WO2022269652A1 - Novel phenylsulfonylurea derivatives of 2-amino-2-deoxy-d-glucopyranose, their method of preparation, and the use thereof - Google Patents

Abstract

The present disclosure provides compounds of the general formula (I), or salts thereof, a method of preparation, and their use for treating diabetes mellitus: Formula (I) wherein R₁ is selected from a group containing alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, halogen, hydroxyl, cyano, or heteroaryl; R₂ is selected from a group containing Br, NO₂, OCH₃, or F; R₃, R₄, R₅, R₆ are selected from a group containing hydrogen, acetyl, acyl, or partially acylated hydroxy groups having the group R₇-(C=O)-; and R₇ is an alkyl, substituted or unsubstituted aryl, or arylalkyl.

Description

NOVEL PHENYLSULFONYLUREA DERIVATIVES OF 2-AMINO-2- DEOXY-D-GLUCOPYRANOSE, THEIR METHOD OF PREPARATION, AND THE USE THEREOF TECHNICAL FIELD [01] The present disclosure relates to compounds and pharmaceutical compositions comprising a series of novel compounds, their method of preparation, pharmaceutical composition thereof, and the use of such pharmaceutical composition for treating diabetes mellitus (“DM”). BACKGROUND [02] DM is a metabolic disease which is characterized by hyperglycemia, lipoproteins abnormalities, defect in reactive oxygen species scavenging enzyme, high oxidative stress- induced damage to pancreatic beta cells and decrease glucose uptake due to impairment of insulin signaling pathway. According to the International Diabetes Federation, the number of people with diabetes has risen from 451 million in 2017 to 463 million in 2019 and estimated to rise to 700 million in year 2045. DM is mainly categorized into Type 1 (insulin-dependent) and Type 2 (non-insulin dependent). In type 2 DM (“T2DM”), insulin resistance is the major problem and accounts for 90-95% of diabetic cases. [03] Oral sulfonylurea formulations are being used as anti-hyperglycemic agents for glycemic control and had been the mainstay of DM treatment therapies for decades given their efficacy and convenience. Though, several clinical trials confirmed their risk of microvascular and macrovascular complications. Therefore, there is an urgent need for a novel drug scaffold with minimal microvascular and macrovascular complications. [04] Many attempts have been done to overcome those two disadvantages. For instance, a study titled “Design, Synthesis and in Vivo Evaluation of Novel Glycosylated Sulfonylureas as Antihyperglycemic Agents” published by Ghadeer Suaifan et. al in 2015 discloses the design, synthesis and in vivo testing of novel glycosylated aryl sulfonylurea compounds as antihyperglycaemic agents in streptozocine-induced diabetic mice. SUMMARY [05] It is an object of the present disclosure to provide a novel compound of the general formula (I), or a pharmaceutically acceptable salt thereof:

wherein R₁ may be selected from a group containing alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, halogen, hydroxyl, cyano, or heteroaryl; R₂ may be selected from a group containing Br, NO₂, OCH₃, or F; R₃, R₄, R₅, R₆ may be selected from a group containing hydrogen, acetyl, acyl, or partially acylated hydroxy groups having the group R₇-(C=O)-; and R₇ may include alkyl, substituted or unsubstituted aryl, or arylalkyl. [06] In some aspects, R₇ may include phenyl, nitrophenyl, halophenyl, alkyl substituted pheny, alkoxy, phenyl, or benzyl groups. [07] In aspects of the present disclosure, the salt may be selected from alkali metal, alkaline earth metal, ammonium or an amine salt. [08] Other aspects of the present disclosure provide a method for preparing the compound of the general formula (I), the method may include the steps of: - Stirring sulfonyl chloride with aqueous NH3 and Tetrahydrofuran (“THF”) at a temperature of about 0°C until reaction completion to form a first mixture; - Evaporating, drying, washing, and crystallizing the first mixture to form substituted aryl sulfonamide derivatives; - Stirring substituted aryl sulfonamide derivatives, Dimethylaminopyridine (“DMAP”), and Diphenylcarbazide (“DPC”) in acetonitrile at room temperature to form a second mixture; - Filtering, washing, and drying the second mixture to form substituted aryl sulfonyl derivatives; - Adding substituted aryl sulfonyl derivatives and Et3N to 1,3,4,6-Tetra-O-acetyl-ß- D-glucosamine dissolved in acetonitrile to form a third mixture; - Refluxing, cooling, and adjusting the pH of the third mixture; - Filtering, washing, and drying third mixture until a first precipitate is formed; - Adding NaOCH₃ dissolved in MeOH to the first precipitate until a final reaction mixture is formed; - Neutralizing, filtering, evaporating, and recrystallizing the final reaction mixture to provide a second precipitate; and - Freeze-drying the second precipitate. [09] Other aspects of the present disclosure provide a pharmaceutical composition including the compound of general formula (I) and/or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier/excipient. [010] In aspects of the present disclosure, the pharmaceutical composition may be formulated as a solid, liquid, or semi-solid dosage form. [011] In some aspects, the pharmaceutical composition may be administered via different routes such as oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, ocular, vaginal, rectal, or intraventricular. [012] In aspects of the present disclosure, the pharmaceutical composition may be used for treating diabetes mellitus. BRIEF DESCRIPTION OF THE DRAWINGS [013] The disclosure will now be described with reference to the accompanying drawings, which illustrate embodiments of the present disclosure, without however restricting the scope of the disclosure thereto, and in which: [014] FIG.1 illustrates a flowchart of a method of preparing a compound of general formula (I), the method being configured in accordance with other embodiments of the present disclosure. [015] FIG.2 illustrates a bar chart of MTT assay results for synthesized compounds in comparison to Metformin and Glimepiride reference drugs. DETAILED DESCRIPTION

Formula (I) wherein R₁ may be selected from a group containing alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, halogen, hydroxyl, cyano, or heteroaryl; R₂ may be selected from a group containing Br, NO₂, OCH₃, or F; R₃, R₄, R₅, R₆ may be selected from a group containing hydrogen, acetyl, acyl, or partially acylated hydroxy groups having the group R₇-(C=O)-; and R₇ may include an alkyl, substituted or unsubstituted aryl, or arylalkyl. [017] In some embodiments, R₇ may be a phenyl, nitrophenyl, halophenyl, alkyl-substituted phenyl, alkoxy, phenyl, or benzyl group. [018] In embodiments of the present disclosure, salt may be selected from alkali metal, alkaline earth metal, ammonium or an amine salt. [019] Reference now is being made to FIG.1 which illustrates a flowchart of a method of preparing the compound of the general formula (I) of the present disclosure according to embodiments of the present disclosure. As illustrated in FIG.1, the method includes the steps of: - Stirring sulfonyl chloride with aqueous NH₃ and THF at about 0°C until reaction completion to form a first mixture (process block 1-1); - Evaporating, drying, washing, and crystallizing the first mixture to form substituted aryl sulfonamide derivatives, referred to as compounds 7a-7f (process block 1-2); - Stirring substituted aryl sulfonamide derivatives 7a-7f, DMAP, and DPC in acetonitrile at room temperature to form a second mixture (process block 1-3); - Filtering, washing, and drying the second mixture to form substituted aryl sulfonyl derivatives, referred to as compounds 8a-8f (process block 1-4); - Adding substituted aryl sulfonyl derivatives 8a-8f and Et3N to 1,3,4,6-Tetra-O-acetyl- ß-D-glucosamine dissolved in acetonitrile to form a third mixture (process block 1-5); - Refluxing, cooling, and neutralizing the pH of the third mixture (process block 1-6); - Filtering, washing, and drying the third mixture to form a first precipitate in order to provide a first precipitate, referred to as compounds 9a-9f (process block 1-7); - Dissolving compounds 9a-9f in MeOH to form a fourth mixture (process block 1-8); - Adding NaOCH₃ gradually to the fourth mixture while monitoring with TLC till reaction completion until a final reaction mixture is produced (process block 1-9); - Neutralizing, filtering, evaporating, and recrystallizing the final reaction mixture to a form a second precipitate (process block 1-10); and - Freeze-drying the second precipitate to provide compounds 9g-9l (process block 1- 11); [020] Other embodiments of the present disclosure further provide a pharmaceutical composition including a compound of general formula (I) and/or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier/excipient. [021] The term “pharmaceutical composition”, as used herein, is intended to include a compound of general formula (I) and/or a pharmaceutically acceptable salt thereof. [022] In embodiments of the present disclosure, the pharmaceutical composition can be, for example, in a liquid form, e.g. a solution, syrup, emulsion and suspension, or in a solid form, e.g. a capsule, caplet, tablet, pill, powder and suppository. Granules, semi-solid forms and gel caps are also considered. In case that the pharmaceutical composition is a liquid or a powder, dosage unit optionally is to be measured, e.g. in the dosage unit of a teaspoon. [023] The pharmaceutical composition in embodiments of the present disclosure can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration. The pharmaceutical composition can be administered to humans and other mammals orally, sublingually, rectally, parenterally, intracisternally, intraurethrally, intraperitoneally, topically (as powder, ointment or drop), as buccal or as an oral or nasal spray. The term "parenterally", as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, subcutaneous, intra-articular injection and infusion. [024] The term “pharmaceutical acceptable carrier/excipient”, as used herein, means a non- toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; binding agents such as hypromellose; disintegrating agents such as crosscarmellose; water; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil; cottonseed oil; safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgement of the formulator. [025] All components of the pharmaceutical composition have to be pharmaceutically acceptable. The term “pharmaceutically acceptable” means at least non-toxic. [026] According to embodiments of the present disclosure, the pharmaceutical composition may be used for treating diabetes mellitus. [027] The disclosure will be further illustrated on the basis of examples and a detailed description from which further features and advantages may be taken. It is to be noted that the following explanations are presented for the purpose of illustrating and description only; they are not intended to be exhaustive or to limit the disclosure to the precise form disclosed. Example 1 Preparation of novel phenylsulfonylurea derivatives of 2-amino-2-deoxy-D-glucopyranose [028] Compounds of the general formula (I) can be prepared by the following proposed scheme:

[029] Using a commercially available 2,4-Dichlorobenzenesulfonyl chloride (compound 6) as a starting material, the synthesis of the novel compound 9f and 9I of general formula (I) was initiated by stirring the starting material (about 1.50 g, and about 6.11 mmol) vigorously with aq. NH₃ (28%, and about 17.0 mL) and THF (about 24 mL) at about 0°C until reaction completion. The evaporation residue, in EtOAc (about 24 mL), was washed with aq 1M HCl (about 15 mL). Drying, evaporation, recrystallisation (EtOAc / Et2O) and washing with cold Et₂O afforded substituted aryl sulfonamide derivatives (compounds 7f) as a white solid. [030] The substituted aryl sulfonamide derivatives 7a-7f (about 1 mmol), DMAP (2mmol), and DPC (about 1.1 mmol) in acetonitrile (about 1.5 mL) were stirred and then allowed to stand at room temperature. Following this, the reaction mixture was filtered, washed with MeOH (2 × about 0.5 mL) and dried to result in the formation of compounds substituted aryl sulfonyl derivatives 8a-f. [031] To a stirred solution of about 1.1 mmol of 1,3,4,6-Tetra-O-acetyl-ß-D-glucosamine (compound 5) dissolved in acetonitrile (about 1.5 mL), substituted aryl sulfonyl derivatives 8a-f (about 1 mmol) and Et3N (about 2 mmol) were added. The mixture was refluxed for about 15 min and then allowed to cool down. The solution was then acidified to form a precipitate. Filtration, washing and drying of the precipitate resulted in the formation of compounds 9a-9f. [032] A mixture of sodium methoxide (about 6.0 mmol) and solutions of substituted aryl sulfonylurea-1,3,4,6-tetra-O-acetyl-D-glucopyranose derivatives 9a-9f (about 1.0 mmol) were reacted at room temperature in MeOH (about 50 mL). The reactions were monitored with thin layer chromatography (“TLC”) (CHCl₃–MeOH 9:1), the TLC plates were sprayed with ninhydrin reagent and were subsequently heated until a pink spot appeared. Upon reaction completion, the solutions were neutralized using Dowex 50WX8-200 ion- exchange resin, filtered and evaporated. Resulting viscous residues were collected, crystallized from MeOH/acetone, dissolved in water, refiltered and freeze dried to form the compounds 9g-l (41-95%). Example 2 Structure Elucidation Data [033] The 12 synthesized compounds may have chemical characterization as follows: N-(4-Bromophenylsulfonyl)-N’-(1,3,4,6-tetra-O-acetyl-2-deoxy- β-D-glucopyranos-2- yl)urea (9a) Yield: 77%; white solid; mp 198-201°C; IR v_max 3312, 3208, 1733, 1661, 1213, 1163, 1035 cm^-1; ¹H NMR ((CD₃)₂SO) δ_H 1.74 (3 H, s, AcO), 1.86 (3 H, s, AcO), 1.99 (6 H, s, 2 × AcO), 3.76 (1 H, q, J = 9.5 Hz, glucose 2-H), 3.96 (2 H, m, glucose 5,6-H₂), 4.14 (1 H, dd, J = 12.9, 4.9 Hz, H-6), 4.82 (1 H, t, J = 9.6 Hz, glucose 4-H), 5.28 (1 H, t, J = 9.8 Hz, glucose 3-H), 5.79 (1 H, d, J = 8.7 Hz, glucose 1-H), 6.65 (1 H, d, J = 9.4 Hz, NH), 7.82 (4 H, m, Ph-H₄), 11.05 (1 H, bs, NH); ¹³C NMR ((CD₃)₂SO) δ_C 20.51, 20.72, 20.81, 20.90, 53.00, 61.95, 68.31, 71.54, 72.19, 91.91, 127.74, 129.75, 132.60, 139.56, 151.65, 169.15, 169.69, 169.95, 170.45; ESIMS m/z 550.0074 [M – H – HOAc] (¹³C¹²C₁₈H₂₀ ⁸¹BrN₂O₁₀S requires 550.0039), 549.0023 [M – H – HOAc]- (¹²C₁₉H₂₀ ⁸¹BrN₂O₁₀S requires 549.0005), 548.0094 [M – H – HOAc]- (¹³C¹²C18H₂₀ ⁷⁹BrN₂O₁₀S requires 548.0059), 547.0048 [M – H – HOAc]- (¹²C₁₉H₂₀ ⁷⁹BrN₂O₁₀S requires 547.0026). N-(4-Nitrophenylsulfonyl)-N’-(1,3,4,6-tetra-O-acetyl-2-deoxy- β-D-glucopyranos-2- yl)urea (9b) Yield: 88%; white solid; mp 172-174°C; IR v_max 3319, 3273, 1744, 1693, 1212, 1165, 1071 cm^-1; ¹H NMR ((CD₃)₂SO) δH 1.67 (3 H, s, AcO), 1.82 (3 H, s, AcO), 1.98 (6 H, s, 2 × AcO), 3.71 (1 H, q, J = 9.5 Hz, glucose 2-H), 3.95 (2 H, m, glucose 5,6-H2), 4.15 (1 H, dd, J = 13.0, 5.0 Hz, glucose 6-H), 4.82 (1 H, t, J = 9.6 Hz, glucose 4-H), 5.28 (1 H, t, J = 9.9 Hz, glucose 3-H), 5.80 (1 H, d, J = 8.7 Hz, glucose 1-H), 6.78 (1 H, d, J = 9.3 Hz, NH), 8.15 (1 H, d, J = 8.9 Hz, Ph 2,6-H2), 8.43 (2 H, d, J = 8.8 Hz, Ph 3,5-H2), 11.36 (1 H, bs, NH); ¹³C NMR ((CD₃)₂SO) δ_C 20.58, 20.79, 20.82, 20.92, 53.39, 61.95, 68.56, 71.82, 72.37, 92.08, 124.83, 129.44, 145.75, 150.48, 151.68, 169.17, 169.68, 169.95, 170.44; ESIMS m/z 598.1099 [M + Na]⁺ (C₂₁H₅N₃NaO₁₄S requires 598.0955). N-(4-Methoxyphenylsulfonyl)-N’-(1,3,4,6-tetra-O-acetyl-2-deoxy- β-D-glucopyranos-2- yl)urea (9c) Yield: 95%; beige solid; mp 165-170°C; IR v_max 3330, 3253, 1749, 1698, 1212, 1156. 1086 cm^-1; ¹H NMR ((CD₃)₂SO) δH 1.74 (3 H, s, AcO), 1.86 (3 H, s, AcO), 1.97 (6 H, s, 2 × AcO), 3.84 (3 H, s, OCH₃), 3.76 (1 H, m, glucose 2-H), 3.96 (2 H, m, glucose 5,6-H₂), 4.15 (1 H, m, glucose 6-H), 4.83 (1 H, t, J = 9.6 Hz, glucose 4-H), 5.29 (1 H, t, J = 9.8 Hz, glucose 3-H), 5.79 (1 H, d, J = 8.6 Hz, glucose 1-H), 6.58 (1 H, d, J = 9.4 Hz, NH), 7.11 (2 H, d, J = 8.8 Hz, Ph 3,5-H₂), 7.81 (2 H, d, J = 8.8 Hz, Ph 2,6-H₂), 10.78 (1 H, bs, NH); 1³C NMR ((CD₃)₂SO) δ_C 20.55, 20.76, 20.83, 20.92, 45.96, 56.21, 61.97, 68.60, 71.75, 72.50, 92.24, 114.59, 129.99, 139.50, 151.82, 163.27, 169.16, 169.69, 169.95, 170.44; ESIMS m/z 583.1204 [M + Na]⁺ (C₂₂H₂₈N₂NaO₁₃S requires 583.1210). N-(4-Fluorophenylsulfonyl)-N’-(1,3,4,6-tetra-O-acetyl-2-deoxy- β-D-glucopyranos-2- yl)urea (9d) Yield: 91%; beige solid; mp 148-150°C; IR v_max 3314, 3226, 1749, 1665, 1552, 1221, 1101, 1039 cm^-1; ¹H NMR ((CD₃)₂SO) δ_H 1.99 (12 H, s, 4 × AcO), 3.83 (1 H, m, glucose 2-H), 3.97 (2 H, m, H-5, H-6), 4.16 (1 H, dd, J = 13.1, 4.9 Hz, glucose 6-H), 4.83 (1 H, t, J = 9.5 Hz, glucose 4-H), 5.29 (1 H, t, J = 9.8 Hz, glucose 3-H), 5.81 (1 H, d, J = 8.6 Hz, glucose 1-H), 6.56 (1 H, d, J = 9.4 Hz, NH), 7.46 (2 H, dd, J = 8.7, 5.3 Hz, Ph 3,5-H₂), 7.95 (2 H, dd, J = 8.6, 5.3 Hz, Ph 2,6-H₂), 10.78 (1 H, bs, NH); ¹³C NMR ((CD₃)₂SO) δ_C 20.80, 20.94, 21.35, 21.46, 52.69, 61.73, 68.32, 70.79, 72.05, 90.53, 107.42, 139.33, 157.41 , 169.07, 169.76, 170.16, 170.42; ESIMS m/z 571.09430 [M + Na]⁺ (C22H₂8FNaO13S requires 571.1010). N-(2-Chlorophenylsulfonyl)-N’-(1,3,4,6-tetra-O-acetyl-2-deoxy- β-D-glucopyranos-2- yl)urea (9e) Yield: 65%; white solid; mp 206-209°C (decomp.); IR v_max 3334, 3286, 1737, 1702, 1283, 1211, 1167, 1031 cm^-1; ¹H NMR ((CD₃)₂SO) δ_H 1.81 (3 H, s, AcO), 1.92 (3 H, s, AcO), 1.98 (6 H, s, 2 × AcO), 3.71 (1 H, q, J = 9.3 Hz, glucose 2-H), 3.98 (2 H, m, glucose 5,6- H₂), 4.15 (1 H, d, J = 9.5 Hz, glucose 6-H), 4.81 (1 H, t, J = 9.3 Hz, glucose 4-H), 5.32 (1 H, t, J = 9.5 Hz, glucose 3-H), 5.84 (1 H, d, J = 8.4 Hz, glucose 1-H), 6.48 (1 H, d, J = 9.1 Hz, NH), 7.58 (1 H, m, Ph-H), 7.68 (2 H, m, Ph-H), 8.05 (1 H, d, J = 7.6 Hz, Ph 6-H), 11.11 (1 H, brs, NH); ¹³C NMR ((CD₃)₂SO) δ_C 20.64, 20.79, 20.81, 20.89, 53.15, 61.98, 68.60, 71.77, 72.30, 92.16, 128.06, 130.93, 131.99, 132.47, 135.26, 137.26, 151.25, 169.17, 169.68, 169.94, 170.43; ESIMS m/z 587.0709 [M + Na]⁺ (C₂₁H₂₅ ³⁵ClN₂NaO₁₂S requires 587.0714). N-(2,4-Dichlorophenylsulfonyl)-N’-(1,3,4,6-tetra-O-acetyl-2-deoxy- β-D-glucopyranos- 2-yl)urea (9f) Yield: 91%; mp 182-187°C (decomp.); white solid; IR v_max 3341, 3252, 1740, 1704, 1536, 1219, 1169, 1036 cm^-1; ¹H NMR ((CD₃)₂SO) δH 1.83 (3 H, s, AcO), 1.94 (3 H, s, AcO), 1.96 (3 H, s, AcO), 1.99 (6 H, s, 2 × AcO), 3.70 (1 H, m, glucose 2-H), 3.96 (2 H, m, 5,6- H₂), 4.13 (1 H, t, J = 8.0 Hz, glucose 6-H), 4.82 (1 H, t, J = 9.7 Hz, glucose 4-H), 5.31 (1 H, t, J = 9.8 Hz, glucose 3-H), 5.84 (1 H, d, J = 8.7 Hz, glucose 1-H), 6.59 (1 H, d, J = 9.3 Hz, NH), 7.68 (1 H, d, J = 6.9 Hz, Ph 5-H), 7.91 (1 H, s, Ph 3-H), 8.05 (1 H, d, J = 8.6 Hz, Ph 6-H), 11.32 (1H, s, NH); ¹³C NMR ((CD₃)₂SO) δ_C 20.64 , 20.82, 20.52, 21.52, 53.25, 61.96, 68.58, 71.58, 72.23, 92.08, 129.82, 131.48, 133.94, 133.94, 136.25, 140.51, 157.77, 169.17, 169.72, 169.95, 170.46; ESIMS m/z 600.0374 [M – H]- (¹³C¹²C₂₀H₂₃ ³⁷Cl³⁵ClN₂O₁₂S requires 600.0353), 598.0407 [M – H]- (¹³C¹²C₂₀H₂3³⁵Cl₂N₂O₁₂S requires 598.0382), 597.0347 [M – H]- (C₂₁H₂₃ ³⁵Cl₂N₂O₁₂S requires 597.0383). N-(4-Bromophenylsulfonyl)-N’-(2-deoxy-D-glucopyranos-2-yl)urea (9g) Yield: 73 %; fluffy beige solid; mp 162-165 °C(decomp.); IR v_max 3300, 2826, 1578, 1353, 1245, 1068 cm⁻¹; ¹H NMR (CD₃OD) δH₃.33-3.45 (2H, m, glucose 2,4-H₂), 3.62-3.68 (1H, m, glucose 3-H), 3.72-3.3.85 (3H, m, glucose 5,6,6-H₃), 5.14 (1H, m, glucose 1β-H ), 6.97 (1H, m, glucose 1α-H), 7.61 (2H, d, J = 8.3 Hz, Ph 3,5-H₂), 7.75 (1H, d, J = 8.3 Hz, NH), 7.83 (2H, d, J = 8.4 Hz, Ph 2,6-H₂); ¹³C-NMR (CD₃OD) 54.47, 60.96, 70.52, 70.77, 72.05, 91.59, 106.78, 127.40, 128.55, 130.86, 131.59, 168.82; MS HRMS (ESI-) m/z 438.98162 (M-H) (C₁₃H₁₆ ⁷⁹BrN₃O₁₀S requires 438.98107). N-(4-Nitrophenylsulfonyl)-N’-(2-deoxy-D-glucopyranos-2-yl)urea (9h) Yield: 60 %; mp 148-152 °C, fluffy beige solid; IR v_max 3252, 2800, 1754, 1584, 1346, 1248, 1071; ¹H NMR ((CD₃)₂SO) δ_H 3.15 (1H, m, glucose 2-H), 3.20-3.64 (5H, m, glucose 3,4,5,6,6-H5), 4.22 (1H, d, J = 8.1 Hz, glucose1 ^ - H), 4.88 (2H, m, glucose1 α -OH, D₂O exchangeable), 5.44 (1H, bs, OH, D₂O exchangeable), 5.98 (1H, bs, OH, D₂O exchangeable), 6.63 (1H, bs, OH, D₂O exchangeable), 7.97 (2H, d, J = 8.3, Ph 2,6-H₂), 8.08 (1H, d, J = 8.7 Hz, NH), 8.23 (2H, d, J = 8.9, Ph 3,5-H₂), 8.42 (1H, d, J = 8.6 Hz, NH); ¹³C NMR ((CD₃)₂SO) δ_C 61.39, 71.35, 71.61, 72.07, 72.41, 91.46, 97.61, 123.34, 124.60, 127.46, 128.15, 148.24, 153.53, 168.24; ¹H-NMR (CD₃OD, 500 MHz) δ_H 3.22 - 3.98 (6H, m, glucose 2,3,4,5,6,6-H6), 4.52 (0.6H, d, J = 8.1 Hz, glucose-1β), 5.05 (1H, s, glucose- 1α), 7.85 (3H, m, NH, 2 X Ar-H), 8.27 (2H, m, 2 X Ar-H), 8.40 (1H, m, NH); ¹³C-NMR (CD₃OD, 500 MHz) 61.04, 70.82, 71.35, 72.04, 91.61, 106.47, 122.82, 123.62, 127.03, 127.57, 148.14, 150.06, 168.79; MS HRMS (ESI-) m/z 406.05619 (M-H) (C13H16N3O10S requires 406.05504). N-(4-Methoxyphenylsulfonyl)-N’-(2-deoxy-D-glucopyranos-2-yl)urea (9i) Yield: 95%; mp 162-164°C, fluffy beige solid; IR v_max 3312, 2926, 1746, 1571.76, 1498, 1352, 1250, 1025cm⁻¹; ¹H NMR ((CD₃)₂SO) δ_H 3.11–3.60 (6H, m, glucose 2,3,4,5,6-H₂), 3.80 (3H, s, CH₃), 4.21 (1H, d, J = 8.1 Hz, glucose 1 β - H), 4.92 (2H, m, glucose 1 α - H and OH, D₂O exchangeable), 5.62 (1H, bs, OH, D₂O exchangeable), 5.84 (1H, bs, OH, D₂O exchangeable), 6.90 (2H, d, J = 8.7, Ph 3,5-H₂), 7.10 (1H, d, J = 8.6 Hz, NH), 7.21(1H, s, OH, D₂O exchangeable), 7.67 (2H, d, J = 7.9, Ph 2,6-H₂), 7.75 (1H, d, J = 8.8 Hz, NH); ¹³C NMR ((CD₃)₂SO) δ_C 55.48, 55.80, 61.43, 70.94, 71.71, 72.39, 91.71, 107.16, 113.20, 114.46, 128.13, 128.64, 149.71, 166.18; ¹H NMR (CD₃OD) δ_H 3.34 – 3.80 (6H, m, glucose 2-H, 3-H, 4-H, 5-H, 6-H₂), 3.85 (3H, s, CH₃) 3.90 (1H, d, glucose 1β-H), 5.13 (1H, s, glucose1α-H), 6.97 (2H, d, J = 8.7 Hz, Ph 3,5-H₂), 7.07 (1H, m, NH), 7.868.02 (3H, m, Ph 2,6-H₂, NH); ¹³C-NMR (CD₃OD) 46.31, 54.62, 61.35, 71.08, 71.20, 71.61, 91.79, 112.78, 113.12, 113.68, 127.83, 128.08, 128.43, 168.99; MS HRMS (ESI-) m/z 391.08167 (M-H) (C₁₄H₁₉N₂O₉S requires 391.08113. N-(4-Fluorophenylsulfonyl)-N’-(2-deoxy-D-glucopyranos-2-yl)urea (9j) Yield: 77 %, fluffy white solid; IR v_max 3421; 2831; 1601, 13361, 1245, 1135; ¹H NMR ((CD₃)₂SO) δ_H 3.16–3.70 (6H, m, glucose 2,3,4,5,6-H₂), 4.15(1H, d, J = 8.0 Hz, glucose 1 β - H), 4.83 (2H, m, glucose 1 α - H and OH), 5.31 (1H, bs, OH), 5.82 (1H, bs, OH), 6.61 (2H, b, NH), 7.11 (1H, dd, J = 8.9, 5.9 Hz, Ph 3,5-H₂), 7.37 (1H, t, J = 8.9, OH), 7.73 (2H, dd, J = 8.2, 5.9 Hz, Ph 2,6-H₂), 7.83 (1H, d, J = 8.7 Hz, NH); ¹³C NMR ((CD₃)₂SO) δ_C 60.00 – 79.00, 91.74, 116.37, 129.05, 130.11, 158.39, 166.71); MS HRMS (ESI-) m/z 403.05819 [M + Na]⁺ (C₁₃H₁₇FN₂NaO₈S requires 403.05873). N-(2-Chlorophenylsulfonyl)-N’-(2-deoxy-D-glucopyranos-2-yl)urea (9k) Yield: 93%; m.p. 173-175 °C, white fluffy solid; IR v_max 3354.2, 2825.32, 1579.92, 1347.54, 1247.93, 1081.71 cm⁻¹; ¹H NMR ((CD₃)₂SO) δ_H 3.03–3.64 (6H, m, glucose 2,3,4,5,6-H₂), 4.22 (1H, d, J = 8.1 Hz, glucose 1β-H), 4.90 (2H, m, glucose 1α-H, OH), 5.54 (1H, bs, OH), 5.96 (1H, bs, OH), 6.41 (1H, bs, OH), 7.29 - 7.39 (4H, m, Ph-H₄), 7.92(1H, d, J = 7.6 Hz, NH), 8.46 (1H, d, J = 8.8 Hz, NHC=O); ¹H-NMR (CD₃OD 500 MHz) δH₃.33 (1H, m, glucose 2-H), 3.61-3.80 ( 5H, m, glucose 3,4,5,6-H₂), 5.14 (1H, m, H-1), 7.46 (1H, t, J = 7.2 Hz, Ph-H), 7.46 (2H, m, Ph-H), 8.11 (1H, d, J = 7.7 Hz, Ph-H), 8.56 (1H, d, J = 7.7 Hz, NH); ¹³C NMR (CD₃OD) δ_C 55.00, 61.31, 71.08, 71.58, 72.00, 91.85, 126.15, 130.41, 130.92, 131.83, 168.95; ESIMS m/z 419.02864 (M+Na) (C₁₃H₁₇ClN₂NaO₈S requires 419.02918). N-(2,4-Dichlorophenylsulfonyl)-N’-(2-deoxy-D-glucopyranos-2-yl)urea (9l) Yield: 41%: mp 148-152 °C, fluffy beige solid; IR v_max 3258, 1613, 1515, 1334, 1253 cm⁻¹; ¹H-NMR (CD₃OD 500 MHz) δH₃.08–3.27 cm⁻¹; (6H, m, glucose 2,3,4,5,6-H₂), 4.22 (0.5H, d, J = 8.1 Hz, glucose 1β-H), 5.29 (0.5H, m, glucose 1β-H, 6.90 (1H, d, J = 7.5 Hz, NH), 7.34 (1H, d, J = 6.5 Hz, Ph 5-H), 7.47 (2H, s, Ph 3-H), 8.03 (1H, d, J = 8.3 Hz, Ph 6-H); 1³C NMR ¹³C NMR (CD₃OD) δ_C 55.00, 61.38, 71.07, 71.59, 76.43, 91.84, 105.17, 126.22, 130.30, 130.87, 131.76, 136.61, 140.96, 168.93; ESIMS m/z 428.99317 [M – H]- (C₁₃H₁₅Cl₂N₂O₈S requires 428.9926). Example 3 In-vitro cytotoxicity [034] The cytotoxicity of synthesized compounds was evaluated against L6 rat skeletal muscle cells maintained in DMEM media supplemented by 10% FBS and 1% penicillin via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (“MTT”) assay. This assay is based on the conversion of the yellow tetrazolium water soluble dye to the purple formazan crystals by viable cells. Thus, the amount of formazan crystals generated is directly proportional to the number of living cells. Initially, about 100µL of cells (2 x 10⁴ cells / mL) were seeded in 96-well plates at about 37°C, 5% CO₂ for about 24 hours. After incubation, the cells were treated with about 100µL of about 50, 100, 150200 and 250µM of each synthesized drug compound. The plates containing the cells were incubated at about 37°C, 5% CO₂ for about 24 hours, after which all the drug solutions were discarded. Following this, about 20µL of MTT solution (about 5mg/mL) was added to each well and the plates were further incubated at about 37°C, 5% CO₂ for about 3 - 5 hours before the medium was removed and wells were washed with DMSO to dissolve formazan crystals formed. The absorbance was measured at 560nm. The percentage of cell viability and the median lethal concentration (LC50) of each synthesized compound (compounds 9a-9l) was calculated using the following formula: % cell viability = x 100

Where A_s is the absorbance of the sample and A_c is the absorbance of the control (full viability, no compound is added). [035] Reference is now being made to FIG.2 which illustrates a bar chart of MTT assay results for synthesized compounds in comparison to Metformin and Glimepiride reference drugs. A high cell viability indicates low cytotoxicity of a compound. The compounds 9a-9l demonstrated a high percentage of cell viability of about 80-90% in the concentration range of 50-250 µM. Additionally, at higher concentration ranges (≥150 µM), the novel phenyl sulfonylurea derivatives showed higher % cell viability and thus lower cytotoxicity than reference drugs Metformin and Glimepiride. Example 4 In-vitro lipid metabolism inhibiting activity [036] As pancreatic lipase and cholesterol esterase play a pivotal role in the hydrolysis and metabolism of dietary triglyceride and cholesterol esters. [037] The effect of synthesized compounds on inhibition of cholesterol esterase activity was performed according to a previously described method. Cholesterol esterase was dissolved in about 100mM sodium phosphate buffer (pH 7.0) and stored at about -80°C. Prior to use, an aliquot was thawed and diluted to about 5µg/mL with about 100mM sodium phosphate buffer. The substrate p-nitro phenyl butyrate (about 0.1mM) was then dissolved in acetonitrile. Following this, a pre-incubated volume (about 1mL) containing about 20µL of each of the synthesized compounds and commercially available antidiabetic drugs as Metformin and Glimepiride (for comparison reasons) in the concentration range of 50µg/mL-250µg/mL, about 20µL of p-nitro phenyl butyrate (p-NPB), about 40µL of 2 % acetonitrile (v/v), about 500µL Triton X-100, and about 400µL of about 100mM sodium phosphate buffer at about 25°C was thoroughly mixed for about 5 minutes. The reaction was then initiated by adding about 20µL cholesterol esterase enzymes. The resulting reaction mixture was thoroughly mixed, incubated for about 15 minutes, and its absorbance was measured at 405nm using Omega Micro Plate reader. The experiment was performed in triplicate and Simvastatin was used as a positive drug control sample throughout cholesterol esterase inhibition assay. The percentage of inhibition was calculated using the formula: % inhibition

) x 100 Where A_s is the absorbance of the sample and A_c is the absorbance of the control sample. [038] The Pancreatic lipase inhibitory activity of the synthesized compounds was evaluated based on a previously described method. Pancreatic lipase was dissolved in about 50mM sodium phosphate buffer (pH 8.0). The substrate p-nitro phenyl butyrate (about 0.1mM) was dissolved in acetonitrile. A pre-incubated volume of about 1mL containing about 200µL of each of the samples Metformin, glimepiride, and synthesized compounds in the concentration range of 50µg/mL-250µg/mL, about 100µL of pancreatic lipase enzyme, and about 700µL Tris-HCL solution (pH 7.4) was mixed thoroughly and incubated for about 15 minutes at 25°C. Following incubation, the reaction was initiated by adding 100µL of p-nitro phenyl butyrate (PNPB) in each test tube. The reaction mixture was then thoroughly mixed, incubated for about 30 minutes, and its absorbance was measured at 405nm using Omega Micro Plate reader. The experiment was performed in triplicate and Orlistat was used as a positive drug control sample. The percentage of inhibition was calculated using the formula: % inhibition

) x 100 where As is the absorbance of the sample and Ac is the absorbance of the control sample. [039] The concentration of each synthesized compound (compounds 9a-9L) required to inhibit 50% of cholesterol esterase and pancreatic lipase activity was expressed as IC₅₀ (μM), where their values can be found below in Table 1. All IC₅₀ values were compared to that of reference drugs i.e. Metformin, Glimepiride, Simvastatin, and Orlistat. By referring to Table 1, it can be noticed that compounds 9a and 9b had the lowest IC₅₀ value and thus highest cholesterol esterase inhibition activity. Similarly, all new hybrid N-(sulfonyl)-N’-D-glucopyranos-2-yl) urea compounds (9a-9l) possessed significantly (p<0.0001) higher anti-cholesterol activity compared to Simvastatin. On the other hand, with regards to pancreatic lipase inhibition, compound 9d had the lowest IC₅₀ value and thus the highest anti-lipase activity. Nevertheless, the majority of the compounds, with the exception of compound 9f, demonstrated a significantly (p<0.0001) higher anti-lipase activity in comparison to Glimepiride and Orlistat. As a result, it can be determined that the synthesized compounds 9a-9l play a key role in controlling the absorption of cholesterol lipids. Table (1)

Example 5 In-vitro and In-vivo anti-glycation activity [040] To evaluate the in-vitro antiglycation activity of synthesized compounds, bovine serum albumin (“BSA”)-glucose assay was performed. About 3mL mixture containing about 1mL of BSA (about 10mg/mL), about 1mL of glucose (about 500mM), and about 1mL of synthesized compounds 9a-9l of various concentrations (about 50µg/mL- about 250µg/mL) in about 0.2M sodium phosphate buffer (pH 7.4) was prepared, mixed, and incubated for about 5 minutes. After incubation, about 0.5mL of sodium azide (about 0.5mM) was added to each mixture tube. The tubes were incubated for 7 days at about 37°C in a dark condition. After 7 days of incubation, the samples were measured at fluorescence intensity (excitation wavelength of 370nm and emission wavelength of 440nm) using Omega micro plate reader. The experiment was carried out in triplicate and Aminoguanidine was used as an inhibitor positive control for glycation of proteins. The percentage of inhibition was calculated using equation below: % inhibition

) x 100 Where F_s is the fluorescence of the sample and F_c is the fluorescence of the control sample. [041] To evaluate the in-vivo antiglycation activity of synthesized compounds, a mixture comprising of glucose (about 2g/dL), heamoglobin (about 12g/dL), and samples (synthesized compounds, metformin and glimepiride) (1mg/mL) was dissolved in distilled water in order to give rise to a 3mL reaction mixture containing about 1mL glucose, about 1mL haemoglobin and about 1mL of test sample with various concentrations (about 50µg/mL-250µg/mL). The reaction tubes were incubated in the dark at about 37°C. The concentrations of glycated haemoglobin were measured at the incubation period of 24hours, 48 hours and 72hours using Omega plate reader at wavelength 443nm. The test was conducted in triplicate and the negative control was prepared without any drug or haemoglobin. The inhibition of glycated haemoglobin was calculated using the following formula: % inhibition

) x 100 Where A_s is the absorbance of the sample and A_c is the absorbance of the control sample. [042] The findings in Table 2 show that the new hybrid N-(sulfonyl)-N’-D-gluco- pyranos-2-yl)urea compounds (9a-9i) exhibited potential anti-glycation activity which may be through the scavenging of the free radicals, carbonyl species, and reactive dicarbonyl species, methylglyoxal (“MGO”), or through chelating of metal ions (Fe) and copper (Cu), thus preventing the autoxidation of reducing sugars or glycation of protein or lips when exposed to sugars. Table (2) In-vitro and In-vivo anti-glycation activity of tested compounds 9a-9i , Glimepiride and ducts

Example 6 In-vitro and ex-vivo gene expression studies [043] The ability of the novel compounds 9a-9l to inhibit and/or induce the expression of genes, particularly insulin receptor substrate 1 (“ISR-1”), phosphoinositide 3-kinase (“PI3K”), protein kinase C (“PKC”), protein kinase B (“AKT”), and glucose transporter type 4 (“GLUT4”) was studied. [044] The in-vitro gene expression study was initiated by differentiating L6 rat skeletal cells into myotubes via Dulbecco's Modified Eagle Medium (“DMEM”) media containing about 2% horse serum with about 1% penicillin for 7 days. All the cultures were grown in T-25 flask under the atmosphere of about 95% air and about 5% CO₂ at about 37° C. Differentiated myotubes were grown at a density of 2 x 10⁴ cells/ well on 96 well microplate and were pre-treated with the DMEM media containing about 25mmol/L glucose and about 100mmol/L insulin for about 24 hours. High glucose- insulin media was discarded after about 24 hours incubation and was replaced with a media containing about 5mmol/L glucose in the absence of the insulin for about 5 hours. Glucose enriched media was discarded after about 5 hours and replaced with about 100mmol/L insulin media for another about 30 minutes. Incubation with glucose and insulin was done in order to induce insulin resistance. The resulting insulin resistance induced cells were treated with novel compounds, glimepiride and metformin for about 24 hours. Table (3) 9a-9i,

IR 1 PI K PK AKT L T4

negative control) [045] The ex-vivo gene expression study was initiated by extracting soleus muscle cells from Male Sprague dweley rats (about180g-250g) were pre incubated at about 37°C under 95% O₂-5% CO₂ in glucose free Kerbs-Henseleit buffer (“KHB”) for about 24 hours. Insulin resistance was induced in the extracted Soleus muscles by replacing KHB buffer containing about 25mmol/L glucose and about 100mmol/lLinsulin for about 24 hours. Insulin resistance induced muscles were treated with novel compounds, glimepiride and metformin for about 3 hours after the induction of insulin resistance. Table (4) Table 4. Ex-vivo Gene expression study of insulin signal transduction of tested compounds 9a-9i,

0 7 3 2 3

3 [046] By referring to Tables 3 and 4, new phenylsulfonylurea derivatives of 2-amino- 2-deoxy-D-glucopyranose (compounds 9a-9l) inhibited the expression of PKC-α, increased the expression of the insulin receptor substrate (“IRS-1”), phosphatidylinositol 3-kinase (“PI3K”), Protein Kinase B (“PKB/AKT2”), and consequently resulted in the translocation of GLUT4 to the plasma membrane in order to maintain the glucose level. Additionally, the new compounds (9a-9i) increased the expression of AKT2 in the treated group compared to glimepiride treated group. As insulin signaling is coordinated through the activation of IRS-PI3K-AKT-GLUT4 signaling pathway, the data in Tables 3 and 4 showed positive results and validated both the in-vivo and in-vitro study. The novel sulfonylurea compounds resulted in reduction of plasma glucose. [047] While embodiments of the present disclosure have been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various additions, omissions, and modifications can be made without departing from the spirit and scope thereof. [048] In describing and claiming the present invention, the following terminology will be used. [049] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. [050] As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a defacto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. [051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are now described. [052] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter. [053] As used herein, the term “about”, when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

Claims

CLAIMS What is claimed is: 1. A novel compound of the general formula (I), or a pharmaceutically acceptable salt thereof:

Formula (I) wherein R₁ is selected from a group containing alkyl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, halogen, hydroxyl, cyano, or heteroaryl; R₂ is selected from a group containing Br, NO₂, OCH₃, or F; R₃, R₄, R₅, R₆ are selected from a group containing hydrogen, acetyl, acyl, or partially acylated hydroxy groups having the group R₇-(C=O)-; and R₇ is an alkyl, substituted or unsubstituted aryl, or arylalkyl. 2. The compound of claim 1, wherein R₇ is selected from phenyl, nitrophenyl, halophenyl, alkyl substituted phenyl, alkoxy, phenyl, or benzyl group. 3. The compound of claim 1, wherein the pharmaceutically acceptable salt is selected from alkali metal, alkaline earth metal, ammonium or an amine salt. 4. A method for preparing the compound of claim 1, the method comprises the steps of: - Stirring sulfonyl chloride with aqueous NH₃ and Tetrahydrofuran (“THF”) at a temperature of about 0°C until reaction completion to form a first mixture; - Evaporating, drying, washing, and crystallizing the first mixture to form substituted aryl sulfonamide derivatives; - Stirring substituted aryl sulfonamide derivatives, Dimethylaminopyridine (“DMAP”), and Diphenylcarbazide (“DPC”) in acetonitrile at room temperature to form a second mixture; - Filtering, washing, and drying the second mixture to form substituted aryl sulfonyl derivatives; - Adding substituted aryl sulfonyl derivatives and Et3N to 1,3,4,6-Tetra-O- acetyl-ß-D-glucosamine dissolved in acetonitrile to form a third mixture; - Refluxing, cooling, and adjusting the pH of the third mixture; - Filtering, washing, and drying third mixture until a first precipitate is formed; - Adding NaOCH₃ dissolved in MeOH to the first precipitate until a final reaction mixture is formed; - Neutralizing, filtering, evaporating, and recrystallizing the final reaction mixture to provide a second precipitate; and - Freeze-drying the second precipitate. 5. A pharmaceutical composition including a compound of general formula (I) and/or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier/excipient. 6. The pharmaceutical composition including a compound according to claim 6, wherein the composition is formulated as a solid, liquid, or semi-solid dosage form. 7. The pharmaceutical composition of claim 6 wherein the composition is administered via different routes such as oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, ocular, vaginal, rectal, or intraventricular. 8. Use of the pharmaceutical composition of claim 6 for treating diabetes mellitus.