CN113185492A - Synthesis and application of novel tetrahydrobenzothiophene-2-urea derivative - Google Patents

Synthesis and application of novel tetrahydrobenzothiophene-2-urea derivative Download PDF

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CN113185492A
CN113185492A CN202110525398.0A CN202110525398A CN113185492A CN 113185492 A CN113185492 A CN 113185492A CN 202110525398 A CN202110525398 A CN 202110525398A CN 113185492 A CN113185492 A CN 113185492A
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江成世
谢洪旭
李光浩
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University of Jinan
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Abstract

The invention relates to the field of medicinal chemistry, in particular to a novel tetrahydrobenzothiophene-2-urea derivative with alpha-glucosidase inhibition activity, which has the following structural general formula:

Description

Synthesis and application of novel tetrahydrobenzothiophene-2-urea derivative
Technical Field
The invention relates to an alpha-glycosidase inhibitor and application thereof, and application of tetrahydrobenzothiophene-2-urea derivatives as novel alpha-glycosidase inhibitors.
Background
Diabetes Mellitus (DM) is a disease of disturbed carbohydrate, protein and fat metabolism caused by absolute or relative insufficiency of insulin secretion caused by dysfunction of islet cells, or utilization of insulin by the body, or both. It is classified into type I diabetes and type II diabetes. The typical clinical manifestations are "more than three and one less", i.e. polydipsia, diuresis, polyphagia and weight loss, the blood sugar level of the patient is higher, and the urine contains substances such as glucose.
Collectively, genetic and environmental factors contribute to the development of diabetes. Type I diabetes is affected by genetic factors and type II diabetes is primarily developed by modern poor lifestyle. Chronic diseases can cause chronic progressive pathological changes, hypofunction and even failure of tissues and organs such as eyes, feet, kidneys, nerves, hearts, blood vessels and the like. At present, the incidence and incidence of diabetes rapidly rise worldwide, and are important causes of cardiovascular and cerebrovascular diseases, death, amputation, blindness, renal failure and heart failure. According to the latest circulation data, the prevalence rate of diabetes in China is increased to 11.2%, and the prevalence rate of diabetes is in a rapid rising trend, and one diabetic patient in every nine people has 2 times of the mortality rate of hepatitis B.
Recent studies have shown that in young patients with early stage diabetes, the condition can be alleviated and reversed. Early diabetes is often not expressed, patients are mostly found to suffer from the diabetes through physical examination, blood sugar test and the like, and postprandial hyperglycemia is the first symptom in the onset process of the diabetes. In human body, saccharides in food are the main source of blood sugar, and disaccharides or polysaccharides in food can be absorbed by human body only after being hydrolyzed into monosaccharides by alpha-glucosidase, thereby causing the increase of blood sugar level. Therefore, inhibition of α -glucosidase activity is an effective target for the treatment of diabetes. Alpha-glucosidase inhibitors can delay carbohydrate absorption by inhibiting alpha-glucosidase enzyme at the brush border of small intestine mucosa, thereby reducing the occurrence of postprandial hyperglycemia symptoms. Moreover, clinical application shows that the single use of the medicine does not usually stimulate the secretion of insulin and does not cause hypoglycemia. In view of the above, the development of novel α -glucosidase inhibitors has become a hot spot for new drug development in recent years.
Disclosure of Invention
The inventor of the invention compares various commercially available substituted benzylamines withN,N' -Carbonyl Diimidazole (CDI) to form different intermediate structures, and finally reacting with 2-amino-4, 5,6, 7-tetrahydrobenzo [ 2 ], [ 2 ] amino-4, 5,6, 7-tetrahydrobenzo [ b ], [ 2 ] amino-2, 2-carbonyl ] respectivelyb]Thiophene-3-nitrile reacts to replace imidazole groups on the intermediate to form urea bonds, and a new compound which has a similar structure and alpha-glycosidase inhibitory activity and is shown in the general formula I is obtained, so that the compound has a potential application in the field of preparing medicines for treating diabetes.
In a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
The structure of the compound is shown as a general formula I
Figure 835842DEST_PATH_IMAGE001
Wherein R is1Is hydrogen, methyl, methoxy, fluorine, chlorine, bromine, phenyl; r2Hydrogen, methyl, ethyl, isopropyl, phenyl.
The preparation method of the tetrahydrobenzo [ b ] thiophene-2-urea derivative shown in the general formula I comprises the following steps:
Figure 487404DEST_PATH_IMAGE002
。
a) reacting different compounds of formula 1 withN,N'Carbonyl Diimidazole (CDI) to give different compounds of the formulae 2 and 3, in which the reaction solvent isN,N-at least one of dimethylformamide, acetone, dimethylsulfoxide, 1, 4-dioxane, tetrahydrofuran, methanol, ethanol, dichloromethane, isopropanol, pyridine and water; the reaction temperature is 0-140 ℃; the reaction time is 8-24 hours.
b) Reacting the compound of the formula 2 or the compound of the formula 3 with 2-amino-4, 5,6, 7-tetrahydrobenzo [ 2 ], [ solution of ] respectivelyb]Reacting thiophene-3-nitrile to obtain a target compound shown in a general formula I under the action of a catalyst; the catalyst used isN,N'-dicyclohexylcarbodiimide,N, N'Diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, sodium hydride, diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1-hydroxy-7-azobenzotriazol, 1-hydroxybenzotriazole, O- (7-Azobenzotriazole) -N,N,N',N'Tetramethyluronium hexafluorophosphate and benzotriazole-N,N,N',N'One or a combination of two or more of tetramethylurea hexafluorophosphate; the solvent isMethanol, ethanol, propanol, isopropanol, acetonitrile, 1, 4-dioxane, dichloroethane, methanol, isopropanol, ethanol, isopropanol, ethyl acetate, and ethyl acetate,N,N-dimethylformamide,N,N-diisopropylethylamine, one or a combination of two or more of water; the reaction temperature is 0-130 ℃; the reaction time is 6-24 hours.
Wherein R is1Is hydrogen, methyl, methoxy, fluorine, chlorine, bromine, phenyl; r2Hydrogen, methyl, ethyl, isopropyl, phenyl.
In a second aspect of the present invention, a pharmaceutical composition comprises a compound represented by formula I in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
In a third aspect of the present invention, there is provided a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for use in:
(i) preparing an alpha-glycosidase inhibitor;
(ii) preparing the medicine for preventing and/or treating diabetes related diseases.
Pharmaceutically acceptable carriers must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof, and generally suitable carriers, diluents and excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the mode and purpose of administration of the compounds of the invention. The solvent is generally selected based on the solvents (GRAS) that one of skill in the art would consider safe for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents (such as water) and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400 or PEG300), and the like, and mixtures thereof. One or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, slip agents, processing aids, colorants, sweeteners, flavorants, flavoring agents and other known additives that provide a tailored appearance to the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) or aid in the manufacture of the drug product (i.e., for use in the preparation of a medicament) may also be included.
Advantageous effects
The compound can inhibit alpha-glycosidase and can be used for preparing medicaments for preventing and/or treating diabetes and other related diseases.
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
By mixing various commercially available substituted benzylamines withN,N'-Carbonyldiimidazole (CDI) to form different intermediate structures, and finally reacting with 2-amino-4, 5,6, 7-tetrahydrobenzo [ 2 ], [ 2 ] amino-4, 5,6,7 ] respectivelyb]Thiophene-3-nitrile reacts to replace imidazole groups on the intermediate to form urea bonds, so that a novel compound which has a similar structure and alpha-glycosidase inhibitory activity and is shown in a general formula I is obtained, and the alpha-glycosidase inhibitory activity can be effectively inhibited. On the basis of this, the present invention has been completed.
Detailed description of the preferred embodiments
The present invention will be described in further detail with reference to specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.
EXAMPLE 1 preparation of Compounds of formula 2 and 3
Various substituted benzylamines (1eq) were dissolved in 70 mL of dichloromethane and a solution of hydrochloric acid in isopropanol was slowly added dropwise to the reaction until a thick white liquid appeared. Then dissolved in 34mL of DMFN,N'Carbonyldiimidazole (CDI, 1.4 eq) was added to the reaction mixture and reacted at room temperature for 1.5 hours. The mixture was extracted with water, an aqueous sodium hydrogencarbonate solution and saturated brine several times, and the organic phase was retained and dried over anhydrous magnesium sulfate for two hours. Finally, the compounds of the formulas 2 and 3 are obtained by column chromatography separation.
EXAMPLE 2 preparation of Compounds of general formula I (formula 4 and formula 5)
The compound of formula 2 or 3 (1eq) with 2-amino-4,5,6, 7-tetrahydrobenzo [ b ] benzene [ b ], [ solution of a ] benzeneb]Thiophene-3-carbonitrile (1eq) was dissolved in 5ml of DMF and then sodium hydride (1.4 eq) was added. The reaction was stirred at room temperature overnight until the reaction was complete. The reaction mixture was diluted with 15mL of water and extracted with dichloromethane (3X 15 mL). And combining organic phases, drying the organic phases by anhydrous magnesium sulfate, filtering the organic phases, concentrating the organic phases to obtain residues, and separating and purifying the residues by silica gel chromatography to obtain the corresponding compounds in the general formula I. The compound numbers and specific structural formulas are shown in the following table 1.
TABLE 1 specific structural formulas of compounds of general formula I
Figure 735982DEST_PATH_IMAGE001
Figure 976864DEST_PATH_IMAGE004
。
Compound 4b, white solid, yield 77.5%.1H NMR (600 MHz, CDCl3) δ 8.59 (s, 1H), 7.29 (dd, J = 7.6, 1.7 Hz, 1H), 7.24 (dd, J = 7.6, 1.7 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.11 (t, J = 6.0 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.55 (m, 2H), 2.46 (m, 2H), 1.81–1.77 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 157.6, 153.7, 151.9, 130.0, 129.5, 128.9, 126.6, 126.2, 120.7, 116.1, 110.3, 55.5, 40.3, 29.8, 24.1, 24.0, 23.3, 22.3. HRMS (ESI+): m/z calcd for C18H19N3O2 [M+H]+: 342.1276, found: 342.1283。
Compound 4c, white solid, yield 75.8%.1H NMR (600 MHz, CDCl3) δ 8.74 (s, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.85 (t, J = 2.0 Hz 1H), 6.78 (dd, J = 8.1, 2.5 Hz, 1H), 6.09 (t, J = 5.7 Hz, 1H), 4.43 (d, J = 5.7 Hz, 2H), 3.77 (s, 3H), 2.55 (t, J = 5.8 Hz, 2H), 2.41 (t, J = 5.8 Hz, 2H), 1.81–1.76 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 160.0, 153.8, 151.8, 139.9, 130.2, 129.8, 126.3, 119.8, 116.2, 113.1, 112.9, 89.2, 55.3, 44.3, 24.0, 24.0, 23.3, 22.3. HRMS (ESI+): m/z calcd for C18H19N3O2 [M+H]+: 342.1276, found: 342.1243。
Compound 4d, white solid, yield 64.1%.1H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 7.33–7.25 (m, 5H), 6.02 (t, J = 5.7 Hz, 1H), 4.47 (d, J = 5.7 Hz, 2H), 2.56 (t, J = 5.9 Hz, 2H), 2.41 (t, J = 5.9 Hz, 2H), 1.81–1.76 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 153.7, 151.8, 138.4, 130.2, 128.8, 127.6, 127.6, 126.3, 116.3, 60.6, 44.4, 24.0, 24.0, 23.3, 22.3. HRMS (ESI+): m/z calcd for C17H17N3O [M+H]+: 312.1171, found: 312.1214。
Compound 4e, white solid, 78.7% yield.1H NMR (600 MHz, CDCl3) δ 8.64 (s, 1H), 7.28 (d, J = 6.8 Hz, 1H), 7.17 (m, 3H), 5.90 (t, J = 5.5 Hz, 1H), 4.45 (d, J= 5.5 Hz, 2H), 2.57 (t, J = 5.5 Hz, 2H), 2.37 (t, J = 6.0 Hz, 2H), 2.35 (s, 3H), 1.84–1.76 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 153.5, 152.1, 136.3, 136.1, 130.6, 130.1, 128.2, 127.8, 126.3, 126.3, 116.4, 88.8, 42.5, 24.0, 23.3, 22.3, 19.2. HRMS (ESI+): m/z calcd for C18H19N3O [M+H]+: 326.1327, found: 326.1372。
Compound 4f, white solid, yield 81.4%.1H NMR (600 MHz, CDCl3) δ 8.70 (s, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.13–7.08 (m, 2H), 7.07 (d, J = 7.5 Hz, 1H), 6.03 (t, J = 5.7 Hz, 1H), 4.42 (d, J = 5.7 Hz, 2H), 2.56 (t, J = 5.9 Hz, 2H), 2.40 (t, J = 5.9 Hz, 2H), 2.32 (s, 3H), 1.83–1.76 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 153.8, 151.8, 138.5, 138.3, 130.2, 128.7, 128.3, 128.3, 126.3, 124.6, 116.3, 89.1, 44.4, 24.0, 24.0, 23.3, 22.3, 21.5. HRMS (ESI+): m/z calcd for C18H19N3O [M+H]+: 326.1327, found: 326.1355。
Compound 4g, white solid, yield 80.7%.1H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.03 (t, J = 5.6 Hz, 1H), 4.40 (d, J = 5.6 Hz, 2H), 2.56 (t, J = 5.9 Hz, 2H), 2.40 (t, J = 5.9 Hz, 2H), 2.32 (s, 3H), 1.84–1.74 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 153.7, 151.9, 137.2, 135.3, 130.1, 129.4, 127.6, 126.2, 116.2, 89.1, 44.2, 24.0, 24.0, 23.3, 22.3, 21.2. HRMS (ESI+): m/z calcd for C18H19N3O [M+H]+: 326.1327, found: 326.1331。
Compound 4h, light yellow solid, 47.2% yield.1H NMR (600 MHz, CDCl3) δ 8.67 (s, 1H), 7.27 (dd, J = 8.6, 5.4 Hz, 2H), 7.00 (t, J = 8.6 Hz, 2H), 6.04 (t, J = 5.7 Hz, 1H), 4.42 (d, J = 5.7 Hz, 2H), 2.59–2.53 (m, 2H), 2.40 (t, J = 5.6 Hz, 2H), 1.79 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 162.3 (d, J = 245.7 Hz), 153.7, 151.7, 134.2, 134.2, 130.2, 129.4, 129.3, 126.5, 116.3, 115.7, 115.5, 89.2, 43.7, 24.0, 24.0, 23.3, 22.2. HRMS (ESI+): m/z calcd for C17H16FN3 [M+H]+: 330.1076, found: 330.1086。
Compound 4i, white solid, yield 80.7%.1H NMR (600 MHz, CDCl3) δ 10.08 (s, 1H), 7.46 (dd, J = 7.5, 1.8 Hz, 1H), 7.39 (dd, J = 7.5, 1.8 Hz, 1H), 7.36–7.31 (m, 2H), 7.29 (t, J = 5.9 Hz, 1H), 4.40 (d, J = 5.9 Hz, 2H), 2.54–2.50 (m, 2H), 2.47–2.40 (m, 2H), 1.77–1.67 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 153.4, 150.1, 136.4, 132.2, 129.9, 129.4, 129.1, 127.5, 127.3, 125.0, 114.9, 88.9, 41.2, 23.5, 23.3, 22.7, 21.8. HRMS (ESI+): m/z calcd for C17H16ClN3 [M+H]+: 346.0781, found: 346.0804。
Compound 4j, white solid, yield 71.1%.1H NMR (600 MHz, DMSO-d 6) δ 10.04 (s, 1H), 7.40–7.24 (m, 5H), 4.34 (d, J = 6.0 Hz, 2H), 2.52 (d, J = 4.8 Hz, 2H), 2.44 (d, J = 6.0 Hz, 2H), 1.74–1.70 (m, 4H). 13C NMR (150 MHz, DMSO-d 6) δ 153.5, 150.1, 142.1, 133.1, 130.3, 129.8, 126.9, 125.8, 125.0, 114.8, 89.0, 42.5, 23.5, 23.3, 22.7, 21.8. HRMS (ESI+): m/z calcd for C17H16ClN3 [M+H]+: 346.0781, found: 346.0792。
Compound 4k, white solid, yield 67.1%.1H NMR (600 MHz, DMSO-d 6) δ 10.03 (s, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.25 (t, J = 5.9 Hz, 1H), 4.32 (d, J = 5.9 Hz, 2H), 2.52 (t, J = 5.2 Hz, 2H), 2.43 (d, J = 5.2 Hz, 2H), 1.77–1.67 (m, 4H). 13C NMR (150 MHz, DMSO-d 6) δ 153.5, 150.2, 138.5, 131.5, 129.8, 129.0, 128.4, 124.9, 114.8, 88.9, 42.4, 23.5, 23.3, 22.7, 21.8. HRMS (ESI+): m/z calcd for C17H16ClN3 [M+H]+: 346.0781, found: 346.0799。
Compound 4l, white solid, yield 68.9%.1H NMR (600 MHz, DMSO-d 6) δ 10.11 (s, 1H), 7.63 (dd, J = 7.9, 1.1 Hz, 1H), 7.41–7.36 (m, 2H), 7.30 (t, J = 6.0 Hz, 1H), 7.24 (ddd, J = 7.9, 6.5, 2.6 Hz, 1H), 4.37 (d, J = 6.0 Hz, 2H), 2.54–2.51 (m, 2H), 2.46–2.42 (m, 2H), 1.78–1.66 (m, 4H). 13C NMR (150 MHz, DMSO-d 6) δ 153.4, 150.1, 137.9, 132.5, 129.8, 129.3, 129.2, 127.9, 125.0, 122.5, 114.8, 88.9, 43.6, 23.5, 23.3, 22.7, 21.8. HRMS (ESI+): m/z calcd for C17H16BrN3 [M+H]+: 390.0276, found: 390.0288。
Compound 4m, white solid, yield 70.5%.1H NMR (600 MHz, DMSO-d 6) δ 10.05 (s, 1H), 7.49 (s, 1H), 7.45 (dt, J = 6.3, 2.5 Hz, 1H), 7.31 (d, J = 4.1 Hz, 2H), 7.26 (t, J = 6.0 Hz, 1H), 4.33 (d, J = 6.0 Hz, 2H), 2.52 (t, J = 3.2 Hz, 2H), 2.43 (t, J = 3.2 Hz, 2H), 1.72 (m, 4H). 13C NMR (150 MHz, DMSO-d 6) δ 153.5, 150.1, 142.3, 130.6, 129.8, 129.8, 126.2, 125.0, 121.7, 114.8, 89.0, 42.5, 23.5, 23.3, 22.7, 21.8. HRMS (ESI+): m/z calcd for C17H16BrN3 [M+H]+: 390.0276, found: 390.0256。
Compound 4n, white solid, yield 72.6%.1H NMR (600 MHz, DMSO-d 6) δ 10.03 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 3H), 4.30 (d, J = 5.9 Hz, 2H), 2.55–2.51 (m, 2H), 2.44 (t, J = 5.1 Hz, 2H), 1.76–1.69 (m, 4H). 13C NMR (150 MHz, DMSO-d 6) δ 153.5, 150.2, 138.9, 131.3, 129.8, 129.4, 124.9, 120.0, 114.8, 88.9, 42.4, 23.5, 23.3, 22.7, 21.8. HRMS (ESI+): m/z calcd for C17H16BrN3 [M+H]+: 390.0276, found: 390.0273。
Compound 4o, light yellow solid, yield 75.2%.1H NMR (600 MHz, CDCl3) δ 8.70 (s, 1H), 7.20 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.04 (t, J = 5.5 Hz, 1H), 4.36 (d, J = 5.5 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 2.55 (t, J = 5.9 Hz, 2H), 2.39 (t, J = 5.9 Hz, 2H), 1.82–1.74 (m, 4H), 1.39 (t, J = 7.0 Hz, 3H).13C NMR (150 MHz, CDCl3) δ 158.4, 153.7, 151.7, 130.2, 130.2, 129.0, 126.2, 116.2, 114.7, 89.2, 63.5, 43.9, 24.0, 24.0, 23.3, 22.3, 15.0. HRMS (ESI+): m/z calcd for C19H21N3O2 [M+H]+: 356.1433, found: 356.1456。
Compound 4p, light yellow solid, yield 45.6%.1H NMR (600 MHz, CDCl3) δ 8.73 (s, 1H), 7.30 (dd, J = 7.5, 1.7 Hz, 1H), 7.21 (td, J = 7.9, 1.7 Hz, 1H), 6.87 (td, J = 7.5, 1.0 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.09 (t, J = 5.9 Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H), 4.05 (q, J = 7.0 Hz, 2H), 2.54 (t, J = 6.0 Hz, 2H), 2.46–2.40 (m, 2H), 1.80–1.74 (m, 4H), 1.42 (t, J = 7.0 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 156.9, 153.8, 151.9, 130.0, 129.4, 128.8, 126.7, 126.1, 120.5, 116.2, 111.1, 89.0, 63.6, 40.2, 24.1, 23.9, 23.3, 22.3, 15.1. HRMS (ESI+): m/ z calcd for C19H21N3O2 [M+H]+: 356.1433, found: 356.1473。
Compound 4q, light yellow solid, yield 71.3%.1H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 6.84 (d, J = 7.4 Hz, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.05 (t, J = 5.6 Hz, 1H), 4.38 (d, J = 5.6 Hz, 2H), 3.84 (s, 6H), 2.55 (t, J = 5.9 Hz, 2H), 2.42–2.37 (m, 2H), 1.80–1.73 (m, 4H).13C NMR (150 MHz, CDCl3) δ 153.7, 151.6, 149.2, 148.5, 130.9, 130.2, 126.3, 119.9, 116.1, 111.2, 111.0, 89.3, 56.0, 56.0, 44.3, 24.0, 24.0, 23.3, 22.3. HRMS (ESI+): m/z calcd for C19H21N3O3 [M+H]+: 372.1382, found: 372.1418。
Compound 4r, light yellow solid, yield 68.4%.1H NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.38 (dd, J = 8.2, 2.4 Hz, 1H), 6.15 (t, J = 5.9 Hz, 1H), 4.37 (d, J = 5.9 Hz, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 2.53 (t, J = 5.7 Hz, 2H), 2.45 (d, J = 5.7 Hz, 2H), 1.82–1.75 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 160.6, 158.6, 153.7, 130.3, 130.0, 126.0, 119.1, 116.0, 103.9, 98.6, 55.5, 55.5, 39.9, 24.1, 23.9, 23.3, 22.3. HRMS (ESI+): m/z calcd for C19H21N3O3 [M+H]+: 372.1382, found: 372.1408。
Compound 4s, yellow solid, yield 71.1%.1H NMR (600 MHz, CDCl3) δ 8.74 (s, 1H), 6.45 (d, J = 2.2 Hz, 2H), 6.33 (t, J = 2.2 Hz, 1H), 6.10 (t, J = 5.7 Hz, 1H), 4.39 (d, J = 5.7 Hz, 2H), 3.75 (s, 6H), 2.55 (t, J = 6.1 Hz, 2H), 2.42 (t, J= 6.1 Hz, 2H), 1.83–1.73 (m, 4H).13C NMR (150 MHz, CDCl3) δ 161.1, 153.8, 151.7, 140.7, 130.3, 126.3, 116.2, 105.4, 99.3, 89.3, 55.4, 44.4, 24.0, 23.3, 22.3. HRMS (ESI+): m/z calcd for C19H21N3O3 [M+H]+: 372.1382, found: 372.1388。
Compound 4t, yellow solid, yield 65.3%.1H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.92–7.87 (m, 3H), 7.79 (s, 1H), 7.53–7.44 (m, 3H), 7.35 (t, J = 5.9 Hz, 1H), 4.51 (d, J = 5.8 Hz, 2H), 2.52 (t, J = 5.4 Hz, 2H), 2.44 (t, J = 5.4 Hz, 2H), 1.76–1.68 (m, 4H).13C NMR (150 MHz, DMSO-d6) δ 153.6, 150.3, 136.9, 132.9, 132.2, 129.8, 128.1, 127.6, 126.3, 125.8, 125.2, 124.9, 114.9, 88.8, 43.2, 23.5, 23.3, 22.7, 21.8. HRMS (ESI+): m/z calcd for C21H19N3O [M+H]+: 362.1327, found: 362.1364。
Compound 4u, yellow solid, 53.4% yield.1H NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 8.00–7.97 (m, 1H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 6.7, 1.5 Hz, 1H), 7.47–7.42 (m, 2H), 7.38 (dd, J = 8.2, 7.0 Hz, 1H), 6.11 (t, J = 5.4 Hz, 1H), 4.86 (d, J = 5.4 Hz, 2H), 2.52 (t, J = 5.8 Hz, 2H), 2.17 (t, J = 5.8 Hz, 2H), 1.80–1.76 (m, 2H), 1.74–1.71 (m, 2H).13C NMR (150 MHz, CDCl3) δ 153.5, 151.6, 133.9, 133.5, 131.4, 130.1, 128.8, 128.6, 126.7, 126.4, 126.0, 125.5, 125.5, 123.4, 116.0, 89.1, 42.4, 23.9, 23.8, 23.3, 22.3. HRMS (ESI+): m/z calcd for C21H19N3O [M+H]+: 362.1327, found: 362.1363。
Compound 4v, yellow solid, 48.9% yield.1H NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 7.57–7.53 (m, 4H), 7.42 (t, J = 7.7 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.36–7.32 (m, 1H), 6.07 (t, J = 5.6 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 2.54 (t, J= 5.6 Hz, 2H), 2.40 (t, J = 5.6 Hz, 2H), 1.76 (m, 2H), 1.69 (m, 2H).13C NMR (150 MHz, CDCl3) δ 153.7, 151.8, 140.8, 140.5, 137.4, 130.2, 128.9, 128.1, 127.5, 127.5, 127.1, 126.4, 116.3, 89.3, 44.2, 24.0, 24.0, 23.2, 22.2. HRMS (ESI+): m/z calcd for C23H21N3O [M+H]+: 388.1484, found: 388.1453。
Compound 5a, yellow solid, 67.2% yield.1H NMR (600 MHz, CDCl3) δ 7.53–7.48 (m, 1H), 7.36 (d, J = 7.4 Hz, 2H), 7.30 (t, J = 8.3 Hz, 3H ), 4.59 (s, 2H), 3.07 (s, 3H), 2.59 (t, J = 5.9 Hz, 2H), 2.52 (t, J = 5.9 Hz, 2H), 1.82–1.76 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 149.7, 136.4, 130.4, 129.1, 128.0, 127.5, 127.1, 114.9, 91.7, 52.7, 34.9, 23.9, 23.9, 23.2, 22.2. HRMS (ESI+): m/zcalcd for C18H19N3O [M+H]+: 326.1327, found: 326.1399。
Compound 5b, yellow solid, yield 51.2%.1H NMR (600 MHz, CDCl3) δ 7.45 (s, 1H), 7.25–7.19 (m, 3H), 7.17 (dd, J = 7.6, 1.9 Hz, 1H), 4.61 (s, 2H), 3.04 (s, 3H), 2.59 (t, J = 5.6 Hz, 2H), 2.53 (t, J = 5.6 Hz, 2H), 2.32 (s, 3H), 1.83–1.76 (m, 4H).13C NMR (150 MHz, CDCl3) δ 153.4, 149.7, 136.4, 133.9, 131.1, 130.5, 128.1, 127.4, 127.2, 126.6, 114.9, 91.9, 50.6, 34.6, 24.1, 24.0, 23.3, 22.3, 19.3. HRMS (ESI+): m/z calcd for C19H21N3O [M+H]+: 340.1484, found: 340.1489。
Compound 5c, yellow solid, 47.1% yield.1H NMR (600 MHz, CDCl3) δ 7.46 (s, 1H), 7.22–7.15 (m, 4H), 4.54 (s, 2H), 3.07 (s, 3H), 2.59 (t, J = 6.1 Hz, 2H), 2.52 (t, J = 6.1 Hz, 2H), 2.34 (s, 3H), 1.85–1.75 (m, 4H).13C NMR (150 MHz, CDCl3) δ 153.4, 149.8, 137.9, 133.3, 130.5, 129.9, 127.6, 127.1, 115.0, 91.7, 52.6, 24.1, 24.0, 23.3, 22.3, 21.2. HRMS (ESI+): m/z calcd for C19H21N3O [M+H]+: 340.1484, found: 340.1513。
Compound 5d, yellow solid, 68.8% yield.1H NMR (600 MHz, CDCl3) δ 7.42–7.36 (m, 3H), 7.33 (dd, J = 7.8, 2.7 Hz, 3H), 4.57 (s, 2H), 3.57–3.45 (m, 2H), 2.58 (t, J = 6.2 Hz, 2H), 2.51 (t, J = 6.2 Hz, 2H), 1.83–1.74 (m, 4H), 1.26 (t, J= 7.2 Hz, 3H).13C NMR (150 MHz, CDCl3) δ 153.1, 149.7, 136.5, 130.4, 129.3, 128.3, 127.4, 127.0, 114.8, 91.7, 50.7, 43.1, 24.0, 23.9, 23.3, 22.3, 13.5. HRMS (ESI+): m/z calcd for C19H21N3O [M+H]+: 340.1484, found: 340.1517。
Compound 5e, yellow solid, 66.4% yield.1H NMR (600 MHz, CDCl3) δ 7.42 (t, J = 7.6 Hz, 2H), 7.39–7.36 (m, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.28 (s, 1H), 4.78–4.70 (m, 1H), 4.46 (s, 2H), 2.55 (t, J = 6.1 Hz, 2H), 2.46 (t, J = 6.1 Hz, 2H), 1.80–1.72 (m, 4H), 1.28 (d, J = 6.8 Hz, 6H).13C NMR (150 MHz, CDCl3) δ 153.7, 149.5, 136.6, 130.5, 129.7, 128.5, 126.9, 126.8, 114.5, 91.6, 47.4, 45.8, 24.0, 23.9, 23.3, 22.3, 20.8. HRMS (ESI+): m/z calcd for C20H23N3O [M+H]+: 354.1640, found: 354.1684。
Compound 5f, yellow solid, 56.4% yield.1H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 3.4 Hz, 1H), 7.43–7.31 (m, 10H), 4.73–4.59 (m, 4H), 2.60 (d, J = 6.0 Hz, 2H), 2.50 (d, J = 6.0 Hz, 2H), 1.81–1.78 (m, 4H).13C NMR (150 MHz, CDCl3) δ 153.8, 149.4, 136.2, 130.6, 129.4, 128.4, 127.7, 127.1, 114.6, 92.0, 51.5, 24.0, 23.9, 23.3, 22.3. HRMS (ESI+): m/z calcd for C24H23N3O [M+H]+: 388.1505, found: 388.1520。
Compound 5g, yellow solid, yield 51.2%.1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 1H), 7.88 (dd, J = 7.8, 1.7 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.55–7.50 (m, 3H), 7.46 (dd, J = 8.2, 7.0 Hz, 1H), 7.39 (dd, J = 7.0, 1.2 Hz, 1H), 5.08 (s, 2H), 2.99 (s, 3H), 2.62 (t, J = 5.6 Hz, 2H), 2.53 (t, J = 5.6 Hz, 2H), 1.84–1.79 (m, 4H).13C NMR (150 MHz, CDCl3) δ 153.4, 149.7, 134.1, 131.7, 131.5, 130.6, 129.0, 129.0, 127.3, 126.9, 126.5, 126.3, 125.4, 123.4, 115.0, 92.1, 50.4, 33.8, 24.1, 24.0, 23.3, 22.3. HRMS (ESI+): m/z calcd for C22H21N3O [M+H]+: 376.1484, found: 376.1527。
The compound of example 3 has inhibitory rate and inhibitory activity against α -glucosidase.
Alpha-glucosidase was purchased from Sigma, p-nitrophenyl-alpha-D-glucoside (PNPG) as substrate was purchased from Aladdin, and sodium salt and phosphate salt required for buffer preparation and quencher were purchased from Shanghai Michelin Biotech, Inc. Reference to published reports on the determination of alpha-glucosidase inhibitory activityThe method is carried out. After 99. mu.L of PBS phosphate buffer (pH 6.8) was added to each well of the 96-well plate, 20mmol of 1. mu.L of the test compound solution or a blank was added to the corresponding well, 25. mu.L of the alpha-glucosidase solution was added thereto, and the plate was incubated at 37 ℃ for 15min with shaking. Adding 25 mu L of PNPG solution, placing the PNPG solution in a shaking table at 37 ℃ for incubation for 15min, then adding 50 mu L of 0.2M sodium carbonate solution, measuring the absorbance at 405nm by using an enzyme-labeling instrument, and calculating the inhibition rate of the compound to be detected on alpha-glycosidase. The concentration of part of the compound was measured again at different gradients in 10, and the IC of the compound was determined from the inhibition curve50The values (inhibitor concentration at which the enzyme activity was inhibited by 50%) and the results are shown in Table 2.
TABLE 2 inhibition rate and inhibition Activity of Compounds on alpha-glycosidase
Compound Inhibition at 100μM (%) IC50（μM） Compound Inhibition at 100μM (%) IC50（μM）
4b 91.64 1.67 4p 81.37 0.96
4c 79.46 0.77 4q 89.57 1.41
4d 64.59 - 4r 88.58 0.59
4e 49.38 - 4s 91.12 0.65
4f 68.75 12.61 4t 53.51 70.11
4g 51.34 - 4u 36.22 -
4h 37.38 - 4v 13.62 -
4i 89.14 16.53 5a 77.83 4.81
4j 76.54 31.23 5b 21.24 -
4k 75.49 34.55 5c 19.28 -
4l 70.28 9.08 5d 8.15 -
4m 84.54 16.19 5e 14.78 -
4n 42.29 - 5f 4.51 -
4o 71.24 22.18 ± 1.52 5g 8.88 -
The preparation steps, identification process and screening for α -glucosidase inhibitory activity of the compounds of the present invention are illustrated in the specific examples above, but those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims (3)

1. A novel tetrahydrobenzothiophene-2-urea derivative characterized by the structure represented by the following general formula I:
Figure 333167DEST_PATH_IMAGE001
wherein R is1Is hydrogen, methyl, methoxy, fluorine, chlorine, bromine, phenyl; r2Hydrogen, methyl, ethyl, isopropyl, phenyl.
2. Use of a novel tetrahydrobenzothiophene-2-urea derivative as claimed in claim 1, characterized by the preparation of antidiabetic agents.
3. A medicament for preventing and/or treating diabetes, characterized in that it is prepared from the derivative as claimed in claim 1 as an active ingredient or a main active ingredient, together with pharmaceutically acceptable adjuvants.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007043652A1 (en) * 2005-10-13 2007-04-19 Taisho Pharmaceutical Co., Ltd. 2-thienylurea derivative
CN107253944A (en) * 2017-07-24 2017-10-17 哈尔滨医科大学 Tetrahydro benzo thiophene derivant and its purposes in glycogen synthase kinase 3-beta inhibitors are prepared
CN111875615A (en) * 2020-07-15 2020-11-03 济南大学 Methoxybenzyl urea compound and application thereof
WO2020263989A1 (en) * 2019-06-24 2020-12-30 University Of Iowa Research Foundation Jnk inhibitors as anticancer agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007043652A1 (en) * 2005-10-13 2007-04-19 Taisho Pharmaceutical Co., Ltd. 2-thienylurea derivative
CN107253944A (en) * 2017-07-24 2017-10-17 哈尔滨医科大学 Tetrahydro benzo thiophene derivant and its purposes in glycogen synthase kinase 3-beta inhibitors are prepared
WO2020263989A1 (en) * 2019-06-24 2020-12-30 University Of Iowa Research Foundation Jnk inhibitors as anticancer agents
CN111875615A (en) * 2020-07-15 2020-11-03 济南大学 Methoxybenzyl urea compound and application thereof

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