CN105816446B - Application of two kinds of halophenol compounds in preparing type II diabetes resisting nephrosis drug - Google Patents
Application of two kinds of halophenol compounds in preparing type II diabetes resisting nephrosis drug Download PDFInfo
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Abstract
The invention discloses two kinds of 4,5,2' trihydroxies 2 of halophenol compound, 5' dibromobenzo-phenones and 4, the new medical use of 5,2' tri- (4 morpholine formyloxy) 2,5' dichloro benzophenones is specially anti-in preparationApplication in patients with type Ⅰ DM nephrosis drug, while invention also discloses the drugs that more than one state the type II diabetes resisting nephrosis that two kinds of halophenol compounds are active constituent.Both compounds can effectively improveThe renal function of patients with type Ⅰ DM nephrotic rats, its primary treatment index uric acid, Urine proteins, microdose urine protein, growth conversioning factor TGF β 1, blood glucose, low-density lipoprotein etc. are better than clinical first-line drug captopril at present, it is shown that the important application prospect in terms for the treatment of diabetic nephropathy.
Description
Technical field
The invention belongs to compound new application fields, are related to two kinds of halophenols with prevention and treatment type-2 diabetes mellitus nephrosis
Compound, specially compound 4,4,5,2'- tri- (4- of 5,2'- trihydroxy -2,5'- dibromobenzo-phenones (LM49) and compound
Morpholine formyloxy) the application of -2,5'- dichloro benzophenones (A8) in preparing type II diabetes resisting nephrosis drug.
Background technology
Diabetic nephropathy (diabetic nephropathy, DN) is common one of the major complications of diabetes, finally
Lead to nephrosis (end-stage renal disease, ESRD).Existing 1.14 hundred million diabetics of China at present, 1.4 hundred million glycosurias
Sick patient's early period, with being continuously increased for the diabetic in global range, the illness rate of DN also improves therewith.In west state
Family DN is the primary cause of disease for leading to ESRD, accounts for the Etiological of 25%-42% and China ESRD.DN is in type-2 diabetes mellitus
Illness rate be about 20%-25%, DN can by initially there are Urine proteins to hypertension, nephrotic syndrome, eventually lead to renal failure and
It is dead.
Treatment DN mainly controls blood glucose, reduces blood fat, inhibits inflammation, anti-oxidation stress, at present clinical application at this stage
Mainly use angiotensin converting enzyme inhibitor/angiotensin receptor antagonist (ACEI/ARB), or even and antidiabetic drug
Drug combination, and the major function of ACEI/ARB is by reducing blood pressure and microdose urine protein, reducing glomerulus osmotic pressure, together
Shi Gaishan utilizes insulin.But to the patient after most DN patients, especially DN IV phases, using ACEI/ARB class medicines
It is after object to will appear electrolyte disturbance more, easily merge hyperkalemia, while having and causing the side effects such as dry cough, postural hypotension.
Therefore, it is clinically directed to drug of the disease not yet especially effectively with specificity at present, in view of the danger of DN, it is suitable to find
Medicine have become the hot research direction of the world of medicine instantly.
The pathogenesis of DN mainly has high sugar, renal blood flow dynamics exception, metabolism disorder of blood lipid, capilary inflammation, oxygen
Change stress and inherent cause etc..And halophenol compound 2', 4,5- trihydroxy -2,5'- dibromobenzo-phenones (LM49) and its can medicine
With salt and 2', (4- morpholines the formyloxy) -2,5'- dichloro benzophenones (A8) of 4,5- tri- and its officinal salt are that seminar is autonomous
Design synthesis, has the effects that very strong hypoglycemic, reducing blood lipid, anti-oxidant, anti-inflammatory.Its active diversity is especially the hair with DN
Interpretation of the cause, onset and process of an illness system is multiple to agree with, and has good development prospect.
But up to the present, for 4,5,2'- trihydroxy -2,5'- dibromobenzo-phenone of compound and compound 4,5,
The pharmacological action of the type II diabetes resisting nephrosis of 2'- tri- (4- morpholines formyloxy) -2,5'- dichloro benzophenones there is no both at home and abroad
Relevant report.
Invention content
The purpose of the present invention is to provide compound 4,5,2'- trihydroxy -2,5'- dibromobenzo-phenones (LM49) and chemical combination
Object 4,5, the new pharmacological use of 2'- tri- (4- morpholines formyloxy) -2,5'- dichloro benzophenones (A8), is specially preparing
Application in type II diabetes resisting nephrosis drug.
It is another object of the present invention to a kind of drug of new type II diabetes resisting nephrosis, the drug with compound 4,
5,2'- trihydroxy -2,5'- dibromobenzo-phenones or compound 4,5,2'- tri- (4- morpholines formyloxy) -2,5'- dichloros
Benzophenone is active constituent, and further includes the common pharmaceutical carrier used with the active ingredient combinations or tax in the drug
Shape agent.It is common that injection, tablet, pill, solid dispersions or capsule etc. can be made in the drug according to different requirements
Preparation.
System of the present invention find for the first time two kinds of halophenol compound 4,5,2'- trihydroxy -2,5'- dibromobenzo-phenones (LM49) and
4,5,2'- tri- (4- morpholines formyloxy) -2,5'- dichloro benzophenones (A8) have the medicine of significant type II diabetes resisting nephrosis
Reason activity, has good development and application values.
Wherein, the structural formula of compound 4,5,2'- trihydroxy -2,5'- dibromobenzo-phenones (LM49) is as follows：
The structural formula of compound 4,5,2'- tri- (4- morpholines formyloxy) -2,5'- dichloro benzophenones (A8) is as follows：
Tri- (the 4- of compound 4,5,2'- trihydroxy -2,5'- dibromobenzo-phenones (LM49) and compound 4,5,2'-
Morpholine formyloxy) -2,5'- dichloro benzophenones (A8) are all two kinds of halophenol compounds well-known to those skilled in the art,
Preparation method is also easy to implement.
The present invention gives consolidating for two kinds of compounds of various dose by establishing SD Rat Type II diabetic nephropathy models, gavage
During which body dispersion is monitored the relevant indices such as blood glucose, blood fat, urine volume, urine, renal function and inflammatory factor,
Confirm that two kinds of compounds have very strong Renoprotective Effect to II diabetic nephropathy rats, it is shown that in prevention and treatment glycosuria
Important application prospect in terms of sick nephrosis.
The main innovation point of the present invention is：(1) halophenol compound 4,5,2'- trihydroxies -2,5'- dibromobenzo-phenones
(LM49) and its officinal salt and (4- morpholines the formyloxy) -2,5'- dichloro benzophenones (A8) of 4,5,2'- tri- and its pharmaceutically acceptable
Salt is that applicant independently formulates, and has the effects that very strong hypoglycemic, reducing blood lipid, anti-oxidant, anti-inflammatory, active diversity and DN
Pathogenesis multiple agree with.To can effectively improve Type II diabetic nephropathy big with solid dispersions administration for (2) two kinds of compounds
The renal function of mouse is primary treatment index uric acid, Urine proteins, microdose urine protein, growth conversioning factor TGF-β 1, blood glucose, low
Density lipoprotein etc. is better than clinical first-line drug captopril at present.
Description of the drawings
Fig. 1 dyes for hematoxylin-eosin (HE), and under the microscope, each group rat kidney pathology compare (HE × 200) electricity；
Fig. 2 dyes for Masson, and under the microscope, each group rat kidney pathology compare (Masson × 400) electricity.
Specific implementation mode
Compound 4,5,2'- trihydroxy -2,5'- dibromobenzo-phenones and (the 4- morpholine methanoyls of compound 4,5,2'- tri-
Base) the application of -2,5'- dichloro benzophenones in preparing type II diabetes resisting nephrosis drug.
A kind of drug of type II diabetes resisting nephrosis, active constituent are 4,5,2'- trihydroxy -2,5'- dibromo of compound
Benzophenone or compound 4,5,2'- tri- (4- morpholines formyloxy) -2,5'- dichloro benzophenones.It is also wrapped in the drug
Include the common pharmaceutical carrier or excipient used with the active ingredient combinations.Injection can be made in the drug according to specific requirement
The common formulations such as agent, tablet, pill, solid dispersions or capsule.
Come that there is anti-type-2 diabetes mellitus to two kinds of halophenol compounds in the present invention below by way of specific EXPERIMENTAL EXAMPLE
The function of nephrosis is further elaborated, it should be noted that embodiment below is all illustrative, is not done to the present invention
Any restriction.
Material
Experimental animal：
Male SD rat, 180~220g of weight, animal origin：National Institute for Food and Drugs Control, credit number：
SCXK- (capital) 2014-0013, quality certification number：11400500008465, this experiment animal used and related disposition meet animal
The requirement of welfare, experiment will pass through the Ethic review of the mechanism animal welfare committee before carrying out.
Feed：
High glucose and high fat feed formula：10% lard, 20% sucrose, 2.5% cholesterol, 0.5% sodium taurocholate, 67% basis
Material.Feed resource：Beijing Australia of section pulls together feed corporation,Ltd, credit number：SCXK- (capital) 2014-0010, quality certification number：
11002900016120。
Drug and reagent：
LM49 (is prepared, purity >=99.5%, lot number 20150320) by the big experimental teaching of medicinal chemistry room of Shanxi medical courses in general；A8
(being prepared by the big experimental teaching of medicinal chemistry room of Shanxi medical courses in general, purity >=99.5%, lot number 20150112)；Polyvinylpyrrolidone
(PVP K30) (USP26, Jiangyin Jia Feng Chemical Co., Ltd.s)；Tween 80 (pharmaceutical grade, Sichuan Kingsoft pharmaceutical Co. Ltd)；Nothing
Water-ethanol (analyzes pure, Beijing chemical reagents corporation)；Captopril (Shanghai Xudong Hipu Medicine Co., Ltd, product batch number
140603)；Streptozotocin (Sigma, product batch number 1126C038)；- 1 β enzyme linked immunosorbent detection reagents of Rat Interleukin
Box (Nanjing is built up, lot number 1501261)；- 6 enzyme-linked immunologic detecting kit of Rat Interleukin (build up, lot number by Nanjing
1412271)；Rat microalbumin (Alb) enzyme-linked immunologic detecting kit (Nanjing is built up, lot number 1506201)；Rat is solvable
Property intercellular adhesion molecule (sICAM-1) detection kit (Nanjing is built up, lot number 1501201)；Rat tumor albus tumor necrosis factor
(TNF-α) enzyme-linked immunologic detecting kit (Nanjing is built up, lot number 1507281)；The white vascular cell adhesion molecule of rat
(sVCAM-1) enzyme-linked immunologic detecting kit (Nanjing is built up, lot number 1508221)；Total antioxidant capacity (T-AOC) kit
(Nanjing is built up, lot number 20151010)；BCA protein quantifications kit (doctor's moral biology, lot number 10K12B46)；Urea (BUN)
Kit (Shanghai Foxing Changzheng medical science Co., Ltd, lot number P1311021)；Uric acid (UA) kit (answers the star Long March in Shanghai
Medical science Co., Ltd, lot number PF1405011)；Creatinine (CREA) kit (answers the limited public affairs of star Long March medical science in Shanghai
Department, lot number D1404063)；Clinical chemistry integrates quality controlled serum (Shanghai Foxing Changzheng medical science Co., Ltd, lot number
842UN)；Malonaldehyde (MDA) testing cassete (Nanjing is built up, lot number 20150126)；Rat nuclear factor (NF- κ B) enzyme linked immunological
Kit (Nanjing is built up, lot number 1507251)；SOD kits (WST-1 methods, Nanjing are built up, lot number 20150127)；Masson
Dye liquor (Nanjing is built up, lot number 20150915).
Instrument：
Thermostat water bath (Shanghai and be in instrument manufacturing Co., Ltd)；BP-121S electronic balances (Shanghai precision scientific instrument
Company)；TU-1810 ultraviolet-uisible spectrophotometers (Beijing Puxi General Instrument Co., Ltd)；(U.S. is strong for blood glucose meter
It is raw)；Microplate reader (Rayto, RT-6100)；Low speed autobalancing centrifuge (Hebei province Anxin County Bai Yang centrifuges factory)；Ultralow temperature
Refrigerator (Haier)；30 automatic clinical chemistry analyzers (U.S. Thermo) of Konelab Prime.
The preparation of solid dispersions：
It is prepared using solvent method：It is 1 by the mass ratio of LM49, PVPK30, tween80:5:1 and A8, PVPK30,
The mass ratio of tween80 is 1:4:1, respectively precision weigh each medicine, with appropriate absolute ethyl alcohol dissolve, be stirred continuously it is uniformly mixed,
It is placed in evaporation in 60 DEG C of water-baths and removes absolute ethyl alcohol, obtain thick object, be placed in -20 DEG C of refrigerators and freeze 2h, taking-up is placed in true
Drying for 24 hours, 80 mesh sieve is crushed after embrittlement, is placed in drier and saves backup in empty drying box.
It is prepared by diabetic nephropathy animal model：
Chain urea is injected intraperitoneally in healthy adult male SD rat (180-220g) high glucose and high fat feed feeding 4 weeks, fasting overnight
Rhzomorph (STZ) 40mg/kg is helped, normally the sodium citrate buffer solution of group injection same volume, after 72h, fasting 12h surveys modeling rat
Fasting blood-glucose, continuous 3 fasting blood-glucoses>16.7mmol/L thinks Glycemia Decline success.Rat after modeling success, administration phase
Between continue feeding high lipid food, normal group feeds normal diet.
After being administered 6 weeks, 6h urine is collected with metabolic cage.
Overnight fasting, intraperitoneal anesthesia extract abdominal aorta blood examination and survey index of correlation.Kidney is cleaned with physiological saline, is recorded
Double kidney weights calculate Kidney coefficients (double kidney weight/weight).Longitudinal sectional same position nephridial tissue (including the glomerulus for taking left side kidney
And renal tubule) immerse in 10% neutral formalin and analyzed for Pathomorphology.Another part is detected for biochemical indicator, right
Side kidney is used for Mechanism Study, is stored in -80 DEG C of refrigerators.
Group and dose design：
After modeling success, in addition to normal group (10), other animals are randomly divided into 8 groups, every group 12.Be divided into model group,
LM49 solid dispersions low dose groups (content of dispersion 3mg/kg), LM49 solid dispersions middle dose group (content of dispersion 9mg/
Kg), LM49 solid dispersions high dose group (content of dispersion 27mg/kg), A8 solid dispersions low dose group (content of dispersion 3mg/
Kg), A8 solid dispersions middle dose group (content of dispersion 9mg/kg), A8 solid dispersions high dose group (content of dispersion 27mg/
Kg), captopril control group (content of dispersion 15mg/kg).
Medication：
Administration route：Gavage.
Administered volume：Normal group and model group give physiological saline 1.0ml/100g, positive control, LM49 solids point
The high, medium and low dosage group of granular media, the high, medium and low dosage group of A8 solid dispersions give the drug of various concentration, administered volume respectively
For 1.0ml/100g.
Drug is prepared：Solid dispersions physiological saline solution, positive control are suspended with 0.5%CMC-Na and are administered.
Administration time：Terminate to start to be administered in modeling.
Dosage rate：Weekly administration 7 days is administered 6 weeks altogether.
Statistical method：
With 20 softwares of IBM SPSS Statistics carry out data processing, data withIt indicates, each comparison among groups
Using one-way analysis of variance (ANOVA), according to homogeneity test of variance as a result, as variance uses LSD to examine together, such as heterogeneity of variance
It is examined using Dunnett's T3, with P<0.05 is statistically significant for difference.
As a result with analysis：
1, the influence of LM49, A8 to diabetic nephropathy function
Table 1 LM49, A8 to diabetic nephropathy function influence (N=6)
Note：Compared with normal note,##P<0.01,##P<0.05；Compared with model group,□□P<0.01,□P<0.05
Table 2 LM49, A8 to diabetic nephropathy rats uric acid and growth conversioning factor influence (N=6)
Note：Compared with normal note,##P<0.01,##P<0.05；Compared with model group,□□P<0.01,□P<0.05；With low dose
Amount group compares,▲▲P<0.01,▲P<0.05；Compared with middle dose group,○○P<0.01,○P<0.05；Compared with Kapp profit group,●●P<
0.01,●P<0.05
Table 3 LM49, A8 to Urine proteins and microalbumin in diabetic nephropathy rats urine influence (N=6)
Note：Compared with normal note,##P<0.01,##P<0.05；Compared with model group,□□P<0.01,□P<0.05；With low dose
Amount group compares,▲▲P<0.01,▲P<0.05；Compared with middle dose group,○○P<0.01,○P<0.05；Compared with Kapp profit group,●●P<
0.01,●P<0.05
2, the influence of LM49, A8 to blood glucose level in diabetic nephropathy rats serum
Table 4 LM49, A8 to blood glucose in diabetic nephropathy rats serum influence (N=6)
Note：Compared with normal note,##P<0.01,##P<0.05；Compared with model group,□□P<0.01,□P<0.05；With low dose
Amount group compares,▲▲P<0.01,▲P<0.05；Compared with middle dose group,○○P<0.01,○P<0.05；Compared with Kapp profit group,●●P<
0.01,●P<0.05
3, LM49, A8 are to diabetic nephropathy rats cholesterol in serum (TCHO), triglyceride (TG), high-density lipoprotein
(HDL-C), the influence of low-density lipoprotein (LDL-C) level
Table 5 LM49, A8 to cholesterol and triglyceride levels in clear in diabetic nephropathy rats serum influence (n
=6)
Note：Compared with normal note,##P<0.01,##P<0.05；Compared with model group,□□P<0.01,□P<0.05；With low dose
Amount group compares,▲▲P<0.01,▲P<0.05；Compared with middle dose group,○○P<0.01,○P<0.05；Compared with Kapp profit group,●●P<
0.01,●P<0.05
Table 6 LM49, A8 to HDL-C in diabetic nephropathy rats serum, the influences of LDL-C levels (N=6)
Note：Compared with normal note,##P<0.01,##P<0.05；Compared with model group,□□P<0.01,□P<0.05；With low dose
Amount group compares,▲▲P<0.01,▲P<0.05；Compared with middle dose group,○○P<0.01,○P<0.05；Compared with Kapp profit group,●●P<
0.01,●P<0.05
4, the influence of LM49, A8 to inflammatory factor in diabetic nephropathy tissue
Table 7 LM49, A8 are to inflammatory factor TNF-α in diabetic nephropathy tissue, NF- κ B and adhesion molecule ICAM-
1 influence (N=6)
Note：Compared with normal note,##P<0.01,##P<0.05；Compared with model group,□□P<0.01,□P<0.05；With low dose
Amount group compares,▲▲P<0.01,▲P<0.05；Compared with middle dose group,○○P<0.01,○P<0.05；Compared with Kapp profit group,●●P<
0.01,●P<0.05
Table 8 LM49, A8 are to inflammatory factor IL-1 β, IL-6 and adhesion molecule VCAM-1 in diabetic nephropathy tissue
Influence (N=6)
Note：Compared with normal note,##P<0.01,##P<0.05；Compared with model group,□□P<0.01,□P<0.05；With low dose
Amount group compares,▲▲P<0.01,▲P<0.05；Compared with middle dose group,○○P<0.01,○P<0.05；Compared with Kapp profit group,●●P<
0.01,●P<0.05
5, the influence of LM49, A8 to the diabetic nephropathy tissue oxygen factor
Table 9 LM49, A8 to the diabetic nephropathy tissue oxygen factor influence (N=6)
The studies above shows that LM49 has specific anti-Diabetic Nephropathy effect, can effectively mitigate nephridial tissue lesion, energy
Significantly reduce growth turn in uric acid, blood glucose, cholesterol, triglyceride, low-density lipoprotein white level and nephridial tissue in rat blood serum
Change the factor, Urine proteins and Microalbuminuria, significantly inhibits the inflammation such as TNF-α in nephridial tissue, NF- κ B, IL-6, IL-1 β
The expression of the factor reduces renal tubule water sample lesion, glomerulus Fibrosis levels.The above results also indicate that simultaneously, and LM49 has very strong
Anti- Diabetic Nephropathy effect, primary treatment index uric acid, Urine proteins, microdose urine protein, growth conversioning factor
TGF-β 1, blood glucose, low-density lipoprotein etc. are better than clinical first-line drug captopril at present, it is shown that important application prospect.
A8 has stronger anti-Diabetic Nephropathy effect, can effectively mitigate nephridial tissue lesion, can significantly reduce rat serum
Conversion is grown in clear in uric acid, glycosylated hemoglobin, blood glucose, cholesterol, triglyceride, low-density lipoprotein white level and nephridial tissue
The factor, Urine proteins and Microalbuminuria, significantly inhibit the inflammation such as TNF-α in nephridial tissue, NF- κ B, IL-6, IL-1 β because
The expression of son reduces renal tubule water sample lesion, glomerulus Fibrosis levels.It is very strong anti-big to show that A8 has for the above results simultaneously
Mouse diabetic nephropathy acts on, primary treatment index renal index, uric acid, Urine proteins, microdose urine protein, growth conversioning factor
TGF-β 1, blood glucose, low-density lipoprotein etc. are substantially better than clinical first-line drug captopril at present, it is shown that before important application
Scape.
Conclusion：
It can illustrate that compound L M49 and A8 have the function of specific type II diabetes resisting nephrosis by above-mentioned experiment.Especially
It is that high dose group effect is more notable, and compound A-28 ratio LM49 has higher type II diabetes resisting nephrosis activity, it is shown that very
Good application and development foreground.
Claims (4)
1. compound 4,5,2'- trihydroxy -2,5'- dibromobenzo-phenones or compound 4,5,2'- tri- (4- morpholines formyloxy) -
Application of the 2,5'- dichloro benzophenones in preparing type II diabetes resisting nephrosis drug.
2. the drug of type II diabetes resisting nephrosis, it is characterised in that：The active constituent of the drug is compound 4,5,2'- tri-
(4- morpholines formyloxy) -2,5'- dichloro benzophenones.
3. the drug of type II diabetes resisting nephrosis according to claim 2, it is characterised in that：Further include in the drug and institute
State the common pharmaceutical carrier or excipient that active ingredient combinations use.
4. the drug of type II diabetes resisting nephrosis according to claim 2 or 3, it is characterised in that：The drug is injection
Agent, tablet, pill, solid dispersions or capsule.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
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| CN201610278158.4A CN105816446B (en) | 2016-04-29 | 2016-04-29 | Application of two kinds of halophenol compounds in preparing type II diabetes resisting nephrosis drug |
| US16/097,348 US20190133968A1 (en) | 2016-04-29 | 2017-04-27 | Applications of benzophenones in preparation of drug |
| PCT/CN2017/082173 WO2017186141A1 (en) | 2016-04-29 | 2017-04-27 | Use of benzophenone compound in pharmaceuticals |
| JP2019507980A JP6698214B2 (en) | 2016-04-29 | 2017-04-27 | Use of benzophenone compounds in the pharmaceutical field |
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| CN201610278158.4A CN105816446B (en) | 2016-04-29 | 2016-04-29 | Application of two kinds of halophenol compounds in preparing type II diabetes resisting nephrosis drug |
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| CN107007610B (en) * | 2017-04-25 | 2021-03-02 | 山西医科大学 | Application of benzophenone compound in pharmacy |
| CN113274374A (en) * | 2021-04-29 | 2021-08-20 | 广西医科大学 | Medicine for resisting diabetic nephropathy and application |
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| CN103169666A (en) * | 2012-12-24 | 2013-06-26 | 山西医科大学 | Preparation method and application of halide phenolic compound solid dispersion |
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Application publication date: 20160803 Assignee: Shanxi Medical University Asset Management Co., Ltd Assignor: Shanxi Medial University Contract record no.: X2019980000611 Denomination of invention: Application of two halophenol compounds in preparation of medicines of resisting type II diabetic nephropathy Granted publication date: 20181002 License type: Common License Record date: 20191115 |
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