CN111153895B - Diphyllin and application thereof in preparation of medicine for preventing or treating diabetes - Google Patents
Diphyllin and application thereof in preparation of medicine for preventing or treating diabetes Download PDFInfo
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- CN111153895B CN111153895B CN202010051687.7A CN202010051687A CN111153895B CN 111153895 B CN111153895 B CN 111153895B CN 202010051687 A CN202010051687 A CN 202010051687A CN 111153895 B CN111153895 B CN 111153895B
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- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 18
- RFXQCUDAHXPYOF-UHFFFAOYSA-N diphyllin Natural products COc1cc2c(c3ccc4OCOc4c3)c5C(=O)OCc5c(O)c2cc1O RFXQCUDAHXPYOF-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 229960002819 diprophylline Drugs 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title claims abstract description 11
- KSCFJBIXMNOVSH-UHFFFAOYSA-N dyphylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC(O)CO)C=N2 KSCFJBIXMNOVSH-UHFFFAOYSA-N 0.000 title claims abstract 3
- 238000002360 preparation method Methods 0.000 title description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 26
- 239000008280 blood Substances 0.000 abstract description 15
- 210000004369 blood Anatomy 0.000 abstract description 15
- 241000699670 Mus sp. Species 0.000 abstract description 13
- 206010022489 Insulin Resistance Diseases 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
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- 239000008103 glucose Substances 0.000 description 21
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229940125396 insulin Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 5
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
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- 230000003914 insulin secretion Effects 0.000 description 3
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- 239000012453 solvate Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000013218 HFD mouse model Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- -1 aryl naphthalene lactone Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- STRNXFOUBFLVIN-UHFFFAOYSA-N diethyl but-2-ynedioate Chemical compound CCOC(=O)C#CC(=O)OCC STRNXFOUBFLVIN-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 235000021590 normal diet Nutrition 0.000 description 2
- 238000007410 oral glucose tolerance test Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229940081310 piperonal Drugs 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000007446 glucose tolerance test Methods 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229930013686 lignan Natural products 0.000 description 1
- 150000005692 lignans Chemical class 0.000 description 1
- 235000009408 lignans Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- 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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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
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- Emergency Medicine (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to diphyllin shown as a formula I and application thereof in preparing a medicine for preventing or treating diabetes,
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a natural product diphyllin in preparation of medicines for preventing and treating diabetes.
Background
With the continuous improvement of living standard, the change of dietary structure, the life style of little movement and sitting, and other factors, diabetes becomes the third most serious chronic disease after tumor and cardiovascular disease, which threatens human health. IDF Diabetes Atlas-8 issued by the International Diabetes Association (IDF)thEdition indicates that the overall incidence of diabetes is 8.8% and the total number of patients reaches 4.25 hundred million in 20-79 years old adult population all over the world. China is currently the fastest growing region of diabetes worldwide, and has become the world's first major diabetic country in number (1.14 billion).
Diabetes mellitus is a metabolic disease characterized mainly by hyperglycemia due to absolute or relative insufficiency of insulin secretion. Among them, type I diabetes is mainly caused by insufficient insulin secretion, and needs to rely on insulin injection to maintain blood sugar; type II diabetes is hyperglycemic with a reduced biological effect of insulin, accounting for approximately 90% of all diabetic cases.
The diphyllin is a natural product of aryl naphthalene lactone type lignans widely distributed in plant kingdom. Has wide activity, and has biological activity in multiple aspects of antibiosis, antiphlogosis, antioxidation, liver protection, antivirus, platelet activating factor inhibition, tumor resistance and the like. However, there is no report on the role of the compound in regulating blood sugar of the body.
Disclosure of Invention
The invention aims to provide a novel diphyllin compound, and reports the function of regulating the blood sugar of an organism for the first time.
The specific technical scheme of the invention is as follows:
a compound of formula I, a pharmaceutically acceptable salt, prodrug, solvate, or isotopologue thereof:
the diphyllin (namely the compound shown in the formula I) is prepared by a chemical synthesis method.
(1) Reacting compound S1 with Br2The reaction yielded compound S2.
(2) Ring formation from S2 with ethylene glycol (glycol) gives compound S3.
(3) The compound S3 reacts with S4 piperonal in the presence of n-butyllithium, and then reacts with diethyl butynedioate to prepare the compound S5.
(4) Reacting the compound S5 with borane dimethyl sulfide complex to obtain the diphyllin (formula I).
The invention evaluates the effect of diphyllin on the blood glucose and insulin resistance of mice administered orally for 8 consecutive weeks (50mg/kg/day and 100 mg/kg/day). Experimental results show that under the condition that the oral administration dosage is 50mg/kg/day and 100mg/kg/day, the compound can obviously improve the oral glucose tolerance and insulin sensitivity of mice and shows a certain antidiabetic effect.
It is another object of the present invention to provide a method for the prevention and treatment of diabetes, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention.
The invention also provides application of the compound shown as the formula I, and a pharmaceutically acceptable salt, a prodrug, a solvate (preferably a hydrate) or an isotopologue thereof in preparing a medicament or a health-care product for preventing and treating diabetes.
It is another object of the present invention to provide a composition comprising a therapeutically effective amount of diphyllin of formula I, its pharmaceutically acceptable salts, prodrugs, solvates (preferably hydrates), or isotopologues. The pharmaceutical composition further comprises pharmaceutically acceptable auxiliary materials.
According to the invention, a therapeutically effective amount of the compound of the invention and any one or more pharmaceutically acceptable excipients may be formulated into a pharmaceutical composition. The preparation can be any pharmaceutically acceptable dosage form, including but not limited to tablets, capsules, pills, injections and the like.
To practice the methods of the present invention, the compounds may be administered orally, parenterally, subcutaneously, intravenously, by inhalation spray, or by implanted reservoirs and the like.
The invention discloses application of the compound in a medicament for treating diabetes. Animal experiment means prove that the compound can obviously improve the oral glucose tolerance and the insulin sensitivity of mice for the first time. Experiments prove that the compound has obvious improvement effect on oral glucose tolerance and insulin sensitivity, and is expected to be developed into a medicament for treating diabetes.
Drawings
FIG. 1 shows the results of the oral glucose tolerance and insulin sensitivity tests on mice with Compound I of the present invention (FIGS. 1 and A are the blood glucose values at-15 min before and 0, 15, 30, 60, 90 and 120min after administration of glucose; FIGS. 1 and B are the area under the blood glucose curve within 120 min; FIGS. 1 and C are the blood glucose values at-15 min before and 0, 15, 30, 60, 90 and 120min after administration of insulin; and FIGS. 1 and D are the area under the blood glucose curve within 120 min).
Detailed Description
The following examples illustrate specific steps of the present invention, but are not intended to limit the invention.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The invention is described in further detail below with reference to specific examples and data, it being understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
The compounds and intermediates of the present invention can be prepared by those skilled in the art by synthetic routes described below, as illustrated in the following examples.
EXAMPLE 1 preparation of Compound I according to the invention
S1(33.2g, 200mmol) was dissolved in methanol (160mL) and Br was slowly added dropwise under ice bath2(11.26mL, 220 mmol) and after the addition was complete, stirring was continued at room temperature for 6 hours. After TLC detection reaction, 300mL of ice water was added, a large amount of solid precipitated, the pH was adjusted to 9 with 2mol/L aqueous sodium hydroxide solution, filtration was carried out, the aluminum cake was washed with ice water and dried to obtain 49.1g of white solid S2 with a yield of 95%.1H NMR(400MHz,Chloroform-d)δ10.18(s,1H),7.41(s, 1H),7.05(s,1H),3.96(s,3H),3.92(s,3H)。
S2(9.76g, 40mmol), ethylene glycol (3.35mL, 60mmol), p-toluenesulfonic acid (480mg) were refluxed in toluene (200mL), water was split with a Dean-Stark trap, TLCAfter the reaction was detected to be completed (3 hours), triethylamine (10mL) was added, the mixture was stirred for 15 minutes, and the mixture was concentrated under reduced pressure to obtain an oily substance, which was diluted with ethyl acetate (200mL), washed with a 2mol/L aqueous solution of sodium hydroxide (2X 100mL), dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid, which was then slurried with ethanol and washed with hot ethanol to obtain 10.2g of S3 as a white solid with a yield of 89%.1H NMR(400 MHz,Chloroform-d)δ7.11(s,1H),7.01(s,1H),5.99(s,1H),4.17(m,2H),4.06(m,2H), 3.89(s,3H),3.88(s,3H)。
S3(2.9g, 10mmol) was placed in a two-necked flask, vacuum was pulled, nitrogen was replaced, 40mL of ultra-dry tetrahydrofuran was injected, butyl lithium (2.5mol/L, 4.8mL, 12mmol) was slowly added dropwise at-78 deg.C, stirring was carried out for 15min, a solution of S4 piperonal (1.5g, 10mmol) in ultra-dry tetrahydrofuran (10mL) was added dropwise, stirring was continued for 30min, gradually returned to room temperature, and stirring was carried out for 2.5 h. After the reaction, 50mL of glacial acetic acid and diethyl butynedioate (1.7g, 10mmol) were added and heated at 140 ℃ under reflux for one hour. Tetrahydrofuran was removed by rotary evaporation, the pH of the solution was adjusted to about 7 with saturated sodium bicarbonate solution, extracted with dichloromethane and column chromatographed with P/E3: 1 to yield 3.01g of S5 as a yellow solid in 64% yield. S5(3.01g, 6.4 mmol) was dissolved in 40mL of tetrahydrofuran, the balloon-equipped rubber stopper was closed, borane dimethylsulfide complex (6.4 mL, 64mmol) was added dropwise, and the reaction was allowed to proceed overnight. Quenching reaction with 20mL of methanol, removing tetrahydrofuran by rotary evaporation, acidifying with 2mol/L hydrochloric acid until the pH value is 2-3, stirring for 30min, extracting with dichloromethane, and recrystallizing with methanol to obtain 866.4mg of diphyllin (formula I), wherein the yield is 36%.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),7.62(s,1H),7.02(d,J＝7.9Hz, 1H),6.96(s,1H),6.86(d,J＝1.6Hz,1H),6.75(dd,J＝7.9,1.76Hz,1H),6.11(s,2H),5.36(s, 2H),3.94(s,3H),3.65(s,3H)。
EXAMPLE 2 oral glucose tolerance test and insulin sensitivity test of Compound I according to the invention
80C 57 mice (male) were purchased in the unit animal house at 4-5 weeks of age, and the group experiment was started with high fat diet induction modeling until the average body weight was more than 35 g. All mice were randomized for body weight on day 2 prior to dosing, followed by fasting for 6h (without water deprivation) for fasting blood glucose determination. 32 mice were selected according to their random body weight and fasting blood glucose, and divided into 4 groups of 8 mice each. Model control group (vehicle), positive control group (metformin 250mg/kg), 50mg/kg administration group and 100mg/kg administration group are respectively provided, and the normal diet group (chow) is another group, and the normal diet quantity of the mice purchased in the same batch is 7.
Oral Glucose Tolerance Test (GTT): setting a normal control group, a model control group, a compound I administration group and a positive control group. Mice were subjected to oral glucose tolerance experiments 4 weeks after dosing: gastric glucose was gavaged at 1.5g/kg after 6h of fasting, blood glucose levels at-15 min before sugar administration, 0, 15, 30, 60, 90 and 120min after sugar administration were measured (fig. 1, a), and the area under the blood glucose curve (AUC) in 120min was calculated (fig. 1, B). Compound I significantly improved the glucose levels and area under the curve after oral glucose loading in HFD mice at 50mg/kg and 100mg/kg for 4 weeks, which was significantly different from the model control group.
Insulin sensitivity test (ITT): setting a normal control group, a model control group, a compound I administration group and a positive control group. Mice were subjected to insulin release experiments at 6 weeks post-dose. The blood glucose values of the mice at-15 min before and 0, 15, 30, 60, 90 and 120min after fasting for 6h with Insulin (fig. 1, C) were measured by 0.75 u/kg abdominal administration of Insulin, and the area under the blood glucose curve (AUC) was calculated within 120min (fig. 1, D). Compound I significantly improved insulin-loaded glucose levels and area under the curve in HFD mice at 50mg/kg and 100mg/kg doses 6 weeks after administration, which was significantly different from the model control group.
Claims (1)
1. An application of diphyllin shown in formula I or its pharmaceutically acceptable salt in preparing medicine for preventing or treating diabetes,
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