CN102309489B - Medicine for treating diabetic nephropathy - Google Patents
Medicine for treating diabetic nephropathy Download PDFInfo
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- CN102309489B CN102309489B CN201110240738A CN201110240738A CN102309489B CN 102309489 B CN102309489 B CN 102309489B CN 201110240738 A CN201110240738 A CN 201110240738A CN 201110240738 A CN201110240738 A CN 201110240738A CN 102309489 B CN102309489 B CN 102309489B
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Abstract
The invention discloses tetrahydropyridine and an application of a derivative thereof, concretely relates to an application of tetrahydropyridine and the derivative thereof in the preparation of the medicine for treating diabetic nephropathy, wherein the tetrahydropyridine derivative comprises 1,4,5,6-tetrahydro-2-methyl-5-hydroxy-4-pyrimidine carboxylic acid. The effect of oral administration is good, and the scope of dosage is 0.01-100mg/kg. Both of tetrahydropyridine and the derivative thereof have good security and effectiveness, 1-50mg/kg of administration dosage can performance the good prevention effect.
Description
Technical field
The present invention relates to the application in preparation diabetic nephropathy medicine of tetrahydropyrimidine and derivant thereof.
Background technology
Diabetic nephropathy is also referred to as the diabetes glomerulosclerosis, is a kind of chronic complicating diseases that diabetes cause, is one of diabetes general microangiopathies performance; Clinical symptoms is an albuminuria; Gradual renal function injury, hypertension, edema etc.; The severe renal MSOF can appear in late period, even causes death.Glomerular sclerosis is the common pathological characters of the sick nephropathy of most of glycosurias.
The early stage main pathological characters of diabetic nephropathy is that glomerule is loose, and glomerule and renal tubular basement membrane thicken and the carrying out property of mesangial region extracellular matrix is gathered; Later stage is the fibrosis of matter between glomerule, renal tubules, and glomerular sclerosis finally causes albuminuria and renal failure.Its pathogenesis is comparatively complicated; Think at present; Its generation maybe be relevant with multiple factors such as nephridial tissue carbohydrate metabolism disturbance, hemodynamic abnormalities, vaso-active substance, somatomedin and chemokine and heredity, but do not find the definite pathogenesis of diabetic nephropathy as yet.
Along with the change of the aging of population, various countries' expanding economy and people life style, the sickness rate of diabetes (DM) worldwide increases rapidly, and the incidence rate of diabetic nephropathy is also up to 47%.The research and development of diabetic nephropathy medicine have caused the attention of field of medicaments, but still lack at present to diabetic nephropathy, the ideal medicine of curative effect.
Tetrahydropyrimidine, chemistry is called 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 2-Methyl-1,4,5,6-
Tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5,6-tetra-hydropyrimi-
Dine-4-carboxylic acid or 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid,
CAS number is 96702-03-3, is the amino acid derivativges of finding in the marine organism in 1985, has the guarantor
Wet effect in recent years, has been used to cosmetics.
Summary of the invention
To above-mentioned prior art, the purpose of this invention is to provide a kind of new purposes of tetrahydropyrimidine and derivant thereof, tetrahydropyrimidine and derivant thereof the application in preparation diabetic nephropathy medicine specifically.
For realizing above-mentioned purpose, the technical scheme that the present invention adopts is:
The application in preparation diabetic nephropathy medicine of tetrahydropyrimidine and derivant thereof.
Said tetrahydropyrimidinederivatives derivatives is 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
The preparation of said medicine is an oral formulations.
The dose therapeutically effective of said tetrahydropyrimidine and derivant thereof is for being (0.01～100) mg/kg.
Tetrahydropyrimidine described in the technical scheme of the present invention, chemistry 2-Methyl-1 by name, 4; 5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4; 5,6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4; 5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid.1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is commonly called as the hydroxy tetrahydro pyrimidine, and CAS number is 96702-03-3, and this is that those skilled in the art are known.
Its pharmaceutical dosage form can have multiple.Because the ideal physicochemical property of tetrahydropyrimidine, its preparation scope is extremely wide, can be made into oral formulations such as tablet, capsule etc.; External preparation such as emulsifiable paste, ointment etc.; Ejection preparation such as injection, lyophilized powder etc.This is conspicuous those skilled in the art, and the technology of preparing of various preparations also is that those skilled in the art are known.
The inventor's surprised discovery in experimentation, tetrahydropyrimidine and derivant thereof like the hydroxy tetrahydro pyrimidine, have unexpected therapeutical effect to diabetic nephropathy.
The specific embodiment
Below in conjunction with embodiment the present invention is done further explanation.Should be understood that following examples only are used to explain the present invention, rather than restriction protection scope of the present invention.
Embodiment 1 tetrahydropyrimidine and 1,4,5, the acute toxicity testing of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic
40 of SPF level KM mices, male and female half and half, body weight 18g-22g, fasting is 8 hours before the administration, weigh, the single oral gastric infusion, dosage is 120mg/kg, observes 14 days continuously after the administration.Observation item comprises toxic reaction, body weight and histopathology.
The result shows, behind the mice single gastric infusion 10g/kg, does not see the overt toxicity reaction, body weight no significant difference when administration front and back and experiment finish, and pathological study is found significantly unusually.Tetrahydropyrimidine and 1,4,5 are described, the heavy dose of administration of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic single (150g/kg) does not have significant toxic reaction.
Embodiment 2 tetrahydropyrimidines and 1,4,5, the long term toxicity test of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic
28 of machins, male and female half and half, 2 kg-4kg is divided into 5 groups at random, respectively feeding animals drinking water (matched group); 1,4,5 of the tetrahydropyrimidine of high, normal, basic three dosage and high, normal, basic three dosage, 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic, wherein high dose group is 80mg/kg, and middle dose groups is 40mg/kg, and low dose group is 10mg/kg.Administration every day 1 time; Successive administration 30 days is observed before the administration and after the administration and is carried out gross examination of skeletal muscle, the body weight of monkey before the general symptom of record monkey, the record administration and after the administration; And regularly carry out hematology, urine and blood biochemical analysis, the electrocardiogram of monkey before the record administration and after the administration.
The result shows that each dose groups the weight of animals and matched group do not have significant difference, and gross examination of skeletal muscle is no abnormal.The hematology of experimental group animal, urine and blood physicochemical data and matched group do not have significant difference.Tetrahydropyrimidine and 1,4,5 are described, the safety of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic long term administration is good, and toleration meets the requirements.
Embodiment 3 tetrahydropyrimidines and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is studied therapeutic actions for diabetic nephropathy
The SD rat, male and female are regardless of, 200 g-220g; The disposable injection streptozotocin of intraperitoneal 56mg/kg measured rat blood sugar after three days, after the diabetes modeling success; Survey 24 hours urine protein quantitation around the, promptly think diabetic nephropathy modeling success greater than 30mg like twenty-four-hour urine albumen.Get 30 of modeling success rats, be divided into 4 groups at random, irritate stomach for the 1st group and give tetrahydropyrimidine 80mg/kg, be abbreviated as the E group; Irritate stomach for the 2nd group and give 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 10mg/kg is abbreviated as the EO group; Irritate stomach for the 3rd group and organize atorvastatin 5mg/kg, be abbreviated as the A group; Irritate stomach for the 4th group and give normal saline, be abbreviated as the S group.
Each treated animal administration every day 1 time, successive administration 21 days.Administration finishes back the 2nd day, rat is placed collect rat twenty-four-hour urine protein quantification in the metabolic cage.Each treated animal urine protein quantitation data is seen table 1.
Table 1 is respectively organized rat twenty-four-hour urine Tot Prot (mg/24h)
| ? | The E group | The EO group | The A group | The S group |
| Total urinary protein | 7.92 | 7.68 | 19.74 | 37.19 |
Visible by table 1, tetrahydropyrimidine and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic can significantly reduce the urine protein of diabetic nephropathy rat, helps the albuminuria symptom of diabetes-alleviating nephropathy.
Embodiment 4 tetrahydropyrimidines and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is studied therapeutic actions for diabetic nephropathy
The Wistar male rat, body weight 200g-300g, disposable celiac injection streptozotocin 60mg/kg; Measure rat blood sugar after three days; After the diabetes modeling success, survey 24 hours urine protein quantitation around the, promptly think diabetic nephropathy modeling success greater than 30mg like twenty-four-hour urine albumen.Get 30 of modeling success rats, be divided into 4 groups at random, irritate stomach for the 1st group and give tetrahydropyrimidine 30mg/kg, be abbreviated as the E group; Irritate stomach for the 2nd group and give 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 0.5mg/kg is abbreviated as the EO group; Irritate stomach for the 3rd group and organize fluvastatin 15mg/kg, be abbreviated as the L group; Irritate stomach for the 4th group and give normal saline, be abbreviated as the S group.
Each treated animal administration every day 1 time, successive administration 14 days.Weighing rat body weight and kidney weight in wet base, the ratio of calculating kidney weight and rat body weight; Make kidney segment then, make pathological study after the dyeing, counting glomerule cross section nucleus sum, every animal is observed 20 glomerule, calculates the average of each treated animal glomerular sclerosis number.
The kidney weight of normal saline group rat and the ratio of rat body weight are significantly higher than other three groups, and the pathological observation result sees table 2.
Table 2 is respectively organized glomerular sclerosis relatively
| ? | The E group | The EO group | The L group | The S group |
| Glomerular sclerosis average (individual) | 0.8 | 0.1 | 3.7 | 12.6 |
Visible by table 2, tetrahydropyrimidine and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic can significantly improve the glomerular sclerosis symptom of diabetic nephropathy rat, and drug effect is superior to the common drug fluvastatin.
Execute the prescription and the preparation thereof of routine 5 tetrahydropyrimidine oral administration solutions
Tetrahydropyrimidine 200g
Lemon yellow 0.03g
Microcrystalline Cellulose 500g
Micropowder silica gel 4g
Magnesium stearate 15g
Polyvinylpyrrolidone 20 g
With tetrahydropyrimidine, microcrystalline Cellulose, lemon yellow, polyvinylpyrrolidine mix homogeneously, cross 80 mesh sieves
Net adds micropowder silica gel, magnesium stearate, mixes 3 minutes, and tabletting promptly gets.
Embodiment 61, and 4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-capsular prescription of 4-pyrimidine carboxylic and preparation thereof
1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 200g
Microcrystalline Cellulose 50g,
Carboxymethyl starch sodium 60g,
Sodium lauryl sulphate 18g
Silica 1 2g
1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is crossed 100 mesh sieves, and all the other adjuvants are crossed 80 mesh sieves, mixes all
Even, adopt roll-in method to carry out dry granulation, be packed into capsule and get final product.
Embodiment 71, and 4,5, the prescription and the preparation thereof of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic oral administration solution
1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 200g
PEG400 50ml
Sodium benzoate 2.5g
Add water to 1000ml
Take by weighing 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic, it is an amount of to add water; Add Polyethylene Glycol 400 by recipe quantity, stir and make it dissolving, add sodium benzoate and 900ml water, mixing adds water to 1000ml; Filter, be sub-packed in the brown neutral density glass sail of 10ml, gland, sterilization promptly gets.
Claims (2)
1. tetrahydropyrimidine and derivant thereof the application in preparation diabetic nephropathy medicine, said tetrahydropyrimidinederivatives derivatives is 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
2. application according to claim 1 is characterized in that: the preparation of said medicine is an oral formulations.
3. application according to claim 1 is characterized in that: the dose therapeutically effective of said tetrahydropyrimidine and derivant thereof is for being 0.01～100mg/kg.
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| CN201110240738A CN102309489B (en) | 2011-08-22 | 2011-08-22 | Medicine for treating diabetic nephropathy |
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| CN102309489B true CN102309489B (en) | 2012-10-03 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050043339A1 (en) * | 2003-07-23 | 2005-02-24 | Natesan Murugesan | Dihydropyrimidone inhibitors of calcium channel function |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050043339A1 (en) * | 2003-07-23 | 2005-02-24 | Natesan Murugesan | Dihydropyrimidone inhibitors of calcium channel function |
Non-Patent Citations (2)
| Title |
|---|
| 四氢嘧啶类物质的生物合成与转运途径及其生物学功能;姜蔚宇 等;《生命的化学》;20071231;第27卷(第4期);323-326 * |
| 姜蔚宇 等.四氢嘧啶类物质的生物合成与转运途径及其生物学功能.《生命的化学》.2007,第27卷(第4期),323-326. |
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Effective date of registration: 20200703 Address after: 262515 No. 3787 New York Road, Qingzhou Economic Development Zone, Weifang City, Shandong Province Patentee after: Shandong Yizhou Biotechnology Co., Ltd Address before: 250101 Shandong city of Ji'nan province high tech Zone Shun Road No. 750 Patentee before: JINAN HUANTAI MEDICAL TECHNOLOGY Co.,Ltd. |