CN105030761B - The new application of elbow aspergillus chlorins compound - Google Patents

Abstract

The invention belongs to field of pharmaceutical chemistry technology, relate in particular to the application of elbow aspergillus chlorins compound or its pharmaceutical composition in the medicine of relevant disease of prevention and/or treatment albumen matter tyrosine phosphatase (PTP) mediation is prepared, the especially application in the disease medicaments such as treatment obesity, diabetes are prepared.

Description

The new application of elbow aspergillus chlorins compound

Technical field

The invention belongs to medicinal chemistry art, the new medical use of elbow aspergillus chlorins compound is related in particular to.

Background technology

Protein tyrosine phosphatase (Protein-tyrosine phosphatase, PTP) is in cellular signal transduction With important effect, they controlled by adjusting the phosphorylation level of intracellular protein tyrosine the growth of cell, differentiation, Metabolism；Cell migration, genetic transcription, ion channel opening and closing, immune response, Apoptosis and Osteogenic developmental are also regulated and controled. The disorder of protein tyrosine phosphatase can cause a variety of diseases, such as diabetes, obesity and osteoporosis (Desai, et al.,1996,Cell,84:599-609；Kishihara et al.,1993,Cell,74:143-156；Hardy S,et al.,Anticaner Agents Med Chem 2011,Jun 27.)。

Protein tyrosine phosphatase is an extended familys, can be divided into transmembrane receptor type in location in the cell by it With intracellular non-receptor type.Current result of study proves that wherein PTP1B, SHP2 and insulin signaling pathway relation is the closest. The 1B of Protein-tyrosine-phosphatase one (Protein tyrosine Phosphatase 1B, PTP1B) is wide expression in vivo Intracellular protein tyrosine phosphatase, by PTPN1 gene codes (Brown-Shimer S., et al., Proc Nat Acad Sci,1990,87:5148-5152).Protein-tyrosine-phosphatase SHP2 [Src homology 2 (SH2) domain Containing phosphotyrosine-phosphatase 2, SHP2] be one kind in PTPN11 gene codes, cytoplasm The non-receptor type Protein-tyrosine-phosphatase of wide expression.SHP2 molecular structures include two Src homologous regions of N-terminal, one, middle part Tyrosine phosphatase (ester) enzymatic activity region, C-terminal one include multiple Tyr phosphorylation sites and a Pro-rich Motif Region [Neel B.G., et al., Trends the Biochem Sci, 2003,28 (6) of tail:284-293].

Insulin (Insulin) with the α subunits of insulin receptor (Insulin receptor, IR) by combining, activation In acceptor intracellular β subunits tyrosine kinase activity, so as to cause tyrosine to participate in the phosphorylation of itself.And the pancreas being activated Island element receptor tyrosine kinase again by phosphorylated insulin receptor substrate (Insulin receptor substrate, IRS), So as to which insulin signaling be handed on.The main cause of insulin resistance is blocking or the decrease of insulin signaling pathway.Grind Study carefully discovery PTP1B and pass through the phosphorus to insulin receptor kinase (insulin receptor kinase, IRK) or IRK active fragments Phosphorylated tyrosine residue dephosphorylation, negative regulator is carried out to insulin signal transduction.The C- that PTPlB passes through catalytically inactive Terminal domains are connected with endoplasmic reticulum, compared with other PTPase, have it is higher remove IR β and IRS phosphorylation activities, so as to suppress The formation of IRS and PI3K P85 subunit compounds and Akt, MAPK phosphorylation level, and insulin-induced glycogen conjunction Into being suppressed, therefore, multiple sites that PTPlB can be in insulin signaling cascade play negative regulation effect.Over-express PTPlB Insulin receptor dephosphorylation can be increased, signal after acceptor is lowered；On the contrary, suppressing the PTPlB of acceptor one combinations, PTPlB fixed point Insulin signaling can be strengthened by being mutated and give the experimental method of inhibiting antibody.[Elchebly M.,et al., Science 1999,283:1544-1548.]。

Prior research has shown that the basic metabolism level and overall energy consumption of PTP1B knock out mice are raised, body Mitigate again, insulin sensitivity enhancing [Klaman L.D., et al.Molecular and Cellular Biology, 20 (15),5479-5489].[Tonks N.K., et al., the Mol Cell Biol, 1990,10 such as Tonks:458-463] reality Test and show, the effect of insulin has been blocked to xenopus oocyte microinjection PTPlB.The research of nearest gene knock-out mice model is Specific regulatory control that PTPlB is insulin action is fully demonstrated, PTPlB can influence the regulation of body weight and energy expenditure. Elchebly etc. reports that PTPlB clpp gene deratization is healthy in phenotype, while there is relatively low Fasting insulin and blood glucose Level, blood glucose such as is decreased obviously at the increased performance of insulin sensitivity in insulin tolerance tests, and this enhancement effect has Specific in a organized way, it can increase intake of the skeletal muscle to glucose, but adipose tissue is had no significant effect.It is more exciting , it is not in fat or increased weight in High-fat diet to knock out mouse, and IR exacerbation [Elchebly does not occur yet M.,et al.,Science 1999,283:1544-1548].This result of study proposes a possibility：Suppress PTPlB Two subject matters of metabolic syndrome, Impaired Glucose Tolerance Treated and obesity are can effectively solve the problem that, PTPlB is research and development anti-diabetic One important novel targets of medicine.

Protein tyrosine phosphatase SHP-1 (SH2-containing tyrosine phosphatase 1, SHP-1), It is the intracellular non-receptor type tyrosine phosphatase containing SH2 domains.SHP-1 expression quantity in some hematopoietic cells is higher, and Play down regulation during hematopoietic cell signal transduction, such as JAK-STATs paths [Yajun Han, et al., Blood, 2006Vol.108,2796-2803]；In the last few years, studies have found that SHP-1 also has effect [Dubois in terms of blood glucose is controlled MJ, et al., Nat Med, 2006, Vol.12,549-556], it can be by adjusting the insulin signaling in liver and muscle Path, and liver insulin clearance, maintain blood sugar concentration stabilization.There are some researches show congenital functional deficiency SHP-1 Mouse, compared with wild-type mice, the insulin signaling pathway in its liver and muscle is strengthened, and with obvious Glucose-tolerant and insulin sensitivity [Witkiewicz A, et al., Hum Pathol, 2007,38 (3):462- 7]).Therefore, the enhancing of SHP-1 activity is to cause one of major reason of diabetes B, regard SHP-1 as 2 type glycosurias for the treatment of The drug targets albumen of disease and insulin resistance has broad application prospects.

Macrophage protein tyrosine phosphatase 2 (MEG2), is initially out of, people macrophage MEG-01 and umbilical vein Clone, and therefore gain the name in the cDNA library of chrotoplast.MEG2 is expressed in various kinds of cell, in human brain, pancreas, leucocyte, huge Higher [Kruger JM, et al., the J Biol Chem.2002Jan 25 of expression quantity in phagocyte etc.；277(4):2620-8； Wang X,et al.,J Immunol,2002,168(9):4612-9].Cho CY etc. have found that MEG2 is insulin-dependent The regulatory factor of FOXO1 Subcellular Localizations, unconventionality expression of the gene in cell can suppress insulin-induced insulin by Body phosphorylation, so as to suppress the signal path of insulin.Make MEG2 expression reductions using RNAi technology, can substantially increase insulin Effect so that diabetic mice is improved [Cho CY, Cell Metab, 2006,3 (5) to the tolerance of diabetes: 367-78].MEG2 inhibitor is proved to effect [Zhang S, et al., the J Am with potential anti-type ii diabetes Chem Soc,2012,134(43):18116-24]。

Diabetes (diabetes mellitus) be one kind as caused by interacting h and E, with hyperglycaemia, The clinical syndrome that insulin resistance is characterized.Diabetes be because insulin secretion definitely or quite deficiency and target tissue cell To insulin sensitivity reduction, cause a series of disease of metabolic disorders such as sugar, albumen, fat, water and electrolyte.Hyperglycaemia is The clinical outstanding feature of diabetes, but prolonged illness can cause the infringement of multiple systems.Due to high premature coronary heart disease in diabetic population, lack The serious complication such as iron or hemorrhagic angiosis, blindness, acra ring subcutaneous ulcer, so diabetes are with very high fatal rate and cause Residual rate.According to IDF's issue in 2012《Diabetes map》Estimation, diabetes number of patients in 2012 is 3.71 Hundred million, wherein death toll is 4,800,000.Latest data shows that diabetes ascendant trend is still continuing.By the end of 2013 end of the years, 5,100,000 people die from diabetic complication altogether.And occupy the 4th of world today's cause of death, seriously endanger the strong of the mankind Health.Diabetes mellitus in China number is more than 100,000,000, and with the problem of lifestyle change and aging and in quick ascendant trend. In addition, according to World Health Organization's data in 2012, whole world obesity number surpassed 500,000,000, the fat and fat relevant disease brought Turn into the great hygiene and health problem that the whole world faces already.

Generally diabetes are divided into two classes, type i diabetes (insulin dependent diabetes, IDDM) and type ii diabetes at present (Non-Insulin Dependent Diabetes Mellitus, NIDDM).The cause of disease of type i diabetes is that islet cells is destroyed, so as to cause insulin Definitely not enough, patient has to rely on insulin and sustained life；And type ii diabetes reason is complicated, be due to insulin relatively not Caused by foot or insulin resistance.90% above is II types in diabetes.So the therapeutic strategy of type ii diabetes medicine is to increase Plus insulin secretion and insulin sensitivity enhancing.

In a word, verified Protein-tyrosine-phosphatase mediates the occurrence and development of a variety of diseases to substantial amounts of result of study, Inhibitors of protein tyrosine phosphatase has the medicine effect of fat prevention and treatment, diabetes and related complication.Albumen Tyrosine phosphatase is as target spot [Darry A.J., the Future Med of the drug researches such as new anti-diabetic, obesity Chem,2010,2(10):1563-1576]。

Elbow aspergin belongs to thermophilic azone class (azaphilones) compound containing vinylogy γ-pyridine ketone skeleton, is true The polyketone class secondary metabolite in bacterium source, gains the name because being isolated from Aspergillus deflectus (Aspergillus deflectus).Anke H etc. report elbow aspergin 1a, 1b, 1c, 2a, 2b there is antibacterium, antimycotic and mouse ascites knurl inhibitory action [Anke H, et al.J Antibiot,1981,34(8):923-928]；The report such as Musso L, elbow aspergin 1a, 1b, 2a, 2b is to warm Shock protein 90 (HSP90) has very weak inhibitory activity (to Hsp90-ATPase inhibitory activity IC₅₀More than 50 μM, Hsp90 is tied Close IC₅₀More than 100 μM), elbow aspergin 1b is on human oophoroma cell line IGROV-1, human melanoma cell strain JR8, people Skin cancer cell strain A431 has certain inhibitory activity, IC₅₀About 26 μM (Musso L, et al.Bioorg Med Chem, 2010,18:6031-6043).Up to now, do not find that the compounds of this invention has prevention and/or treatment obesity, diabetes The report of effect.

The content of the invention

The invention aims to provide the new medical use of elbow aspergillus chlorins compound.

The present inventor has found through numerous studies, structure such as following formula elbow aspergillus chlorins compound

Wherein R is n-C₇H₁₅、n-C₉H₁₉、CH(CH₃)(C₈H₁₇)、n-C₁₁H₂₃Or CH (CH₃)(C₁₀H₂₁) in it is any one Kind, with good protein tyrosine phosphatase inhibitory activity, therefore, can as protein tyrosine phosphatase inhibitors, For the relevant disease prevented and/or treatment albumen matter tyrosine phosphatase is mediated, particularly fat, diabetes.

Therefore, the present invention, which completes foregoing elbow aspergillus chlorins compound, is preparing prevention and/or treatment albumen matter junket ammonia Application in the relevant disease medicine of acid phosphoric acid enzyme mediation.

Application of the compound in prevention and/or treatment antiobesity agents is prepared.

Application of the compound in prevention and/or treatment diabetes medicament is prepared, is especially preparing prevention and/or is controlling Treat the application in type II diabetes medicine.

Application of the compound in the other diseases or illness of the mediation for the treatment of albumen tyrosine phosphatase are prepared.

It is simultaneously active component there is provided any one compound in the compound, is carried with pharmaceutically acceptable The pharmaceutical composition of body, auxiliary material or excipient composition.

When being related to above-mentioned medical usage, according to the common knowledge of those skilled in the art, elbow of the present invention is not only Aspergillus chlorins compound in itself, its pharmaceutically acceptable salt, isomers, ester or pro-drug can be provided with it is same or Close medical usage.Above-mentioned pharmaceutically acceptable salt includes sodium, potassium, calcium salt, and amine salt；The amine includes ammonia, alkyl Amine, aniline and amino acid；The amino acid includes arginine, lysine.Above-mentioned pharmaceutically acceptable salt can also form molten Agent compound, and with same or close medical usage；The solvate includes hydrate, alcohol adduct.Aforementioned prodrugs Elbow aspergillus chlorins compound of the present invention can be discharged after metabolic alterations in vivo.

The medical usage of elbow aspergillus chlorins compound of the present invention, is specifically realized by the following method：

Pharmaceutical composition is conventionally prepared, it includes above-mentioned elbow aspergillus chlorins compound and pharmaceutical acceptable carrier. Wherein, the weight/mass percentage composition of the elbow aspergillus chlorins compound is 0.1-99%, preferably 5-75%.The pharmaceutical composition is pressed It is different according to method of administration, oral formulations can be divided into, sublingual or cheek drug-delivery preparation, suction preparation, injection, rectally preparation, Percutaneous drug administration preparation etc..Wherein, preferred oral formulations.

When preparing oral formulations, the content of the chlorins compound of elbow aspergillus described in unit dosage forms is 1-500mg, preferably 1-250mg.Selectable formulation includes tablet, pill, lozenge, capsule, liquid, gel, syrup, slurries, suspension etc..Its In, preferred tablet, capsule.Pharmaceutical acceptable carrier includes lactose, sucrose, mannitol, starch, gelatin, bassora gum, Methyl cellulose It is element, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, alginic acid, mosanom, talcum powder, hard Fatty acid magnesium, superfine silica gel powder, fat oil, atoleine, liquid macrogol etc..

When preparing sublingual or cheek drug-delivery preparation, the form of tablet or dragee can be taken, is conventionally prepared.

When preparing suction preparation, the form of pressurised aerosol can be taken.Suitable propellant includes dichlorodifluoro first Alkane, trichlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide.Pharmaceutical acceptable carrier includes lactose, starch.

When preparing injection, the content of the chlorins compound of elbow aspergillus described in unit dosage forms is 0.1-100mg, preferably 0.1-25mg.Selectable formulation includes oleo-injection, water type injection or freeze drying powder injection.Pharmaceutical acceptable carrier includes fat Oil, ethyl oleate, triglycerides, liposome, sodium carboxymethylcellulose, glucan, PVPP, agar, algae Acid, mosanom.

When preparing rectally preparation, the form of suppository or enema can be taken.Pharmaceutical acceptable carrier include cocoa butter, Glyceride.

When preparing percutaneous drug administration preparation, the form of patch can be taken.Pharmaceutical acceptable carrier includes Sodium Polyacrylate, poly- third Olefin(e) acid ester, polyvinylpyrrolidone, polyethylene glycol.

Aforementioned pharmaceutical compositions are in use, dose therapeutically effective should be reached, and according to the property of disease, the year of patient Age, body weight carry out Reasonable adjustment.Generally, the dosage of the elbow aspergillus chlorins compound is 0.01-100mg/kg body weight, Preferably 0.1-10mg/kg body weight, more preferably 1-5mg/kg body weight.Dosage and frequency should finally be determined by doctor.

Embodiment

Present disclosure is further illustrated with specific embodiment below, but is not meaned in any way to this hair It is bright to be limited.Method therefor is conventional method unless otherwise instructed in the following example.

The specifications and models of part raw material involved by the following example are as follows：

NMR：Bruker Avance 500, TMS is internal standard

High-pressure liquid phase system (analysis)：Waters companies, 2 515 type pumps, 996 detectors

High-pressure liquid phase system (preparation)：Waters companies, 600 type pumps, 2487 detectors

ELIASA：Perkin Elmer companies Victor2 1420Multilabel Counter

Analytic type chromatographic column：Chromasil ODS column(4.6×250mm,10μm)

Prepare chromatographic column：Phenomenex ODS column(21.2×250mm,10μm)

Hplc grade methanol and acetonitrile are purchased from Merck companies of Germany, and other reagents are that analysis is pure, purchased from Beijing chemical reagent Factory.

The preparation of embodiment 1, elbow aspergillus chlorins compound

Curved cephamycin-type compound of the present invention passes through Aspergillus deflectus (Aspergillus deflectus) Prepared by NCC0415 fermentations, Aspergillus deflectus (Aspergillus deflectus) the bacterial strain NCC0415 has been deposited in Chinese micro- life Thing culture presevation administration committee common micro-organisms center, preservation date on April 25th, 2014, deposit number is CGMCC No.9095, preservation address is：Ke Yuan institutes of microbiology of Yard 1, BeiChen xi Road, Chaoyang District, Beijing City 3 China.

(a) Aspergillus deflectus (Aspergillus deflectus) NCC0415 seed liquor is prepared

Aspergillus deflectus (Aspergillus deflectus) fungi NCC0415 is inoculated in seed culture medium, 25, turned Fast 200rpm cultures 72h obtains seed liquor.The preparation method of seed culture medium is：20.0 grams of cornstarch, 10.0 grams of glucose, 4.0 grams of hot moulding soybean cake powder, 6.0 grams of malt flour, 3.0 grams of dusty yeast, 2.0 grams of sodium chloride, 1.0 grams of epsom salt, plus originally Water dissolving is settled to 1000ml, pH value 6.5-7.0,121 sterilizing 30min.

(b) Aspergillus deflectus (Aspergillus deflectus) NCC0415 solid fermentation product is prepared

Seed liquor is inoculated in the 750mL triangular flasks equipped with 100 grams of solid rice fermentation culture mediums with 5% inoculum concentration In, 25, quiescent culture 14 days.The preparation method of fermentation medium is：Rice presses 4 with water:1 ratio is well mixed, during immersion Between 3-10 hours.Then hot moulding soybean cake powder is added by the 2.5% of gross weight, is sub-packed in after being well mixed in 750mL triangular flasks, often Bottled 100 grams of amount, plug, sterilize at 121 DEG C 30min；

(c) preparation of elbow aspergillus chlorins compound

Fungi NCC0415 rice fermentation product 4kg, add industrial ethyl acetate 8L and extract, stir, soak 2 hours, Filtering.It is repeated once.Merge acetic acid ethyl acetate extract, plus anhydrous sodium sulfate drying twice.Filtering, filtrate decompression, which is evaporated, to be carried Take medicinal extract 125g.

NCC0415 extracts medicinal extract 125g and adds 625ml petroleum ethers, stirs, and -4 DEG C stand 2 hours, split-phase.Lower floor consolidates Body phase 32g is dry extract A；Upper strata petroleum ether phase vacuum distillation to no liquid is steamed, and remaining -4 DEG C of grease is stood overnight, and is discarded Upper oil phase.Precipitated again with a small amount of petroleum ether, discard washing clear liquid, volatilize to obtain precipitate B 1.7g.

Precipitate B is dissolved with DMSO, HPLC preparations is carried out after 0.45um membrane filtrations, the aqueous solution of 88% acetonitrile is flowing Phase；Flow velocity 18ml/min；UV detector Detection wavelengths are set to 254nm.Chromatographic peak is collected successively, and evaporated under reduced pressure is obtained respectively： NCC0415-C1 (15mg, RT：4min), NCC0415-C3 (110mg, RT：6min), NCC0415-C5 (120mg, RT： 7.4min), NCC0415-C7 (9mg, RT：9.8min), NCC0415-C8 (28mg, RT：12.4min).

The chemical constitution of the above-mentioned each compound of gained, physicochemical property and nuclear magnetic data are as follows：

(1) NCC0415-C1 (also known as elbow aspergin 1a)：

Yellow crystalline powder, molecular formula：C₂₁H₂₄O₅,¹H NMR(500MHz,CDCl₃)δ8.77(s,1H),6.09(s, 1H), 5.28 (s, 1H), 3.15 (ddd, 1H), 2.82 (ddd, 1H), 2.21 (s, 3H), 1.68 (s, 3H), 1.52~1.68 (m, 2H),0.87(t,3H)；¹³C NMR(125MHz,CDCl₃)δ197.25,190.31,168.08,165.18,158.71, 153.28,144.11,123.63,111.14,108.40,104.93,87.62,42.13,31.65,29.07,28.98, 26.16,23.43,22.59,19.41,14.07。

(2) NCC0415-C3 (also known as elbow aspergin 1b)：

Yellow crystalline powder, molecular formula：C₂₃H₂₈O₅,¹H NMR(500MHz,CDCl₃)δ8.77(s,1H),6.09(s, 1H), 5.28 (s, 1H), 3.15 (ddd, 1H), 2.83 (ddd, 1H), 2.21 (s, 3H), 1.68 (s, 3H), 1.52~1.68 (m, 2H), 1.19~1.35 (m, 12H), 0.87 (t, 3H)；¹³C NMR(125MHz,CDCl3)δ197.25,190.30,168.08, 165.17,158.69,153.28,144.09,123.63,111.14,108.40,104.94,87.61,42.14,31.86, 29.42,29.42,29.24,29.03,26.17,23.43,22.66,19.41,14.11。

(3) NCC0415-C5 (also known as elbow aspergin 2a)：

Yellow crystalline powder, molecular formula：C₂₄H₃₀O₅,¹H NMR(500MHz,CDCl₃)δ8.71(s,1H),6.08(s, 1H), 5.27 (s, 1H), 3.57 (m, 1H), 2.20 (s, 3H), 1.77 (m, 1H), 1.67 (s, 3H), 1.19~1.38 (m, 12H), 0.98(d,3H),0.86(t,3H)；¹³C NMR(126MHz,CDCl₃)δ201.03,190.27,167.80,165.95, 158.69,153.04,144.14,123.28,111.13,108.40,104.90,87.53,43.48,32.01,31.84, 29.76,29.45,29.23,27.17,26.16,22.63,19.37,16.72,14.07。

(4) NCC0415-C7 (also known as elbow aspergin 1c)：

Yellow crystalline powder, molecular formula：C₂₅H₃₂O₅,¹H NMR(500MHz,CDCl₃)δ8.77(s,1H),6.09(s, 1H), 5.28 (s, 1H), 3.14 (ddd, 1H), 2.84 (ddd, 1H), 2.20 (s, 3H), 1.68 (s, 3H), 1.52~1.68 (m, 2H), 1.19~1.35 (m, 16H), 0.87 (t, 3H)¹³C NMR(125MHz,CDCl₃)δ197.23,190.32,168.06, 165.17,158.69,153.28,144.10,123.59,111.10,108.39,104.89,87.60,42.13,31.89, 29.60,29.58,29.45,29.41,29.32,29.00,26.17,23.38,22.68,19.42,14.13.

(5) NCC0415-C8 (also known as elbow aspergin 2b)：

Yellow crystalline powder, molecular formula：C₂₆H₃₄O₅,¹H NMR(500MHz,CDCl₃)δ8.73(s,1H),6.10(s, 1H), 5.28 (s, 1H), 3.59 (m, 1H), 2.21 (s, 3H), 1.78 (m, 1H), 1.69 (s, 3H), 1.19~1.38 (m, 16H), 0.99(d,3H),0.88(t,3H)；¹³C NMR(126MHz,CDCl₃)δ201.06,190.34,167.82,166.01, 158.72,153.09,144.20,123.27,111.13,108.43,104.89,87.55,43.49,32.02,31.89, 29.79,29.61,29.60,29.53,29.33,27.19,26.20,22.68,19.42,16.76,14.12。

Embodiment 2 MEG2, SHP1, SHP2 and PTP1B inhibitory activity are determined

MEG2, SHP1, SHP2 and PTP1B are using gene engineering method after expression in escherichia coli, through affine layer Recombinant human protein's matter tyrosine phosphatase that analysis purifying is obtained.

The assay method of inhibitory activity is as follows：It is added to after elbow aspergin class diluted chemical compound prepared by embodiment 3 In 96 orifice plates, and it is separately added into every reaction buffers of the μ l containing any zymoprotein of MEG2, SHP1, SHP2 or PTP1B of hole 100, room After the lower incubation of temperature 15 minutes, the buffer solution of 100 μ l 4-NPPs containing 5mM (pNPP) reaction substrates is added.37 DEG C anti- 30min, plus 0.2M NaOH terminating reactions should be incubated, the light absorbs determined with ELIASA under 405nm change.

Inhibiting rate is calculated as follows：

Inhibiting rate=(1- experimental groups absorbance values/blank control group absorbance values) × 100%.

The evaluation criterion of inhibitory activity：

IC₅₀Value is the elbow aspergin class compound concentration (μ g/ml) when inhibiting rate is 50%

The inhibitory activity of the elbow aspergillus chlorins compound is as shown in table 1.

Table 1

Sequence number

Compound number

Compound name

MEG2

SHP1

SHP2

PTP1B

1	NCC0415-C1	Elbow aspergin 1a	1.3	6.6	15.6	7.2
							2	NCC0415-C3	Elbow aspergin 1b	1.9	6.5	18.9	7.2
3	NCC0415-C5	Elbow aspergin 2a	0.8	3.2	6.4	1.2
							4	NCC0415-C7	Elbow aspergin 1c	0.2	0.9	8.2	1.6
5	NCC0415-C8	Elbow aspergin 2b	0.3	2.8	6.6	1.2

The above results show that elbow aspergillus chlorins compound prepared by the present invention has significant PTP inhibitory activity, can use Prevent or the disease mediated medicines for the treatment of PTP in preparing.

Embodiment 3 has the preparation of the pharmaceutical composition of PTP inhibitory action

The elbow aspergillus chlorins compound of the preparation of 10g embodiments 1 is weighed, sucrose 50g, dextrin 100g is added, added after mixing Wet granular is made in ethanol, dries, and adds superfine silica gel powder 2g, mixes again, loads capsule shells, is made with PTP inhibitory action Medicine 500.

Using compound of the present invention as active component, prepare, can be prepared into each according to methods known in the art Clinical required preparation is planted, this is no longer going to repeat them.

Claims (2)

1. structure such as formula（1）Shown elbow aspergillus chlorins compound or the pharmaceutical composition containing such compound are being prepared in advance Application in the medicine of the disease of anti-or treatment albumen matter tyrosine phosphatase mediation,

Formula（1）

Wherein R is n-C₇H₁₅、n-C₉H₁₉、CH(CH₃) (C₈H₁₇)、n-C₁₁H₂₃Or CH (CH₃) (C₁₀H₂₁) in any one, its The disease that middle protein tyrosine phosphatase is mediated is diabetes.

2. structure such as formula（1）Shown elbow aspergillus chlorins compound or the pharmaceutical composition containing such compound are being prepared in advance Application in the medicine of the disease of anti-or treatment albumen matter tyrosine phosphatase mediation,

Formula（1）

Wherein R is n-C₇H₁₅、n-C₉H₁₉、CH(CH₃) (C₈H₁₇)、n-C₁₁H₂₃Or CH (CH₃) (C₁₀H₂₁) in any one, its The disease that middle protein tyrosine phosphatase is mediated is obesity.