CN112441963B - Divalent DNJ derivative, synthetic method and application thereof - Google Patents
Divalent DNJ derivative, synthetic method and application thereof Download PDFInfo
- Publication number
- CN112441963B CN112441963B CN201910807683.4A CN201910807683A CN112441963B CN 112441963 B CN112441963 B CN 112441963B CN 201910807683 A CN201910807683 A CN 201910807683A CN 112441963 B CN112441963 B CN 112441963B
- Authority
- CN
- China
- Prior art keywords
- dnj
- divalent
- dnj derivative
- reaction
- bivalent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a bivalent DNJ derivative, a synthesis method and application thereof. The structural formula of the bivalent DNJ derivative is shown as the formula 1:
starting with N- (4-aminobutyl) -2,3,4, 6-tetrabenzyl-1-deoxynojirimycin, reacting it with terephthaloyl chloride and then hydrodebenzylating it at normal pressure 10% Pd/C. The method has the advantages of mild reaction conditions, simple operation and higher yield. IC of divalent DNJ derivatives of the invention to alpha-glycosidase 50 The value is 0.302 +/-0.030 mM, and the alpha-glycosidase can be used as an effective alpha-glycosidase inhibitor for preparing hypoglycemic drugs and drugs for treating diabetes and obesity.
Description
Technical Field
The invention relates to a bivalent DNJ derivative, a synthesis method and application thereof, belonging to the technical field of enzyme inhibitors.
Background
1-Deoxynojirimycin (DNJ), a highly potent alpha-glucosidase inhibitor, has a significant effect in lowering blood glucose. However, there are still some problems with the application of DNJ: DNJ reaches the site of inhibition in vivo only through at least two membrane barriers, plasma and endoplasmic reticulum, resulting in differences in enzyme and cellular levels of DNJ in vivo. Scientists have recently improved the activity and selectivity of DNJ for different enzymes by structurally modifying the DNJ. The diabetes-specific drug miglitol marketed by Bayer in the early 90 th of the 20 th century and the meglumine developed by Oxford Glycos science in 2003 for the treatment of gaucher's disease are derivatives of DNJ. In addition, the research finds that DNJ and the derivatives thereof have wide prospects in the aspects of antivirus, cancer, HIV treatment and the like.
The theory of multivalent binding in biological systems is that multiple ligands bind to multiple receptors at the instant of binding between biological entities (molecules, surfaces), which is ubiquitous in biological systems. The multivalent binding drug can be bound with multiple positions of biological receptors in a multivalent way, and has the characteristics of improvement of physiological activity, long activity duration, improvement of absorption and metabolism in vivo and the like which are not possessed by monomer drugs. The multi-target and multi-valence combined drug is used as an important strategy for designing new drugs and is widely applied to the development of new compounds. For example, zanamivir (zanamivir) is a Neuraminidase (NA) inhibitor similar to sialic acid, and is linked with an appropriate carbon chain (18 carbons) to synthesize a bivalent zanamivir derivative, which has a biological activity 100 times that of zanamivir. In the last decade, the use of multivalent binding drug strategies in the field of iminosugars has increased.
The current research on multivalent DNJ derivatives has focused on combining different backbones and DNJ active units by click reactions to give multivalent DNJ derivatives and testing their inhibitory activity against α -mannosidase (j.am.chem.soc.2013, 135, 18427-18435. Modification of DNJ using a multivalent strategy to enhance or improve its inhibitory activity against α -glucosidase has been rarely studied, and the inhibition of α -glucosidase by currently reported multivalent DNJ derivatives is generally significantly reduced or lost (tetrahedron 2014,70, 9387-9393), while the multivalent DNJ derivatives reported by Gouin et al are not inhibitory to α -glucosidase (org. Biomol. Chem.2009,7, 357-363). Therefore, it is of research interest to develop and synthesize new multivalent DNJ derivatives and test their inhibitory activity against α -glucosidase.
Disclosure of Invention
The invention aims to provide a divalent DNJ derivative capable of inhibiting alpha-glucosidase activity, a synthesis method and application thereof in preparing an alpha-glucosidase activity inhibitor.
The technical solution for realizing the purpose of the invention is as follows:
a divalent DNJ derivative or a pharmaceutically acceptable salt thereof, having a structural formula shown in formula 1:
the synthesis method of the divalent DNJ derivative comprises the following steps:
step 2, in the presence of tetrahydrofuran and methanol, the content of Compound 4 in the catalyst 10% Pd/C, H 2 In the presence of hydrochloric acid, regulating the pH value of a reaction system to be 2-4, and carrying out debenzylation reaction to prepare a divalent DNJ derivative 1, wherein the reaction process is as follows:
further, in the step 1, the reaction temperature is 0-30 ℃; the reaction time is 6-8 h.
Further, in step 2, the volume ratio of tetrahydrofuran to methanol is 1.
Further, in step 2, the percentage by weight of Pd/C in the catalyst 10% is 10% to 30% based on the weight of the compound 4; the pressure of the hydrogen is 1-2 atm.
Further, in the step 2, the reaction time is 5-7 h.
The use of the divalent DNJ derivative or a pharmaceutically acceptable salt thereof for inhibiting the activity of alpha-glucosidase.
The application of the divalent DNJ derivative or the pharmaceutically acceptable salt thereof in preparing the alpha-glucosidase activity inhibitor.
The application of the divalent DNJ derivative or the pharmaceutically acceptable salt thereof in preparing the hypoglycemic drug.
The application of the divalent DNJ derivative or pharmaceutically acceptable salt thereof in preparing medicines for treating diabetes and obesity.
Compared with the prior art, the invention has the following advantages:
(1) The synthesis method of the bivalent DNJ derivative has the advantages of mild reaction conditions, simple operation and higher yield; (2) The divalent DNJ derivative has high inhibition rate on alpha-glycosidase.
Drawings
FIG. 1 is a graph of compound concentration versus inhibition.
Detailed Description
The present invention will be described in more detail with reference to the following examples and the accompanying drawings.
The synthesis method of the bivalent DNJ derivative comprises the following steps:
example 1
Preparation of Compound 4
N- (4-Aminobutyl) -2,3,4, 6-tetrabenzyl-1-deoxynojirimycin (compound 2, 248.7mg, 0.418mmol) was dissolved in dry dichloromethane (2 ml), triethylamine (15 drops) was added dropwise and the mixture was cooled to 0 ℃ under ice bath. Terephthaloyl chloride (compound 3) was dissolved in dried dichloromethane (6 ml) and slowly added dropwise to the above solution. After the dropwise addition, the mixture was stirred at 0 ℃ for 15min, and then the temperature was raised to room temperature to carry out a reaction for 7h. Thin layer chromatography (1.V) Ethyl acetate :V Methanol :V 37% ammonia water Detecting whether the reaction of reactants is finished or not in a position of 0.025; 2.V Petroleum ether :V Ethyl acetate =1. After the reaction is finished, the solvent is dried by spinning under reduced pressure, and column chromatography is carried out (silica gel: 200-300 meshes, V) Petroleum ether :V Ethyl acetate = 1). 1 H NMR(500MHz,CDCl 3 )δ7.77(s,4H),7.40–7.23(m,36H),7.15(d,J＝6.9Hz,4H),6.35(s,2H),4.96(d,J＝11.1Hz,2H),4.85(dd,J＝26.5,10.9Hz,4H),4.67(q,J＝11.6Hz,4H),4.50–4.38(m,6H),3.71–3.52(m,8H),3.47(t,J＝8.9Hz,2H),3.39(d,J＝5.7Hz,4H),3.09(dd,J＝11.1,4.5Hz,2H),2.75(d,J＝7.9Hz,2H),2.60–2.49(m,2H),2.31(d,J＝9.2Hz,2H),2.17(t,J＝10.8Hz,2H),1.60–1.40(m,8H). 13 C NMR(126MHz,CDCl 3 )δ166.75,139.02,138.51,137.71,137.37,128.50,128.48,128.46,128.40,128.38,128.00,127.91,127.88,127.74,127.64,127.52,127.27,87.28,78.56,78.42,75.35,75.25,73.47,72.87,65.79,64.33,54.36,51.85,39.98,27.48,22.06,18.49.
Preparation of a divalent DNJ derivative (Compound 1)
Compound 4 (58.9mg, 0.0453mmol) is dissolved in a mixed solvent (V) of methanol and tetrahydrofuran MeOH :V THF 1,6 ml), to which concentrated hydrochloric acid (3 drops) was added dropwise to adjust the pH to 3, followed by addition of 10% pd/C (10.2 mg). Replacing air in the whole reaction system with hydrogen under normal pressure, reacting at room temperature for 6h, and detecting the reaction process by thin layer chromatography (1.V) Petroleum ether ：V Ethyl acetate Detecting whether the reaction of reactants is finished or not by using a = 1; 2.V Ethyl acetate ：V Methanol ：V 37% ammonia water Detection of product formation by = 1.5. After the reaction was completed, palladium on carbon was removed by filtration through celite, the filter cake was washed with methanol several times, and the filtrate was collected and concentrated to obtain 59.4mg of a yellow oily liquid. Purification by thin layer chromatography preparative method (V) Ethyl acetate ：V Methanol ：V 37% ammonia water = 1.5. 1 H NMR(500MHz,CD 3 OD)δ7.87(s,4H),3.86(dd,J＝5.3,2.4Hz,4H),3.52–3.31(m,8H),3.14(t,J＝9.1Hz,2H),3.05(dd,J＝11.1,4.3Hz,2H),2.92(s,2H),2.67(s,2H),2.30–2.15(m,4H),2.04–1.97(m,1H),1.61(s,8H). 13 C NMR(100MHz,CD 3 OD)δ166.70,138.55,128.48,80.12,71.45,70.23,67.46,58.66,57.19,55.35,42.08,28.36,26.31.
Example 2
Hypoglycemic activity test:
in order to test the hypoglycemic activity of the divalent DNJ derivative, alpha-PNPG is used as a reaction substrate, p-nitrophenol with visible absorption is obtained by enzymolysis of alpha-glucosidase, the absorbance of the p-nitrophenol is measured by an ultraviolet method, the activity of the alpha-glucosidase is obtained, and the inhibition effect of a sample to the alpha-glucosidase is obtained in the near future, and the specific steps are as follows:
1. determination of alpha-glucosidase Activity
110. Mu.L of pH6.8 phosphate buffer solution was put into a 96-well plate, 20. Mu.L of 0.2U/mL α -glucosidase solution was added, 10. Mu.L of DMSO was then added, and the mixture was reacted at 37 ℃ for 15min. Taking out, adding 20 mu L of 2.5mmol/L PNPG solution, and reacting for 15min at constant temperature of 37 ℃. Taking out, and finally adding 80 mu L of 0.2mol/L Na 2 CO 3 The solution stops the reaction. OD was measured at a wavelength of 405nm, and the average value was obtained in triplicate.
Definition of enzyme activity: under a solution system with 37 ℃ and pH6.8, the substrate PNPG hydrolyzes 1 mu mol of p-nitrophenol per minute, and the enzyme quantity is defined as one enzyme activity unit.
2. Method for determining and calculating inhibition effect of sample on alpha-glucosidase activity
110. Mu.L of pH6.8 phosphate buffer solution was put in a 96-well plate, 20. Mu.L of 0.2U/mL alpha-glucosidase solution was added, 10. Mu.L of the sample was then added, and the mixture was reacted at 37 ℃ for 15min. Taking out, adding 20 mu L of 2.5mmol/L PNPG solution, and reacting for 15min at constant temperature of 37 ℃. Taking out, and finally adding 80 mu L of 0.2mol/L Na 2 CO 3 The solution stops the reaction. OD was measured at a wavelength of 405nm, and the average value was obtained in triplicate.
The experiment was divided into four groups of three wells each. Control a (buffer + enzyme solution + substrate); blank control b (buffer); sample assay group c (sample + enzyme solution + substrate); sample control d (sample + buffer). The calculation formula of the inhibition rate is I% = [1- (c-d)/(a-b) ] × 100%, and the IC50 value of each part is obtained by measuring the inhibition rate of samples with different concentrations on the activity of alpha-glucosidase and using GraphPad Prism 8 software.
Definition of inhibitor activity units: the amount of inhibitor required to reduce 1 enzyme activity unit under the same conditions.
3. Analysis of results
As shown in FIG. 1, the inhibitory activity of the bivalent DNJ derivative on alpha-glucosidase is in a positive dose-effect relationship with the concentration. IIIC of valence DNJ derivative 1 50 The value is 0.302 +/-0.030 mM, which indicates that the compound has remarkable hypoglycemic effect. DNJ IC determined by this method 50 The value was 0.155. + -. 0.017mM.
Claims (9)
1. A divalent DNJ derivative or a pharmaceutically acceptable salt thereof, wherein the structural formula is shown as formula 1:
2. the method of synthesizing a bivalent DNJ derivative according to claim 1, comprising the steps of:
step 1, in the presence of dichloromethane and triethylamine as an acid-binding agent, reacting N- (4-aminobutyl) -2,3,4, 6-tetrabenzyl-1-deoxynojirimycin with terephthaloyl chloride to prepare a compound 4, wherein the reaction process comprises the following steps:
step 2, in the presence of tetrahydrofuran and methanol, the compound 4 is subjected to catalyst 10% Pd/C, H 2 In the presence of hydrochloric acid, regulating the pH of a reaction system to be 2 to 4, and carrying out debenzylation reaction to prepare a divalent DNJ derivative 1, wherein the reaction process is as follows:
3. the method for synthesizing the divalent DNJ derivative according to claim 1, wherein the reaction temperature in step 1 is 0-30 ℃; the reaction time is 6 to 8h.
4. The synthesis method according to claim 2, wherein in the step 2, the volume ratio of the tetrahydrofuran to the methanol is 1 to 1.
5. The method of claim 2, wherein in step 2, the catalyst comprises 10% Pd/C of 10% to 30% by weight of compound 4; the pressure of the hydrogen is 1 to 2atm.
6. The synthesis method according to claim 2, wherein the reaction time in the step 2 is 5 to 7h.
7. Use of the divalent DNJ derivative of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of an inhibitor of α -glucosidase activity.
8. Use of a bivalent DNJ derivative according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a hypoglycemic medicament.
9. Use of a bivalent DNJ derivative according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of diabetes and obesity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910807683.4A CN112441963B (en) | 2019-08-29 | 2019-08-29 | Divalent DNJ derivative, synthetic method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910807683.4A CN112441963B (en) | 2019-08-29 | 2019-08-29 | Divalent DNJ derivative, synthetic method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112441963A CN112441963A (en) | 2021-03-05 |
| CN112441963B true CN112441963B (en) | 2023-01-03 |
Family
ID=74740729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910807683.4A Active CN112441963B (en) | 2019-08-29 | 2019-08-29 | Divalent DNJ derivative, synthetic method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112441963B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56108767A (en) * | 1980-01-28 | 1981-08-28 | Nippon Shinyaku Co Ltd | Bismoranoline derivative |
| CN101696186A (en) * | 2009-10-29 | 2010-04-21 | 同济大学 | Method for synthesizing 1-deoxynojirimycin derivative |
| CN102166211A (en) * | 2011-03-22 | 2011-08-31 | 复旦大学 | Use of derivatives of 1-deoxynojiri mycin containing 1,2,3-triazoles as alpha-glucosidase inhibitors |
| CN102166210A (en) * | 2011-03-22 | 2011-08-31 | 复旦大学 | Use of derivatives of 1-deoxynojiri mycin as alpha-glucosidase inhibitors |
| CN107973745A (en) * | 2016-10-21 | 2018-05-01 | 南京理工大学 | Mono- deuterated derivatives of DNJ-C-6, synthetic method and purposes |
-
2019
- 2019-08-29 CN CN201910807683.4A patent/CN112441963B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56108767A (en) * | 1980-01-28 | 1981-08-28 | Nippon Shinyaku Co Ltd | Bismoranoline derivative |
| US4336373A (en) * | 1980-01-28 | 1982-06-22 | Nippon Shinyaku Company, Ltd. | Bis-piperidine compounds |
| CN101696186A (en) * | 2009-10-29 | 2010-04-21 | 同济大学 | Method for synthesizing 1-deoxynojirimycin derivative |
| CN102166211A (en) * | 2011-03-22 | 2011-08-31 | 复旦大学 | Use of derivatives of 1-deoxynojiri mycin containing 1,2,3-triazoles as alpha-glucosidase inhibitors |
| CN102166210A (en) * | 2011-03-22 | 2011-08-31 | 复旦大学 | Use of derivatives of 1-deoxynojiri mycin as alpha-glucosidase inhibitors |
| CN107973745A (en) * | 2016-10-21 | 2018-05-01 | 南京理工大学 | Mono- deuterated derivatives of DNJ-C-6, synthetic method and purposes |
Non-Patent Citations (2)
| Title |
|---|
| Inhibition of intestinal α-glucosidase and postprandial hyperglycemia by N-substituted moranoline derivatives;Yoshikuni, Yoshiaki，等;《Journal of Pharmacobio-Dynamics》;19881231;第11卷(第5期);第356-362页 * |
| Yoshikuni, Yoshiaki，等.Inhibition of intestinal α-glucosidase and postprandial hyperglycemia by N-substituted moranoline derivatives.《Journal of Pharmacobio-Dynamics》.1988,第11卷(第5期),第356-362页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112441963A (en) | 2021-03-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110627801A (en) | HDAC inhibitor and application thereof | |
| CN111434654B (en) | Triazole hexanone biaryl (hetero) ring derivative and preparation method and application thereof | |
| CN112441963B (en) | Divalent DNJ derivative, synthetic method and application thereof | |
| CN112480076A (en) | Phenylpyridine compound and preparation and application thereof | |
| CN102688234B (en) | Indolone derivatives is as the Synthesis and application of RSK2 inhibitor | |
| CN111961048B (en) | Trifluoromethyl pyrazole amide containing substituted beta-carboline structure and preparation method and application thereof | |
| CN105503977A (en) | 1,3,4-oxadiazole derivative containing glucosamine molecules and preparation method and application thereof | |
| CN102617478B (en) | Synthesis of benzimidazole, oxazole and thiazole derivatives and application thereof | |
| CN101343263B (en) | Method for synthesis of 5-nitryl-4, 5-dihydrofuran derivant | |
| CN111233843B (en) | Gamma-butenolide derivative and preparation method and application thereof | |
| CN113717143A (en) | Synthetic method and application of daphnetin derivatives | |
| CN106831474A (en) | A kind of α of aryl containing α, β diamino acid ester derivant and its synthetic method and application | |
| CN107216241B (en) | Optically active 1, 5-pentanediol derivative and synthetic method and application thereof | |
| CN104557665A (en) | Optically active 3-substituted indole derivatives as well as synthesis method and application thereof | |
| CN113831330B (en) | New method for three-step synthesis of drug molecule 3- (2-thiophene-2-methylene) hydrazinoquinoxaline-2-ketone | |
| CN112961081B (en) | Bibenzamide urea compound and preparation method and application thereof | |
| CN112920133B (en) | (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound and preparation method and application thereof | |
| CN106892898B (en) | Azasugar-derived quinazolines | |
| CN111875605B (en) | Preparation and application of bisamide compound containing substituted pyrazole and beta-carboline units | |
| CN117430524A (en) | Chalcone amide alpha-glucosidase inhibitor and preparation method and application thereof | |
| CN111825608A (en) | Tetrahydroquinoline and tetrahydroisoquinoline compounds and application thereof | |
| CN116253736B (en) | Pyrazole beta-lactam derivative and preparation method and application thereof | |
| CN117263936B (en) | Imidazo [1,2-a ] pyridine derivative, preparation method thereof and application thereof in drug for inhibiting central nervous system penetrating HDAC6 | |
| CN114478509B (en) | Five-membered heterocycle substituted benzamide compound and preparation method and application thereof | |
| WO2004013109A1 (en) | Resorcinol derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |