, 1H), 9.02 (dd, J = 1.5, 9.5 Hz, 1H), 8.93 (t, J = 6.0 Hz, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.58 (q, J = 6.5 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H), 2.58 (s, 3H). – 13C NMR (125 MHz, DMSO-d6): δ = 162.99, 156.84, 143.54, 142.82, 142.36, 142.04, 140.5, 140.25, 140.04, 139.89, 138.59, 134.62, 129.07, 125.68, 111.6, 111.47, 40.0, 34.65, 21.31. – MS ((+)-ESI): m/z (%) = 494.0 (100) [M+H]+. – MS ((−)-ESI): m/z (%) = 491.9 (100) [M−H]−.
4.10.3 N-[4-(N-{[4-Cyano-3-(trifluoromethyl)phenyl]carbamoyl}sulfamoyl)phenethyl]-5-methylpyrazine-2-carboxamide (8c)
Yield: 71.9%, white powder; m.p. 165–166 °C. – IR (film, KBr): ν = 3356 (NH), 2227 (C=N), 1658 (C=C, aromatic), 1529 (C=O, amide), 1333 and 1149 (O=S=O), 1183 (CF3) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.03 (s, 1H), 8.50 (s, 1H), 7.96 (br s, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 7.5 Hz, 1H), 3.66 (t, J = 7.5 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.61 (s, 3H). – 13C NMR (125 MHz, DMSO-d6): δ = 165.57, 158.6, 144.54, 144.37, 143.44, 136.76, 130.21, 129.98, 128.79, 128.76, 128.67, 128.49, 127.7, 121.94, 117.15, 41.55, 36.28, 21.55. – MS ((+)-ESI): m/z (%) = 533.0 (100) [M+H]+. – MS ((−)-ESI): m/z (%) = 531.0 (100) [M−H]−.
4.10.4 N-(4-{N-[(3-Fluoro-4-methoxyphenyl)carbamoyl]sulfamoyl}phenethyl)-5-methylpyrazine-2-carboxamide (8d)
Yield: 81.9%, white powder; m.p. 181–182 °C. – IR (film, KBr): ν = 3298 (NH), 1650, (C=C, aromatic), 1521 (C=O, amide), 1223 (C–O), 1341 and 1161 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.01 (d, J = 1.5, Hz, 1H), 8.93 (t, J = 6.0 Hz, 1H), 8.80 (s, 1H), 8.57 (d, J = 1.0 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 2.5, 13.5 Hz, 1H), 7.05 (d, J = 13.0 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H) 3.77 (s, 3H), 3.59 (q, J = 7.0 Hz, 2H), 2.97 (t, J = 7.0 Hz, 2H), 2.57 (s, 3H). – 13C NMR (125 MHz, DMSO-d6): δ = 162.99, 158.08, 156.85, 143.53, 142.83, 142.36, 142.04, 129.21, 129.08, 127.47, 125.68, 116.11, 114.15, 111.85, 109.34, 57.01, 34.76, 34.64, 21.30. – MS ((+)-ESI): m/z (%) = 487.9 (60) [M+H]+. – MS ((−)-ESI): m/z (%) = 485.9 (100) [M−H]−.
4.10.5 5-Methyl-N-[4-(N-{[4-nitro-3(trifluoromethyl)phenyl]carbamoyl}sulfamoyl)phenethyl]pyrazine-2-carboxamide (8e)
Yield: 68.4%, white powder; m.p. 182–183 °C. – IR (film, KBr): ν = 3371 (NH), 1662 (C=C, aromatic), 1547 (C=O, amide), 1494 (NO2), 1346 and 1149 (O=S=O), 1182 (CF3) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.73 (s, SO2NH, 1H), 9.00 (s, H-3‴, 1H), 8.93 (t, J = 6.0 Hz, CONH), 8.57 (s, H-6’’’, 1H), 8.12 (d, J = 9.0 Hz, 1H, H-5), 8.02 (d, J = 2.0 Hz, 1H, H-2), 7.88 (d, J = 8.0 Hz, 2H, H-2′, H-6′), 7.80 (dd, J = 2.5, 8.0 Hz, 1H, H-6), 7.50 (d, J = 8.0 Hz, 2H, H-3′, H-5′), 3.59 (q, J = 7.0 Hz, 2H, H-2″), 2.97 (t, J = 7.0 Hz, 2H, H-1″), 2.56 (s, 3H, CH3). – 13C NMR (125 MHz, DMSO-d6): δ = 163.01 (C-7′), 156.86 (C-8′), 154.33 (C-5‴), 143.54 (C-2‴), 142.84 (C-4′), 142.80 (C- 6‴), 142.36 (C-3‴), 133.77 (C-1), 129.64 (C-3), 129.09 (2C, C-3′, C-5′), 127.55 (C-2), 125.69 (2C, C-2′, C-6′), 125.17 (C-5), 124.92 (C-4), 123.58 (CF3), 121.41 (C-1′), 114.48 (C-6), 40.00 (C-2″), 34.78 (C-1″), 21.3 (CH3). – MS ((+)-ESI): m/z (%) = 552.9 (100) [M+H]+. – MS ((−)-ESI): m/z (%) = 550.9 (100) [M−H]−.
4.10.6 N-(4-[N-(Cyclopentylcarbamoyl)sulfamoyl]phenethyl)-5-methylpyrazine-2-carboxamide (8f)
Yield: 76.4%, white powder; m.p. 202–203 °C. – IR (film, KBr): ν = 3325 (NH), 2957 (CH, alkane), 1683 (C=C, aromatic) 1530 (C=O, amide), 1333 and 1160 (S=O=S) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.02 (d, J = 1.5 Hz, 1H), 8.93 (t, J = 6.0 Hz, 1H), 8.59 (d, J = 1.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.38 (d, J = 7.0 Hz, 1H), 3.77–3.70 (m, 1H), 3.58 (q, J = 7.5 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.57 (s, 3H), 1.75–1.68 (m, 2H), 1.58–1.52 (m, 2H), 1.49–1.42 (m, 2H), 1.29–1.23 (m, 2H). – 13C NMR (125 MHz, DMSO-d6): δ = 162.99, 156.79, 150.82, 145.03, 142.79, 142.35, 142.03, 138.2, 129.13, 127.23, 51.00, 40.00, 34.7, 32.29, 23.05, 21.28. – MS ((+)-ESI): m/z (%) = 431.9 (60) [M+H]+. – MS ((−)-ESI): m/z (%) = 430.0 (100) [M−H]−.
4.10.7 N-(4-{N-[(2-Hydroxy-4-nitrophenyl)carbamoyl]sulfamoyl}phenethyl)-5-methylpyrazine-2-carboxamide (8g)
Yield: 76.9%, white powder; m.p. 196–198 °C. – IR (film, KBr): ν = 3399 (OH), 3234 (NH), 1655 (C=C, aromatic, 1538 (C=O, amide), 1425 (NO2), 1327 and 1185 (O=S=O), 1153 (C–N) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 11.24 (s, 2H), 9.0 (d, J = 1.5 Hz, 1H), 8.93 (t, J = 6.0 Hz), 8.77 (s, 1H), 8.57 (d, J = 0.5 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.70 (dd, J = 2.5, 9.0 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 3.57 (q, J = 7.0 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.56 (s, 3H). – 13C NMR (125 MHz, DMSO-d6): δ = 162.99, 156.82, 145.81, 145.51, 143.51, 142.80, 142.77, 142.40, 142.34, 142.03, 135.51, 129.05, 125.66, 118.26, 111.14, 108.62, 40.00, 34.75, 21.26. – MS ((+)-ESI): m/z (%) = 501.0 (100) [M+H]+. – MS ((−)-ESI): m/z (%) = 498.8 (20) [M−H]−.
4.10.8 N-{4-[N-(Benzylcarbamoyl)sulfamoyl]phenethyl}-5-methylpyrazine-2-carboxamide (8h)
Yield: 84.2%, white powder; m.p. 199–200 °C. – IR (film, KBr): ν = 3339 (NH), 1650 (C=C, aromatic), 1533 (C=O, amide), 1336 and 1163 (O=S=O) cm−1. – 1H NMR (500 MHz, DMSO-d6): δ = 9.02 (d, J = 1.0 Hz, 1H), 8.94 (t, J = 6.0 Hz, 1H), 8.59 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 7.0 Hz, 2H), 7.19 (t, J = 7.0 Hz, 1H), 7.13 (d, J = 7.0 Hz, 2H), 6.97 (t, J = 6.0 Hz, 1H), 4.15 (d, J = 6.0 Hz, 2H), 3.59 (q, J = 6.5 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 2.57 (s, 3H). – 13C NMR (125 MHz, DMSO-d6): δ = 163.10, 156.88, 151.63, 145.14, 142.86, 142.44, 142.07, 139.15, 138.18, 129.21, 128.25, 127.29, 127.00, 126.85, 42.74, 40.00, 34.77, 21.33. – MS ((−)-ESI)): m/z (%) = 451.9 (100) [M−H]−. – MS ((+)-ESI): m/z (%) = 453.8 (60) [M+H]+.
Suppoting information
Copies of the spectra are given as supplementary material available online (https://doi.org/10.1515/znb-2020-0134).
Author contribution: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
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Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/znb-2020-0134).
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