CN115246805B - Chromone-aniline alpha-glucosidase inhibitor and preparation method and application thereof - Google Patents
Chromone-aniline alpha-glucosidase inhibitor and preparation method and application thereof Download PDFInfo
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- CN115246805B CN115246805B CN202210868714.9A CN202210868714A CN115246805B CN 115246805 B CN115246805 B CN 115246805B CN 202210868714 A CN202210868714 A CN 202210868714A CN 115246805 B CN115246805 B CN 115246805B
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- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 title claims abstract description 25
- 239000003888 alpha glucosidase inhibitor Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 43
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims abstract description 18
- 239000003472 antidiabetic agent Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 239000000460 chlorine Substances 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229940127003 anti-diabetic drug Drugs 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 10
- JECYUBVRTQDVAT-UHFFFAOYSA-N 2-acetylphenol Chemical class CC(=O)C1=CC=CC=C1O JECYUBVRTQDVAT-UHFFFAOYSA-N 0.000 abstract description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract description 8
- 102100024295 Maltase-glucoamylase Human genes 0.000 abstract description 8
- 108010028144 alpha-Glucosidases Proteins 0.000 abstract description 8
- FSMYWBQIMDSGQP-UHFFFAOYSA-N 4-oxochromene-3-carbaldehyde Chemical class C1=CC=C2C(=O)C(C=O)=COC2=C1 FSMYWBQIMDSGQP-UHFFFAOYSA-N 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 abstract description 3
- 230000003178 anti-diabetic effect Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 description 62
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 31
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- 229910052799 carbon Inorganic materials 0.000 description 31
- 239000007787 solid Substances 0.000 description 30
- 238000010309 melting process Methods 0.000 description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 26
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- 239000008280 blood Substances 0.000 description 9
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- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 7
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- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 4
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- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- IMPPGHMHELILKG-UHFFFAOYSA-N 4-ethoxyaniline Chemical compound CCOC1=CC=C(N)C=C1 IMPPGHMHELILKG-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 2
- ZTPHGPLCHXGENO-UHFFFAOYSA-N 7-hydroxy-4-oxochromene-3-carbaldehyde Chemical compound O1C=C(C=O)C(=O)C=2C1=CC(O)=CC=2 ZTPHGPLCHXGENO-UHFFFAOYSA-N 0.000 description 2
- QGYSQLKEWOCOAL-UHFFFAOYSA-N OC(C=C1OC=C2CNC3=CC=CC=C3)=CC=C1C2=O Chemical compound OC(C=C1OC=C2CNC3=CC=CC=C3)=CC=C1C2=O QGYSQLKEWOCOAL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- AVYGCQXNNJPXSS-UHFFFAOYSA-N 2,5-dichloroaniline Chemical compound NC1=CC(Cl)=CC=C1Cl AVYGCQXNNJPXSS-UHFFFAOYSA-N 0.000 description 1
- VBLXCTYLWZJBKA-UHFFFAOYSA-N 2-(trifluoromethyl)aniline Chemical compound NC1=CC=CC=C1C(F)(F)F VBLXCTYLWZJBKA-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- XEFRNCLPPFDWAC-UHFFFAOYSA-N 3,4,5-trimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1OC XEFRNCLPPFDWAC-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- WOYZXEVUWXQVNV-UHFFFAOYSA-N 4-phenoxyaniline Chemical compound C1=CC(N)=CC=C1OC1=CC=CC=C1 WOYZXEVUWXQVNV-UHFFFAOYSA-N 0.000 description 1
- BLQFHJKRTDIZLX-UHFFFAOYSA-N 5-amino-2-methoxyphenol Chemical compound COC1=CC=C(N)C=C1O BLQFHJKRTDIZLX-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 102000004366 Glucosidases Human genes 0.000 description 1
- 108010056771 Glucosidases Proteins 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000021258 carbohydrate absorption Nutrition 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000010030 glucose lowering effect Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 210000000110 microvilli Anatomy 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- KLAKIAVEMQMVBT-UHFFFAOYSA-N p-hydroxy-phenacyl alcohol Natural products OCC(=O)C1=CC=C(O)C=C1 KLAKIAVEMQMVBT-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached 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
- A61P3/08—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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a chromone-aniline alpha-glucosidase inhibitor, a preparation method and application thereof. The chemical structure of the alpha-glucosidase inhibitor is shown as a formula (I):the preparation method comprises the steps of using DMF and phosphorus oxychloride to treat substituted o-hydroxyacetophenone to obtain substituted 4-oxo-4H-benzopyran-3-aldehyde, and then using sodium triacetoxyborohydride to catalyze and react with aniline containing different substituents in dichloromethane to obtain the target compound. The alpha-glucosidase inhibitor provided by the invention has good activity of inhibiting alpha-glucosidase, and can be used as a lead for researching novel antidiabetic drugsAnd (3) a compound.
Description
Technical Field
The invention belongs to the technical field of new medicine research and development and medicine synthesis, and in particular relates to a chromone-aniline alpha-glucosidase inhibitor, a preparation method thereof and application thereof in preparing antidiabetic medicines.
Background
Diabetes is a metabolic disease characterized by hyperglycemia with many serious complications including cardiomyopathy, nephropathy, retinopathy and neuropathy. For diabetic patients, controlling postprandial hyperglycemia may reduce the occurrence of complications. Alpha-glucosidase is located at the brush border of the small intestine, and hydrolyzes the glycosidic bond of polysaccharide into monosaccharides such as glucose, which is mainly responsible for hyperglycemia.
Currently, the administration of glucosidase inhibitors is one of the preferred methods of treating type II diabetes, and alpha-glucosidase inhibitors reduce postprandial hyperglycemia by inhibiting alpha-glucosidase and delaying carbohydrate absorption. Three alpha-glucosidase inhibitors (acarbose, miglitol and voglibose) have been used clinically to treat type 2 diabetes. However, long-term use of α -glucosidase inhibitors has side effects on the gastrointestinal tract, such as abdominal pain, flatulence, diarrhea, and enteritis.
Therefore, the development of novel, efficient and low side effect alpha-glucosidase inhibition is of great significance.
Disclosure of Invention
In view of the above, the present invention aims to solve the problems in the prior art, and provide a chromone-aniline α -glucosidase inhibitor, a preparation method thereof, and an application of the chromone-aniline α -glucosidase inhibitor in preparing antidiabetic drugs.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a chromone-aniline alpha-glucosidase inhibitor, which has a structure shown in a formula (I):
wherein R in formula I 1 At least hydrogen, fluorine, chlorine, bromine, hydroxyl,One of C1-C3 alkoxy; r is R 2 At least one of hydrogen, fluorine, chlorine, bromine, iodine, C1-C3 alkoxy, C1-C3 alkyl, nitro, amino, hydroxyl and trifluoromethyl.
The invention also claims a preparation method of the chromone-aniline alpha-glucosidase inhibitor, which specifically comprises the following steps:
step 1: POCl (point of care testing) 3 Dropwise adding the mixture into dry DMF, and vigorously stirring the mixture at 50 ℃ for 2 hours to obtain a reaction mixture;
step 2: dissolving substituted o-hydroxyacetophenone in DMF, then dropwise adding the solution into the reaction mixture obtained in the step 1, stirring the mixture for 2 hours at 58 ℃, cooling the mixture, and filtering the cooled mixture to obtain substituted 4-oxo-4H-benzopyran-3-aldehyde;
step 3: the compound of the general formula (I) is prepared by placing substituted 4-oxo-4H-benzopyran-3-aldehyde, methylene dichloride, aniline containing different substituents and sodium triacetoxyborohydride into a reaction bottle and stirring at room temperature for 0.5 hour.
Preferably, the molar ratio of the substituted o-hydroxyacetophenone to the phosphorus oxychloride is 1:3-7, and 1-5 ml of DMF is added to each 1mmol of substituted o-hydroxyacetophenone.
Preferably, the molar ratio of the substituted 4-oxo-4H-benzopyran-3-aldehyde, the aniline containing different substituents and the sodium triacetoxyborohydride is 1:1-2:1-4, and 2-10 ml of methylene dichloride is added to each 1mmol of substituted 4-oxo-4H-benzopyran-3-aldehyde.
In addition, the invention also claims the application of the chromone-aniline alpha-glucosidase inhibitor in preparing antidiabetic drugs.
Compared with the prior art, the chromone-aniline alpha-glucosidase inhibitor and the preparation method and application thereof have the following advantages:
1. the chromone-aniline alpha-glucosidase inhibitor provided by the invention has good activity of inhibiting the alpha-glucosidase inhibitor, and can be used as a novel lead compound for anti-diabetes research;
2. the preparation method of the chromone-aniline compound provided by the invention is simple, the synthetic route is shorter, the mass preparation is easy, and the price is low;
3. the chromone-aniline alpha-glucosidase inhibitor provided by the invention has lower toxicity to normal human cells and higher safety.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram showing a route for preparing a chromone-aniline alpha-glucosidase inhibitor according to the invention.
FIG. 2 is a graph showing the effect of a chromone-aniline alpha-glucosidase inhibitor on postprandial blood glucose of a normal mouse; wherein, (a) the effect of compound 2 and acarbose on postprandial blood glucose; (B) an increase in AUC 0-120 minutes after sucrose administration in mice.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The present invention will be further specifically illustrated by the following examples, which are not to be construed as limiting the invention, but rather as falling within the scope of the present invention, for some non-essential modifications and adaptations of the invention that are apparent to those skilled in the art based on the foregoing disclosure.
The invention discloses a chromone-aniline alpha-glucosidase inhibitor, which has a structural general formula shown in a formula (I):
wherein R in formula I 1 At least one of hydrogen, fluorine, chlorine, bromine, hydroxyl and C1-C3 alkoxy; r is R 2 At least one of hydrogen, fluorine, chlorine, bromine, iodine, C1-C3 alkoxy, C1-C3 alkyl, nitro, amino, hydroxyl and trifluoromethyl.
The present invention also provides a process for preparing a chromone-anilines a-glucosidase inhibitor of formula I above, as shown in figure 1, comprising the steps of:
step 1: POCl (point of care testing) 3 Drop wise to dry DMF, followed by vigorous stirring of the mixture at 50 ℃ for 2h; then dissolving the substituted 2-hydroxyacetophenone in DMF and adding dropwise to the above reaction mixture; stirring the mixture at 58 ℃ for 2 hours, cooling, and filtering to obtain substituted 4-oxo-4H-benzopyran-3-aldehyde;
step 2: and (3) placing the substituted 4-oxo-4H-benzopyran-3-aldehyde, methylene dichloride, aniline containing different substituents and sodium triacetylborohydride into a reaction bottle, and stirring at room temperature for 0.5 hour to prepare the compound shown in the general formula (I).
In order to further explain the technical scheme disclosed by the invention, the inventor also carries out the following embodiments:
embodiment one:
preparation of 3- (((4-bromophenyl) amine) methyl) -7-hydroxy-4H-benzopyran-4-one (1)
The structural formula of compound 1 is shown below:
the preparation method comprises the following specific steps:
step 1: POCl (point of care testing) 3 (4.5 ml) was added dropwise to dry DMF (13 ml) and the mixture was vigorously stirred at 50℃for 2h. The substituted 2, 4-dihydroxyacetophenone (10 mmol) was then dissolved in DMF (3.40 ml) and added dropwise to the reaction mixture. The mixture was stirred at 58 ℃ for 2H, then 300g of crushed ice was stirred at room temperature for a further 6H, and finally the solid was filtered through recrystallization to obtain 7-hydroxy-4-oxo-4H-benzopyran-3-aldehyde.
Step 2: 7-hydroxy-4-oxo-4H-benzopyran-3-aldehyde (1.4 mmol), methylene chloride (5 ml), p-bromoaniline (1.4 mmol) and sodium triacetylborohydride (2 mmol) were placed in a reaction flask, stirred at room temperature for 0.5 hour, the reaction solution was diluted with methylene chloride, extracted twice with saturated sodium carbonate, and finally purified by silica gel column chromatography to obtain compound 1.
Wherein the compound 1 is yellow solid, the yield is 69.73 percent, and the melting range is 221.3-218.5 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 1 are shown as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.74(s,1H),8.15(s,1H),7.97(d,J＝8.8Hz,1H),7.24(d,J＝8.8Hz,2H),6.98(dd,J＝8.8,2.4Hz,1H),6.87(d,J＝2.0Hz,1H),6.64(d,J＝8.8Hz,2H),6.04(t,J＝5.6Hz,1H),4.09(d,J＝5.6Hz,2H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.51,162.48,157.66,153.33,147.44,131.24,126.56,120.14,116.03,115.00,114.23,106.61,102.08,38.12；
HRMS calcd for C 16 H 11 BrNO 3 - [M+H] - :m/z＝343.9928,found 343.9934.
the preparation method of the following examples is similar to that of the first example, except that the p-bromoaniline in the first example is replaced by other corresponding substituted anilines.
Embodiment two:
preparation of 3- (((4-chlorophenyl) amine) methyl) -7-hydroxy-4H-benzopyran-4-one (2)
The structural formula of compound 2 is shown below:
wherein the compound 2 is yellow solid, the yield is 12.4 percent, and the melting process is 205.8-211.9 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 2 are shown as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.82(s,1H),8.13(s,1H),7.92(d,J＝8.8Hz,1H),7.08(d,J＝8.0Hz,2H),6.93(d,J＝8.8Hz,1H),6.83(s,1H),6.62(d,J＝8.0Hz,2H),4.02(s,2H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.54,162.49,157.67,153.34,147.08,128.43,126.57,120.19,119.30,116.04,115.01,113.68,102.09,38.22；
HRMS calcd for C 16 H 11 ClNO 3 - [M+H] - :m/z＝300.0433,found 300.0430.
embodiment III:
preparation of 3- (((2-ethoxyphenyl) amine) methyl) -7-hydroxy-4H-benzopyran-4-one (3)
The structural formula of compound 3 is shown below:
wherein the compound 3 is yellow solid, the yield is 12.6 percent, and the melting range is 178.8-191.5 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 3 are shown as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.83(s,1H),8.13(s,1H),7.92(d,J＝8.8Hz,1H),6.92(dd,J＝8.8,2.0Hz,1H),6.78-6.81(m,2H),6.74(t,J＝7.6Hz,1H),6.60(dd,J＝7.6,1.2Hz,1H),6.54(td,J＝7.6,1.2Hz,1H),5.20(t,J＝6.4Hz,1H),4.12(d,J＝6.4Hz,2H),3.99(q,J＝7.2Hz,2H),1.33(t,J＝6.8Hz,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:176.50,163.16,158.34,153.91,146.53,138.29,121.62,121.06,116.81,115.67,110.68,102.77,64.20,39.24,15.30；
HRMS calcd for C 18 H 16 NO 4 - [M+H] - :m/z＝310.1085,found 310.1082.
embodiment four:
preparation of 3- (((4-ethoxyphenyl) amine) methyl) -7-hydroxy-4H-benzopyran-4-one (4)
The structural formula of compound 4 is shown below:
wherein compound 4 was a yellow solid in 12.3% yield; the melting process is 184.9-200.1 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 4 are shown as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.76(s,1H),8.08(s,1H),7.91(dd,J＝8.8,2.8Hz,1H),6.91(dt,J＝8.8,2.4Hz,1H),6.81(t,J＝2.4Hz,1H),6.69(dd,J＝9.2,2.4Hz,2H),6.55(dd,J＝8.8,2.4Hz,2H),5.38(s,1H),3.99(d,J＝4.4Hz,2H),3.86(qd,J＝6.8,2.4Hz,2H),1.25(td,J＝6.8,2.4Hz,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.66,162.43,157.64,153.18,150.15,142.27,126.55,120.69,116.04,115.37,114.95,113.53,102.06,63.27,14.70；
HRMS calcd for C 18 H 16 NO 4 - [M+H] - :m/z＝310.1085,found 310.1085.
fifth embodiment:
preparation of 7-hydroxy-3- (((4- (trifluoromethyl) phenyl) amine) methyl) -4H-benzopyran-4-one (5)
The structural formula of compound 5 is shown below:
wherein compound 5 was a yellow solid in 16.0% yield; the melting process is 195.9-206.9 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 5 are shown as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.70(s,1H),8.14(s,1H),7.93(dd,J＝8.8,2.0Hz,1H),7.37(d,J＝7.6Hz,2H),6.93(dt,J＝10.4,2.0Hz,1H),6.83(s,1H),6.74(d,J＝8.0Hz,2H),6.52(d,J＝5.2Hz,1H),4.11(d,J＝5.2Hz,2H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.67,162.70,157.85,153.74,151.30,126.78,126.28,126.25,124.04,119.98,116.16,115.70,115.39,115.23,111.65,102.27,37.86；
HRMS calcd for C 17 H 11 F 3 NO 3 - [M+H] - :m/z＝334.0697,found 334.0692.
example six:
preparation of 7-hydroxy-3- (((4-methoxyphenyl) amine) methyl) -4H-benzopyran-4-one (6)
The structural formula of compound 6 is shown below:
wherein compound 6 was a yellow solid in 16.3% yield; the melting process is 171.8-176.9 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 6 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.62(s,1H),8.06(s,1H),7.91(d,J＝8.4Hz,1H),6.91(dd,J＝8.4,2.0Hz,1H),6.80(d,J＝1.2Hz,1H),6.70(d,J＝8.8Hz,2H),6.58(d,J＝9.2Hz,2H),5.26(s,1H),4.01(d,J＝2.4Hz,2H),3.63(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.67,162.44,157.65,153.19,151.01,142.29,126.56,120.68,116.05,114.96,114.58,113.56,102.07,55.23；
HRMS calcd for C 17 H 14 NO 4 + [M+H] + :m/z＝296.0928,found 296.0923.
embodiment seven:
preparation of 7-hydroxy-3- ((phenylamino) methyl) -4H-benzopyran-4-one (7)
The structural formula of compound 7 is shown below:
wherein compound 7 was a yellow solid in 7.8% yield; the melting process is 210.1-218.1 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 7 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.67(s,1H),8.09(s,1H),7.92(dd,J＝8.8,2.0Hz,1H),7.04-7.08(m,2H),6.92(dt,J＝8.8,2.8Hz,1H),6.81(t,J＝2.4Hz,1H),6.61(d,J＝6.8Hz,2H),6.54(t,J＝7.6Hz,1H),5.71(s,1H),4.01(s,2H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.81,162.62,157.81,153.51,148.27,128.95,126.77,120.55,116.13,115.16,112.41,102.23,38.29；
HRMS calcd for C 16 H 12 NO 3 - [M+H] - :m/z＝266.0823,found 266.0820.
example eight:
preparation of 7-hydroxy-3- (((4-phenoxyphenyl) amine) methyl) -4H-benzopyran-4-one (8)
The structural formula of compound 8 is shown below:
wherein compound 8 was a yellow solid in 10.6% yield; melting process is 181.8-188.0 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 8 are shown as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.82(s,1H),8.16(s,1H),7.93(d,J＝8.8Hz,1H),7.27-7.31(m,2H),7.00(t,J＝7.2Hz,1H),6.93(dd,J＝8.8,2.4Hz,1H),6.82-6.86(m,5H),6.66(d,J＝8.8,Hz,2H),5.86(s,1H),4.04(d,J＝4.8Hz,2H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.60,162.46,158.64,157.67,153.28,146.02,145.03,129.51,126.57,121.74,120.69,120.50,116.53,116.07,114.99,113.30,102.09,38.67；
HRMS calcd for C 22 H 16 NO 4 - [M+H] - :m/z＝358.1085,found 358.1080.
example nine:
preparation of 7-hydroxy-3- ((p-methylphenyl) methyl) -4H-benzopyran-4-one (9)
The structural formula of compound 9 is shown below:
wherein compound 9 was a yellow solid in 14.1% yield; melting process is 129.9-133.5 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 9 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.69(s,1H),8.08(s,1H),7.92(d,J＝8.8Hz,1H),6.91-6.94(m,3H),6.81(d,J＝2.0Hz,1H),6.60(d,J＝8.4Hz,2H),4.05(s,2H),2.15(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.59,162.56,157.67,153.56,144.64,129.93,129.30,126.55,125.86,121.65,120.04,115.98,115.05,113.53,102.11,19.92；
HRMS calcd for C 17 H 14 NO 3 - [M+H] - :m/z＝280.0979,found 280.0975.
example ten:
preparation of 7-hydroxy-3- ((m-methylphenyl) methyl) -4H-benzopyran-4-one (10)
The structural formula of compound 10 is shown below:
wherein compound 10 was a yellow solid in 17.1% yield; the melting process is 191.9-203.0 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 10 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.67(s,1H),8.07(s,1H),7.92(d,J＝8.8Hz,1H),6.90-6.96(m,2H),6.81(d,J＝2.0Hz,1H),6.36-6.44(m,3H),5.61(s,1H),4.04(d,J＝5.2Hz,2H),2.17(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.61,162.44,157.65,153.15,148.14,137.74,128.61,126.55,120.56,117.02,116.04,114.96,113.03,109.59,102.06,38.26,21.14；
HRMS calcd for C 17 H 14 NO 3 - [M+H] - :m/z＝280.0979,found 280.0975.
example eleven:
preparation of 7-hydroxy-3- ((o-methylphenyl) methyl) -4H-benzopyran-4-one (11)
The structural formula of compound 11 is shown below:
wherein compound 11 was a yellow solid in 14.2% yield; the melting process is 189.9-197.1 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 11 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.67(s,1H),8.04(s,1H),7.93(d,J＝8.8Hz,1H),6.91-6.97(m,3H),6.80(d,J＝2.4Hz,1H),6.49-6.54(m,2H),5.10(t,J＝5.6Hz,1H),4.15(d,J＝5.2Hz,2H),2.10(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:176.50,163.14,158.33,153.92,146.31,130.36,127.28,127.24,122.72,121.02,116.84,116.68,115.67,110.26,102.74,39.19,17.97；
HRMS calcd for C 17 H 14 NO 3 - [M+H] - :280.0979,found 280.0976.
embodiment twelve:
preparation of 7-hydroxy-3- (((3-methoxyphenyl) amine) methyl) -4H-benzopyran-4-one (12)
The structural formula of compound 12 is shown below:
wherein compound 12 is a white solid in 12.0% yield; the melting range is 183.1-185.9 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 12 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.67(s,1H),8.09(s,1H),7.92(d,J＝8.8Hz,1H),6.90-6.97(m,2H),6.81(d,J＝2.0Hz,1H),6.12-6.23(m,3H),5.74(t,J＝6.0Hz,1H),4.04(d,J＝5.6Hz,2H),3.65(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.56,162.45,160.26,157.65,153.29,149.52,129.45,126.56,120.54,116.04,114.98,105.35,102.08,101.72,98.19,54.53,38.16；
HRMS calcd for C 17 H 14 NO 4 - [M+H] - :m/z＝296.0928,found 296.0924.
embodiment thirteen:
preparation of 7-hydroxy-3- (((3- (trifluoromethyl) phenyl) amine) methyl) -4H-benzopyran-4-one (13) Compound 13 has the following structural formula:
wherein compound 13 was a yellow oil in 10.9% yield; the melting process is 188.6-191.4 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 13 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:8.17(s,1H),7.92(d,J＝8.8Hz,1H),7.27(t,J＝7.6Hz,1H),6.82-6.95(m,7H),4.10(s,2H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.47,162.64,157.68,153.60,148.43,126.54,119.94,115.99,115.69,115.11,112.08,112.04,108.52,102.13,38.11；
HRMS calcd for C 17 H 11 F 3 NO 3 - [M+H] - :334.0697,found 334.0694.
fourteen examples:
preparation of 7-hydroxy-3- (((3, 4, 5-trimethoxyphenyl) amine) methyl) -4H-benzopyran-4-one (14)
The structural formula of compound 14 is shown below:
wherein compound 14 was a yellow oil in 6.7% yield; the melting process is 184.4-191.7 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 14 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.64(s,1H),8.11(s,1H),7.88(d,J＝8.8Hz,1H),6.88(dd,J＝8.8,2.0Hz,1H),6.78(d,J＝2.4Hz,1H),5.91(s,2H),5.49(s,1H),4.00(d,J＝4.4Hz,2H),3.65(s,6H),3.49(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.59,162.46,157.64,153.42,153.36,144.82,129.04,126.57,120.79,116.07,115.00,102.10,90.53,59.99,55.53,38.39；
HRMS calcd for C 19 H 18 NO 6 - [M+H] - :m/z＝356.1140 found 356.1137.
example fifteen:
preparation of 3- (((4-fluorophenyl) amine) methyl) -7-hydroxy-4H-benzopyran-4-one (15)
The structural formula of compound 15 is shown below:
wherein compound 15 was a yellow solid in 5.1% yield; the melting process is 205.1-216.9 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 15 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.62(s,1H),8.08(s,1H),7.91(d,J＝8.8Hz,1H),6.87-6.93(m,3H),6.81(d,J＝2.0Hz,1H),6.59-6.63(m,2H),5.62(t,J＝6.0Hz,1H),4.03(d,J＝5.6Hz,2H)；
13 C NMR(100MHz,DMSO-d 6 )δ:176.61,155.95,154.23,148.73,140.97,134.17,125.44,124.97,123.22,121.48,118.49,115.71,113.92；
HRMS calcd for C 16 H 11 FNO 3 - [M+H] - :m/z＝284.0728,found 284.0725.
example sixteen:
preparation of 3- (((2, 4-dimethylphenyl) amine) methyl) -7-hydroxy-4H-benzopyran-4-one (16)
The structural formula of compound 16 is shown below:
wherein compound 16 was a yellow solid in 18.7% yield; melting process is 180.5-183.7 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 16 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:10.67(s,1H),8.02(s,1H),7.92(d,J＝8.8Hz,1H),6.92(dd,J＝8.8,2.4Hz,1H),6.77-6.80(m,3H),6.44(d,J＝8.0Hz,1H),4.91(s,1H),4.11(d,J＝2.4Hz,2H),2.12(s,3H),2.07(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.86,162.45,157.63,153.20,143.33,130.53,126.82,126.54,124.56,122.18,120.43,116.00,114.97,109.91,102.05,19.84,17.21；
HRMS calcd for C 18 H 16 NO 3 - [M+H] - :m/z＝294.1136,found 294.1133.
example seventeenth:
preparation of 3- ((p-toluidine) methyl) -4H-benzopyran-4-one (17)
The structural formula of compound 17 is shown below:
wherein compound 17 was a yellow solid in 48.44% yield; the melting process is 157.6-160.1 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 17 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:8.24(s,1H),8.09(dd,J＝8.0,1.2Hz,1H),7.80(td,J＝7.2,1.6Hz,1H),7.63(d,J＝8.8Hz,1H),7.49(td,J＝8.0,0.8Hz,1H),6.88(d,J＝8.0Hz,2H),6.53(d,J＝8.0Hz,2H),5.66(t,J＝6.0Hz,1H),4.06(d,J＝6.0Hz,2H),2.12(s,3H)；
13 C NMR(100MHz；DMSO-d 6 )δ:176.57,155.95,154.27,145.94,134.20,129.42,125.46,124.97,124.61,123.21,121.25,118.49,112.61,38.62,20.11；
HRMS calcd for C 17 H 14 NO 2 - [M-H] - :m/z＝264.1030,found 264.1031.
example eighteenth:
preparation of 3- (((2- (trifluoromethyl) phenyl) amine) methyl) -4H-benzopyran-4-one (18)
The structural formula of compound 18 is shown below:
wherein compound 18 was a yellow solid in 38.8% yield; melting process is 116.8-119.1 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 18 are as follows:
1 H NMR(400MHz,CDCl 3 )δ:8.26(dd,J＝8.0,1.2Hz,1H),7.87(t,J＝0.8Hz,1H),7.68(td,J＝7.2,2.0Hz,1H),7.41-7.48(m,3H),7.35(t,J＝7.2Hz,1H),6.74-6.79(m,2H),4.40(s,2H)；
13 C NMR(100MHz,CDCl 3 )δ:178.17,156.66,155.22,153.34,143.69,133.95,125.78,125.38,123.91,121.08,118.35,116.04,115.82,114.78,114.70,41.55；
HRMS calcd for C 17 H 11 F 3 NO 2 - [M-H] - :m/z＝318.0747,found 318.0745.
example nineteenth:
preparation of 3- (((2, 4-dimethylphenyl) amine) methyl) -4H-benzopyran-4-one (19)
The structural formula of compound 19 is shown below:
wherein compound 19 was a yellow solid in 27.4% yield; the melting process is 108.3-116.5 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 19 are as follows:
1 H NMR(400MHz,CDCl 3 )δ:8.23(dd,J＝8.0,1.6Hz,1H),7.91(s,1H),7.66(td,J＝6.8,1.6Hz,1H),7.39-7.44(m,2H),6.90(d,J＝5.6Hz,2H),6.57(d,J＝8.8Hz,1H),4.31(s,2H),2.22(s,3H),2.18(s,3H)；
13 C NMR(100MHz,CDCl 3 )δ:178.24,156.66,153.42,142.89,133.82,131.38,127.45,127.28,125.79,125.27,123.96,123.37,121.25,118.32,110.97,40.99,20.49,17.63；
HRMS calcd for C 18 H 17 NNaO 2 + [M+Na] + :m/z＝268.0779,found 302.1151.
example twenty:
preparation of 3- (((4-fluorophenyl) amine) methyl) -4H-benzopyran-4-one (20)
The structural formula of compound 20 is shown below:
wherein the compound 20 is brown solid, the yield is 29.5 percent, and the melting process is 167.0-170.7 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 20 are as follows:
1 H NMR(400MHz,CDCl 3 )δ:8.23(dd,J＝7.6,1.2Hz,1H),7.92(s,1H),7.67(td,J＝7.2,1.6Hz,1H),7.40-7.45(m,2H),6.86-6.91(m,2H),6.60-6.63(m,2H),4.23(s,2H)；
13 C NMR(100MHz,CDCl 3 )δ:177.87,156.66,153.28,144.52,133.99,133.37,126.96,126.91,125.85,125.43,123.79,120.45,118.34,117.31,112.70,40.05；
HRMS calcd for C 16 H 11 FNO 2 - [M-H] - :m/z＝268.0779,found 268.0779.
example twenty-one:
preparation of 3- (((2-fluorophenyl) amine) methyl) -4H-benzopyran-4-one (21)
The structural formula of compound 21 is shown below:
wherein compound 21 is a brown solid; yield 19.7%; the melting process is 110.2-111.8 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 21 are as follows:
1 H NMR(400MHz,CDCl 3 )δ:8.25(dd,J＝8.4,1.6Hz,1H),7.93(s,1H),7.67(td,J＝7.2,1.6Hz,1H),7.40-7.45(m,2H),7.96-7.01(m,2H),6.67-6.75(m,2H),4.33(s,2H)；
13 C NMR(100MHz,CDCl 3 )δ:177.90,156.63,153.32,135.64,135.54,133.89,125.81,125.34,124.74,124.71,123.84,120.92,118.30,117.97,117.90,114.96,114.78,113.10,40.25；
HRMS calcd for C 16 H 11 FNO 2 - [M-H] - :m/z＝268.0779,found 268.0780.
example twenty two:
preparation of 3- ((anilino) methyl) -4H-benzopyran-4-one (22)
The structural formula of compound 22 is shown below:
wherein compound 22 is a yellow solid; yield 46.8%; melting process is 125.5-127.6 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 22 are as follows:
1 H NMR(400MHz,CDCl 3 )δ:8.23(dd,J＝8.0,1.6Hz,1H),7.93(s,1H),7.67(td,J＝6.8,1.6Hz,1H),7.48-7.37(m,2H),7.24-7.14(m,2H),6.77(t,J＝7.2Hz,1H),6.71(d,J＝7.2Hz,2H),4.29(d,J＝0.8Hz,2H)；
13 C NMR(100MHz,CDCl 3 )δ:178.18,156.65,153.52,146.85,133.91,129.51,125.76,125.34,123.89,120.94,118.85,118.33,114.06,41.06；
HRMS calcd for C 16 H 14 NO 2 + [M+H] + :m/z＝252.1019,found 252.1029.
example twenty-three:
preparation of 3- (((3- (trifluoromethyl) phenyl) amine) methyl) -4H-benzopyran-4-one (23)
The structural formula of compound 23 is shown below:
wherein compound 23 is a yellow solid; yield 58.4%; melting process is 159.8-162.1 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 23 are as follows:
1 H NMR(400MHz,CDCl 3 )δ:8.25(dd,J＝8.0,1.6Hz,1H),7.93(s,1H),7.68(td,J＝6.8,1.6Hz,1H),7.41-7.46(m,2H),7.26(t,J＝6.8Hz,1H),6.97(d,J＝7.6Hz,1H),6.89(s,1H),6.82(dd,J＝8.4,2.4Hz,1H),4.29(d,J＝0.8Hz,2H)；
13 C NMR(100MHz,CDCl 3 )δ:178.12,156.66,153.24,147.77,134.04,129.89,125.78,125.45,123.91,120.77,118.38,116.50,114.64,114.60,109.68,109.64,40.53；
HRMS calcd for C 17 H 11 F 3 NO 2 - [M-H] - :m/z＝318.0747,found 318.0747.
example twenty-four:
preparation of 3- (((4- (trifluoromethyl) phenyl) amine) methyl) -4H-benzopyran-4-one (24)
The structural formula of compound 24 is shown below:
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wherein compound 24 is a brown solid; yield 29.5%; the melting process is 190.6-201.9 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 24 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:8.29(s,1H),8.06(dd,J＝8.0,1.6Hz,1H),7.75-7.80(m,1H),7.61(d,J＝8.4Hz,1H),7.47(t,J＝7.6Hz,1H),7.33(d,J＝8.4Hz,2H),6.70(d,J＝8.4Hz,2H),6.64(t,J＝5.4Hz,1H),4.10(d,J＝5.2Hz,2H)；
13 C NMR(100MHz,DMSO-d 6 )δ:176.43,155.99,154.53,151.27,134.30,126.29,126.25,125.55,124.98,123.24,120.55,118.51,111.67,37.92；
HRMS calcd for C 17 H 11 F 3 NO 2 - [M-H] - :m/z＝318.0747,found 318.0746.
example twenty-five:
preparation of 3- (((4-ethoxyphenyl) amine) methyl) -4H-benzopyran-4-one (25)
The structural formula of compound 25 is shown below:
wherein compound 5 is a yellow solid; yield 24.0%; melting process is 141.5-144.1 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 25 are as follows:
1 H NMR(400MHz,CDCl 3 )δ:8.23(dd,J＝8.0,1.6Hz,1H),7.90(s,1H),7.66(td,J＝6.8,1.6Hz,1H),7.39-7.44(m,2H),6.76(d,J＝8.8Hz,2H),6.61(d,J＝9.2Hz,2H),4.21(d,J＝0.8Hz,2H),3.94(q,J＝6.8Hz,2H),1.36(t,J＝7.2Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ:178.06,156.51,153.18,151.86,141.39,133.68,125.64,125.12,123.82,121.36,118.18,115.65,114.98,63.96,41.60,14.99；
HRMS calcd for C 18 H 16 NO 3 - [M-H] - :m/z＝294.1136,found 294.1137.
example twenty-six:
preparation of 3- (((2, 5-dichlorophenyl) amine) methyl) -4H-benzopyran-4-one (26)
The structural formula of compound 26 is shown below:
wherein compound 26 was a yellow solid in 80.1% yield; the melting process is 134.9-138.9 ℃; and the data for the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of compound 26 are shown below:
1 H NMR(400MHz,CDCl 3 )δ:8.25(dd,J＝8.0,1.6Hz,1H),7.87(s,1H),7.68(td,J＝7.2,1.6Hz,1H),7.40-7.46(m,2H),7.21-7.16(d,J＝9.2,Hz,1H),6.60-6.63(m,2H),4.31(d,J＝1.2Hz,2H)；
13 C NMR(100MHz,CDCl3)δ:177.70,156.54,152.94,144.17,133.90,133.62,129.98,125.74,125.33,123.72,120.28,118.22,117.86,117.64,111.30,39.90；
HRMS calcd for C 16 H 12 Cl 2 NO 2 + [M+H] + :m/z＝320.0240,found 320.0240.
example twenty-seventh:
preparation of 3- (((2-ethoxyphenyl) amine) methyl) -4H-benzopyran-4-one (27)
The structural formula of compound 27 is shown below:
wherein compound 27 was a yellow solid in 56.8% yield; the melting process is 94.5-96.6 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 27 are as follows:
1 H NMR(400MHz,CDCl 3 )δ:8.25(dd,J＝7.6,1.6Hz,1H),7.88(s,1H),7.66(td,J＝7.2,1.6Hz,1H),7.39-7.44(m,2H),6.77-6.84(m,2H),6.67(td,J＝7.6,1.2Hz,1H),6.58(dd,J＝8.0,1.6Hz,1H),4.34(d,J＝0.4Hz,2H),4.08(q,J＝6.8Hz,2H),1.45(t,J＝6.8Hz,3H)；
13 C NMR(100MHz,CDCl 3 )δ:177.84,156.55,153.18,146.41,137.31,133.56,125.67,125.03,123.77,121.35,121.11,118.16,117.18,110.54,110.34,63.81,39.85,15.00；
HRMS calcd for C 18 H 18 NO 3 + [M+H] + :m/z＝296.1281,found 296.1294.
example twenty-eight:
preparation of 3- (((4-nitrophenyl) amine) methyl) -4H-benzopyran-4-one (28)
The structural formula of compound 28 is shown below:
wherein compound 28 was a brown solid in 27.9% yield; melting process is 182.5-198.9 ℃; and the data for the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of compound 28 are shown below:
1 H NMR(400MHz,DMSO-d 6 )δ:10.45(s,1H),8.78(s,1H),8.09(dd,J＝8.0,1.6Hz,1H),7.93(s,1H),7.79(td,J＝7.2,1.6Hz,1H),7.67(d,J＝8.4Hz,1H),7.49(td,J＝8.0,1.6Hz,1H),7.17(t,J＝8.0Hz,2H),7.02(d,J＝7.6Hz,2H),6.71(t,J＝7.2Hz,1H)；
13 C NMR(100MHz,DMSO-d 6 )δ:175.54,156.28,152.82,145.53,134.84,129.63,128.38,126.24,125.73,123.76,120.10,119.47,119.20,112.55,31.68；
HRMS calcd for C 16 H 12 KN 2 O 4 + [M+Na] + :m/z＝335.0429,found 335.0483.
example twenty-nine:
preparation of 3- (((4-hydroxyphenyl) amine) methyl) -4H-benzopyran-4-one (29)
The structural formula of compound 29 is shown below:
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wherein compound 29 is a yellow solid; yield 31.0%; melting process is 168.5-174.9 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 29 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:8.43(s,1H),8.19(s,1H),8.04(dd,J＝8.0,1.6Hz,1H),7.76(td,J＝7.2,1.6Hz,1H),7.59(d,J＝8.4Hz,1H),7.45(td,J＝8.0,0.8Hz,1H),6.50(d,J＝8.8Hz,2H),6.44(d,J＝9.2Hz,2H),5.21(t,J＝6.0Hz,1H)3.97(d,J＝5.6Hz,2H)；
13 C NMR(100MHz,DMSO-d 6 )δ:176.60,155.94,154.21,153.65,148.74,140.96,134.14,125.42,124.96,124.10,123.21,121.48,118.48,115.71,113.92,55.36；
HRMS calcd for C 16 H 12 NO 3 - [M-H] - :m/z＝266.0823,found 266.0818.
example thirty:
preparation of 3- (((4-methoxyphenyl) amine) methyl) -4H-benzopyran-4-one (30)
The structural formula of compound 30 is shown below:
wherein compound 30 was a yellow solid in 35.6% yield; melting process is 151.5-155.3 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 30 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.26(s,1H),8.09(dd,J＝7.6,1.6Hz,1H),7.81(td,J＝7.2,1.6Hz,1H),7.64(d,J＝8.8Hz,1H),7.50(t,J＝7.2,0.8Hz,1H),6.71(d,J＝8.8Hz,2H),6.57(d,J＝9.2Hz,2H),5.49(t,J＝6.4Hz,1H),4.05(d,J＝5.6Hz,2H),3.62(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:176.60,155.96,154.27,151.05,142.34,134.21,125.47,124.98,123.21,121.34,118.49,114.63,113.62,55.27；
HRMS calcd for C 17 H 16 NO 3 + [M+H] + :m/z＝282.1125,found 282.1135.
example thirty-one:
preparation of 3- (((3-hydroxy-4-methoxyphenyl) amine) methyl) -4H-benzopyran-4-one (31)
The structural formula of compound 31 is shown below:
wherein compound 31 is a brown solid in 64.4% yield; the melting process is 151.4-156.1 ℃; and the data of the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum of the compound 31 are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:8.26(s,1H),8.10(dd,J＝8.0,1.6Hz,1H),7.80(td,J＝7.2,1.6Hz,1H),7.62(d,J＝8.4Hz,1H),7.50(t,J＝7.6Hz,1H),7.17(d,J＝8.8Hz,1H),7.11(d,J＝2.8Hz,1H),6.70-6.62(m,2H),6.15(s,1H),5.38(t,J＝5.2Hz,1H),4.12(d,J＝0.8Hz,2H),3.67(s,3H)；
13 C NMR(100MHz,DMSO-d 6 )δ:176.34,155.96,147.50,134.57,125.83,125.01,123.08,118.62,113.82,56.40；
HRMS calcd for C 17 H 16 NO 4 + [M+H] + :m/z＝found 298.1087.
to further verify the excellent effect of the present invention, the inventors also conducted the following experimental comparison:
experiment one
Different concentrations of compound or acarbose (10. Mu.L) and 150. Mu.L of alpha-glucosidase solution (0.2U/ml) were addedInto 96-well plates and the mixture was incubated at 37℃for a further 15 minutes. Then 40. Mu.L of p-nitrophenyl-. Alpha. -D-glucopyranoside (1.25 mM) was added to the above mixture, incubation was continued for 30 minutes, and the IC was calculated by measuring 405nm in a microplate reader 50 The results are shown in Table 1.
TABLE 1 inhibition Activity of alpha-glucosidase of chromone-anilines (IC 50 ):
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It can be seen from Table 1 that some of the compounds had good inhibitory activity against α -glucosidase, with compounds 1, 2,5, 9, 13, 15, 24 and 31 being better active. Wherein the compound 2 has optimal activity and inhibits IC of alpha-glucosidase 50 11.72+ -0.08 μM, superior to the positive control drug acarbose (832.22 + -2.00 μM).
Experiment two
Compound 2 was used to investigate its effect on postprandial blood glucose in normal kunming mice. In this experiment, all experimental mice were fasted for 12 hours (free to drink water) prior to the experiment. All Kunming mice were randomly divided into four groups of 7. The method comprises the following steps of: model group (0.5% CMC-Na solution), acarbose group (20 mg/kg in 0.5% CMC-Na solution), test compound group (220 mg/kg in 0.5% CMC-Na solution) and blank group (0.5% CMC-Na solution). Following dosing, the above groups were each tested for postprandial blood glucose by gavage of 2.5g/kg sucrose (blank control using blank 0.5% cmc-Na solution) at 0 hours, 0.25 hours, 0.5 hours, 1 hour, 1.5 hours and 2 hours using the roche Accu-Chek Instant tail. Kunming mice (25-30 g) were purchased from Changsha Sichuan Biotechnology Inc. under the license number SCXK (Xiang) 2019-0014. All animal procedures were performed according to the guidelines for care and use of laboratory animals, and the experiments were approved by the animal ethics committee of the university of Guizhou medical science.
As can be seen from fig. 2 (a), the blood glucose rapidly increased and peaked after the sucrose was orally taken in the model group, whereas the blood glucose elevation level was significantly lower and the blood glucose was smoothly lowered in the oral acarbose group and the compound 2 group after the sucrose was orally taken. Fig. 2 (B) depicts the change in blood glucose load level of mice after oral administration of sucrose, from which it is seen that compound 2 has a postprandial blood glucose lowering function comparable to acarbose.
Experiment three
Human normal embryonic kidney HEK293 cells were seeded in 96-well plates and incubated at 37℃for 24 hours, and compounds of varying concentrations were added to the 96-well plates and allowed to incubate for an additional 48 hours. After the cell culture is finished, the influence of the compound on the cell growth is measured by adopting a CKK-8 method, and the inhibition IC of the compound on normal cells is calculated by adopting SPSS software 50 。
Experimental results show that compound 2 inhibits IC on normal cells 50 556.12 + -6.42 μm indicates that compound 2 has low toxicity and high safety.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Many possible variations and modifications of the disclosed technology can be made by anyone skilled in the art, or equivalent embodiments with equivalent variations can be made, without departing from the scope of the invention. Therefore, any simple modification, equivalent variation and modification of the above embodiments according to the technical substance of the present invention shall fall within the scope of the technical solution of the present invention.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (2)
1. The application of the chromone-aniline alpha-glucosidase inhibitor in preparing antidiabetic drugs is characterized in that the chromone-aniline alpha-glucosidase inhibitor has a structural general formula shown in a formula (I):
wherein R in formula I 1 Is one of hydrogen, fluorine, chlorine, bromine, hydroxyl and C1-C3 alkoxy; r is R 2 Is one of hydrogen, fluorine, chlorine, bromine, iodine, C1-C3 alkoxy, C1-C3 alkyl, nitro, hydroxyl and trifluoromethyl.
2. The application of the chromone-aniline alpha-glucosidase inhibitor in preparing antidiabetic drugs is characterized in that the structural formula of the chromone-aniline alpha-glucosidase inhibitor is as follows:
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