CN105130932B - Compound and its purposes in the medicine for preparing PTP1B inhibitor and treatment and/or prevention type II diabetes - Google Patents
Compound and its purposes in the medicine for preparing PTP1B inhibitor and treatment and/or prevention type II diabetes Download PDFInfo
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- CN105130932B CN105130932B CN201510482329.0A CN201510482329A CN105130932B CN 105130932 B CN105130932 B CN 105130932B CN 201510482329 A CN201510482329 A CN 201510482329A CN 105130932 B CN105130932 B CN 105130932B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
- A23F3/00—Tea; Tea substitutes; Preparations thereof
- A23F3/06—Treating tea before extraction; Preparations produced thereby
- A23F3/14—Tea preparations, e.g. using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
Abstract
The invention provides two kinds of compounds and its purposes in the medicine for preparing PTP1B inhibitor and treatment and/or prevention type II diabetes.Specifically disclose two kinds of compounds and suppress that there is remarkable result to PTP1B, there are patent medicine potentiality in terms of type ii diabetes are treated, new material base is provided to be developed into treatment type ii diabetes original new drug, the exploitation PTP1B innovative hypoglycemic medicines of inhibitor class.
Description
Technical field
The present invention relates to compound field, relate in particular to compound and its prepare PTP1B inhibitor and treatment and/
Or the purposes of the medicine of prevention type II diabetes.
Background technology
Diabetes (Diabetes Mellitus, DM) are a kind of chronic incretion metabolism diseases, and wherein type ii diabetes are accounted for
Most of, China diabetic has more than 20,000,000, wherein nearly 90% is type ii diabetes, and multiple, year occurs
The characteristics of lightization, seriously threaten national health.
Insulin resistance is the key factor of type ii diabetes morbidity, and protein-tyrosine phosphide enzyme 1B (PTP1B) is in pancreas islet
The effect of key is played in the formation of element resistance.Research confirms negative growth factors of the PTP1B as insulin signaling pathway, can be with
By the insulin receptor being activated or the tyrosine residue dephosphorylation of its substrate, so as to terminate insulin signaling pathway, cause
Resistance of the body to insulin, forms body insulin and lacks and then develop into type ii diabetes relatively.Show in zooscopy
Show, PTP1B knock out mice shows to significantly improve insulin sensitivity in sugar tolerance and insulin tolerance test.
Thus PTP1B inhibitor can play an important role as a kind of new type ii diabetes medicine.
Therefore, the medicine tool of the exploitation innovative hypoglycemic medicine of PTP1B inhibitor classes and treatment and/or prevention type II diabetes
It is significant.
The content of the invention
The invention provides two kinds of new compounds, it can be used for preparing PTP1B inhibitor and treats and/or prevention II
The medicine of patients with type Ⅰ DM.
One aspect of the present invention, there is provided the compound or pharmaceutically acceptable salt thereof as shown in formula I and formula II,
Additionally provide a kind of pharmaceutical composition for preparing PTP1B inhibitor, right in containing effective dose at least
It is required that the compound or pharmaceutically acceptable salt thereof described in 1.
A kind of pharmaceutical composition for treating and/or preventing type II diabetes is provided again, and described pharmaceutical composition contains
Compound and/or its pharmaceutical salts at least one claim 1 of effective dose.
Above-described pharmaceutical composition, wherein described pharmaceutical composition are pharmaceutically acceptable auxiliary including one or more
Material.
Above-described pharmaceutical composition, wherein described pharmaceutical composition are parenteral solution, tablet, pulvis, granule, ball
Agent, capsule, oral liquid, paste, creme or spray.
Additionally provide the purposes of above-described compound and its pharmaceutical salts in the product for preparing PTP1B inhibitor.
Compound and its pharmaceutical salts described in also providing are preparing the use of the product for treating and/or preventing type II diabetes
On the way.
Above-described purposes, the product is medicine or edible product.
Above-described purposes, the edible product is oral liquid, tea-drinking, lozenge, capsule, drink or effervescent tablet.
Two compounds provided by the present invention are and are found first, also not on two chemical syntheses of compound
The relevant report of aspect.Experiment proves that compound shown in Formulas I shows that significantly PTP1B is suppressed to live with compound shown in Formula II
Property；The IC that the compound of structure shown in Formulas I and Formula II suppresses to PTP1B50Value is respectively 32.10 and 30.50 μM, with significantly effect
Really, there are patent medicine potentiality in terms of type ii diabetes are treated, to be developed into treatment type ii diabetes original new drug, exploitation
The innovative hypoglycemic medicine of PTP1B inhibitor classes provides new material base.The present invention PTP1B new to research and development suppresses
The medicine of agent and treatment type II diabetes provides candidate compound, to develop the natural active matter in macro fungi source
There is provided scientific basis.In addition, two above-mentioned compounds are isolated from by popular fungi edible extensively, its security has just
The guarantee of step.
Specific embodiment
With reference to embodiments, specific embodiment of the invention is described in more details, so as to more preferably
Ground understands the solution of the present invention and the advantage of its various aspects.
Experimental technique used in following embodiments is conventional method unless otherwise specified.
Material used, reagent etc. in following embodiments, unless otherwise specified, commercially obtain.
It is prepared by the separation of embodiment 1, compound gold oyster mushroom element A and gold oyster mushroom element E
1st, the fermentation of gold oyster mushroom bacterial strain L736
The preparation of gold oyster mushroom seed culture fluid：By the mycelia of gold oyster mushroom bacterial strain L736 (being purchased from the Chinese Academy of Agricultural Sciences)
It is seeded in the PDB culture mediums of sterilizing, 25 DEG C are cultivated 7 days.PDB culture mediums：200 grams of potato, 20 grams of glucose, agar 15
Gram, water is settled to 1000 milliliters.
Take 10mL seed culture fluids to be inoculated into respectively in equipped with solid medium 500 milliliters of triangular flasks of sterilizing, be inoculated with
20 bottles, 25 DEG C are cultivated 40 days.Solid medium：90 grams of long-grained nonglutinous rices, 120 ml deionized waters.
2nd, the extraction of gold oyster mushroom element A and gold oyster mushroom element E with separate preparation
Fermentation ends, 800 milliliters of ethyl acetate are added in the triangular flask of culture, and soak at room temperature is extracted one week, are repeated
Extract three times, combined ethyl acetate extract solution drying under reduced pressure obtains 13.5 grams of extract medicinal extract.
Medicinal extract is used into silicagel column (Qingdao Marine Chemical Co., Ltd., 200-300 mesh, 200 grams of column chromatography silica gel；Φ6×
80 centimetres) chromatography, carry out gradient elution (100 by mobile phase of methylene chloride-methanol:0,100:1,100:2,100:3,100:
5,100:10,100:20,0:100), 2000 milliliters of each solvent gradient, every 500 milliliters are collected as a cut, respectively
The eluate and methylene chloride-methanol volume ratio for collecting 100% dichloromethane gradient are 100:10 eluate.
By the eluate (700 milligrams) of 100% dichloromethane gradient, (RP-18, YMC- are isolated and purified through preparing HPLC
Pack, 250 × 10 millimeters, 5 microns), it is 78 with acetonitrile-water volume ratio:22 mixed solvent carries out affording gold oyster mushroom
Plain A (2 milligrams), i.e., compound shown in Formulas I.
It is 100 by methylene chloride-methanol volume ratio:10 eluate (2.6 grams) inverted mesolow column chromatography (ODS,
Merck companies, 40-63 microns, 3 × 60 centimetres of Φ), carry out gradient elution (20 by solvent of methanol-water:80,40:60,60:
40,80:20,100:0), 400 milliliters of each solvent gradient, every 100 milliliters are collected as a cut.Collect methanol-water body
Product is than being 40:60 eluted product (60mg) is isolated and purified through preparing HPLC, is 30 with methanol-water volume ratio:70 mixing is molten
Agent carries out affording gold oyster mushroom element E (4 milligrams), i.e., compound shown in Formula II.
3rd, the structural confirmation of compound
Gold oyster mushroom element A, its spectral data is as follows：
HRTOFMS (positive ion mode) m/z:[M+Na]+251.1047(calcd.for C15H16O2Na251.1043)；Its
Molecular formula is C15H16O2。1H-NMR (500MHz, methyl alcohol-d4):δ 7.51 (1H, d, J=8.1Hz, H-4), δ 7.30 (1H, s, H-
7), δ 7.12 (1H, d, J=8.1Hz, H-6), δ 6.94 (1H, m, H-9), δ 2.62 (3H, s, H-13), δ 2.50 (3H, s, H-
14),δ2.30(3H,s,H-11),δ2.05(3H,s,H-12)。13C-NMR (125MHz, methyl alcohol-d4):δ183.5(C-8),δ
157.8(C-10),δ154.3(C-7a),δ149.1(C-2),δ138.7(C-6),δ127.5(C-3a),δ124.9(C-5),δ
124.5(C-3),δ121.4(C-9),δ120.8(C-4),δ112.2(C-7),δ28.5(C-12),δ22.2(C-14),δ21.4
(C-11),δ9.9(C-13)。
Accordingly, determine shown in the structural formula such as formula (I) of gold oyster mushroom element A：
Gold oyster mushroom element E, its spectral data is as follows：
HRTOFMS (positive ion mode) m/z:[M+Na]+307.1516(calcd.for C15H24O5Na307.1516)；Its
Molecular formula is C15H24O5。1H-NMR (500MHz, methyl alcohol-d4):δ 6.65 (1H, s, H-9), δ 4.18 (1H, dd, J=8.2Hz, H-
7a), δ 3.23 (1H, d, J=8.2Hz, H-7), δ 2.30 (1H, m, H-3a), δ 2.22 (1H, m, H-3), δ 2.16 (3H, s, H-
11),δ2.04(1H,m,H-4a),δ1.98(3H,s,H-12),δ1.55(1H,m,H-4b),δ1.50(2H,m,H-5),δ1.21
(3H, s, H-14), δ 0.90 (3H, d, J=6.4Hz, H-13).13C-NMR (125MHz, methyl alcohol-d4):δ199.2(C-8),δ
160.7(C-10),δ120.0(C-9),δ106.9(C-2),δ84.6(C-7a),δ78.1(C-7),δ73.4(C-6),δ43.7
(C-3a),δ41.7(C-3),δ33.6(C-5),δ28.2(C-11),δ26.9(C-14),δ21.2(C-12),δ19.4(C-4),δ
11.7(C-13)。
Accordingly, determine the structural formula of gold oyster mushroom element E as shown in Formula II：
The absolute steric configuration of gold oyster mushroom element E passes through compound and Mo2(OAc)4The circular dichroism that chelating, parsing are determined is poor
Method (the bibliography of spectrum：Di Bari,et al..Determination of absolute configuration of
acyclic 1,2-diols with Mo2(OAc)4.1.Snatzke's method revisited.《The Journal of
organic chemistry》And Frelek, et al..Dinuclear transition .2001,4819-4825.
metal complexes as auxiliary chromophores in chiroptical studies on bioactive
compounds.《Current Organic Chemistry》.2003,1081-1104.) it is defined as 2S, 3S, 3aR, 6S, 7R,
7aS。
Embodiment 2, Protein tyrosine phosphatase 1B (PTP1B) inhibitory activity are determined
Test sample solution：Final concentration be respectively 100.0 μM, 50.0 μM, 25.0 μM, 12.5 μM of gold oyster mushroom element A it is molten
Liquid and gold oyster mushroom element E solution (after being dissolved in a small amount of DMSO, with distilled water diluting to respective concentration, control the final volume of DMSO
Fraction<0.1%).
The above test sample solution of 25 μ L various concentrations is taken, 175 μ L PBSs (50mM, pH 7.0) are added
And 25 μ L p-nitrophenol phosphate ester solutions (2mM；Solvent is to include 50mM citrates, 0.1M sodium chloride, 1mM ethylenediamines
The mixing cushioning liquid of tetraacethyl and 1mM dithiothreitol (DTT)s).Negative control：DMSO, positive control：Sodium vanadate.Mixed solution
Reaction temperature is 37 DEG C, and the reaction time is 30min.Reaction determines light absorption value after terminating at wavelength 405nm, counts as follows
Calculate the inhibiting rate to PTP1B activity of compound.Inhibiting rate=(experimental group light absorption value-negative control group light absorption value)/(control group
Light absorption value-negative control group extinction) × 100%.
To experimental data statistical analysis, IC is used50Software calculates the IC of each test sample50Value result is as shown in table 1.
The Activity determination result that the gold oyster mushroom of table 1 element A and gold oyster mushroom element E suppress to PTP1B
| Test sample | Gold oyster mushroom element A | Gold oyster mushroom element E |
| 32.10±1.42 | 30.50±2.01 |
Result of the test shows：Gold oyster mushroom element A and gold oyster mushroom element E show to show to protein tyrosine phosphatase 1B
The inhibitory action of work, with good anti-type ii diabetes potential applicability in clinical practice.
3, two hypoglycemic zooperies of noval chemical compound of embodiment
First, the structure of Rat Type II diabetes rat model
1st, experimental animal
Wistar male rats (purchased from Beijing experimental animal Co., Ltd of dimension tonneau China) 50 are taken, adaptability raises one
Week：18-25 DEG C of room temperature, humidity 50-60% in 12/12 hour light and shade cycle, freely ingests, drinks water；Give standard rat chow.
2nd, type ii diabetes rat model modeling experiment
Blank group：10 wistar male rats, give common standard rat chow.
Model group：40 wistar male rats, give high glucose and high fat feed.
After blank group and model group rats are fed into 4 weeks, fasting 8 hours took the measurement of rat tail vein blood in the 29th day
Fasting blood-glucose, and streptozotocin 45mg/kg body weight is injected intravenously, fed 72 hours after intravenous injection, fasting 8 hours, take big
Caudal vein blood surveys fasting blood-glucose.
Result shows, after injection streptozotocin, the fasting blood sugar of model group rats is 17.65 ± 0.76mmol/L, is shown
Write the 5.03 ± 0.79mmol/L (P ＜ 0.01) higher than blank group rat.And the situation of model group rats is not good enough, occur many
The diabetic symptoms such as drink, diuresis, many foods are bright, these results suggest that type ii diabetes rat model modeling success.
2nd, administration experiment
Administration experiment packet as shown in table 2, wherein, model group is randomly divided into 4 groups, what every group of 10 step one were successfully constructed
Type ii diabetes rat；Blank control group is 10 normal wistar male rats.
Table 2 is administered experiment packet and treatment
Note：Compound shown in Formulas I, compound shown in Formula II and Rosiglitazone are prepared as 0.5%CMC-Na suspensions.
Each group rat feeds corresponding feed, and gastric infusion under the conditions of, and once a day, successive administration one week takes each
The tail vein measurement fasting blood-glucose of group rat.
Result is as shown in table 3, it is seen then that gold oyster mushroom element A and gold oyster mushroom element E are respectively provided with significantly control type II diabetes mould
The effect of type rat blood sugar value.
The each group rat fasting blood-glucose value of table 3
Finally it should be noted that：Obviously, above-described embodiment is only intended to clearly illustrate example of the present invention, and simultaneously
The non-restriction to implementation method.For those of ordinary skill in the field, can also do on the basis of the above description
Go out the change or variation of other multi-forms.There is no need and unable to be exhaustive to all of implementation method.And thus drawn
Obvious change that Shen goes out or among changing still in protection scope of the present invention.
Claims (9)
1. the compound or pharmaceutically acceptable salt thereof as shown in formula I and formula II,
2. a kind of pharmaceutical composition for preparing PTP1B inhibitor, it is characterised in that at least one right containing effective dose
It is required that the compound or pharmaceutically acceptable salt thereof described in 1.
3. a kind of pharmaceutical composition for treating and/or preventing type II diabetes, it is characterised in that described pharmaceutical composition contains
There are the compound and/or its pharmaceutical salts at least one claim 1 of effective dose.
4. the pharmaceutical composition according to Claims 2 or 3, wherein described pharmaceutical composition include one or more pharmaceutically
Acceptable auxiliary material.
5. pharmaceutical composition according to claim 4, wherein described pharmaceutical composition are parenteral solution, tablet, pulvis, particle
Agent, pill, capsule, oral liquid, paste, creme or spray.
6. the purposes of compound as claimed in claim 1 and its pharmaceutical salts in the product for preparing PTP1B inhibitor.
7. compound as claimed in claim 1 and its pharmaceutical salts are preparing the product for the treatment of and/or prevention type II diabetes
Purposes.
8. purposes as claimed in claims 6 or 7, it is characterised in that the product is medicine or edible product.
9. purposes as claimed in claim 8, it is characterised in that the edible product is lozenge, capsule, drink or effervesce
Piece.
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