CN108619137B - Application of carbazole compounds in preparation of medicines for treating metabolic diseases and complications thereof - Google Patents
Application of carbazole compounds in preparation of medicines for treating metabolic diseases and complications thereof Download PDFInfo
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- CN108619137B CN108619137B CN201810751622.6A CN201810751622A CN108619137B CN 108619137 B CN108619137 B CN 108619137B CN 201810751622 A CN201810751622 A CN 201810751622A CN 108619137 B CN108619137 B CN 108619137B
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- 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
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Abstract
The invention relates to an application of carbazole compounds in preparation of drugs for treating metabolic diseases and complications thereof, wherein the carbazole compounds are 3, 6-dibromo-beta-fluorine-N- (3-methoxyphenyl) -9H-carbazole-9-propylamine, namely P7C 3-A20. The invention proves that P7C3-A20 can obviously reduce blood fat and blood sugar, reduce obesity and reduce fatty liver pathological changes through preparing a high-fat high-sugar diet-induced hyperlipemia, obesity and fatty liver animal model experiment; the experiment of simulating ischemic myocardial damage by using a myocardial cell ischemia and hypoxia model proves that the P7C3-A20 can obviously reduce the myocardial cell damage caused by ischemia and hypoxia. Its advantages are: (1) the compound of the invention can effectively reduce blood fat and blood sugar, lose weight, prevent and treat fatty liver and protect ischemic myocardial damage. (2) Provides a new medicine research and development direction for metabolic diseases and complications thereof, and has good application prospect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of carbazole compounds in preparing medicines for treating metabolic diseases and complications thereof.
Background
In modern life, there are a large number of high-oil, high-sugar, high-fat foods. Although such foods are delicious and attractive, excessive ingestion thereof can cause a series of metabolic problems such as hyperlipidemia, hyperglycemia, obesity, and fatty liver. If these metabolic disorders persist, they cause direct damage to various tissues and organs of human beings, and are liable to induce complications, i.e. cardiovascular diseases such as myocardial ischemia, which are life-threatening. Therefore, attention has been focused on transcription factors involved in the induction of expression of adipocyte differentiation marker genes. Peroxisome proliferator-responsive receptors (hereinafter also referred to as "PPAR") are known to be involved in many physiological and pathological phenomena such as lipid metabolism, regulation of inflammation, differentiation and function regulation of cells, and are therefore particularly attracting attention.
The compound P7C3 has been reported abroad to have better protective effect on neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, memory loss and the like. The chloropropyl carbazole compound is high in oral bioavailability, can pass through a blood brain barrier, and does not show toxicity under effective dose and high dose. In addition, the compounds also have potential protective effects on diseases such as depression, mental disorder and the like.
The Chinese patent application: CN104997771A discloses an application of a compound P7C3-A20 in the preparation of a medicament for treating cerebral ischemic diseases, the invention proves that P7C3-A20 can improve the survival rate of mouse cerebral cortical neurons cultured in vitro in an anoxic glucose-deficient model through cell experiments, and proves that P7C3-A20 can obviously reduce the cerebral infarction area caused by the occlusion of the middle cerebral artery of a rat, and the results show that P7C3-A20 has a cerebral ischemic protection effect, can prevent and treat the cerebral injury caused by cerebral ischemia, and has a wide application prospect in the preparation of medicaments related to the cerebral ischemic injury and/or the cerebral infarction, but the patent only shows that the compound P7C3-A20 is used for preparing the medicament for treating the cerebral ischemic diseases, has a single application, does not describe the use method of the medicament, and is not beneficial to patients.
The Chinese patent application: CN102688295A discloses a traditional Chinese medicine composition for preventing and treating metabolic diseases, a preparation method and application of the composition, belongs to the technical field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine composition prepared from astragalus, kudzu root and white mulberry root-bark. The composition has the effects of inhibiting the proliferation of fat cells and reducing blood fat and blood sugar, and can be applied to preparing medicines for preventing and treating metabolic diseases.
However, the application of the carbazole compound in the preparation of the medicament for treating metabolic diseases and complications thereof is not reported at present.
Disclosure of Invention
The invention aims to provide a new application of a carbazole compound P7C3-A20 aiming at the defects of the prior art.
In order to achieve the purpose, the invention adopts the technical scheme that:
an application of carbazole compound P7C3-A20 in preparing medicines for treating metabolic diseases and their complications is disclosed.
As a preferred embodiment of the present invention, the carbazole-based compound P7C3-A20 has the following structural formula:
as a preferred embodiment of the present invention, the metabolic disease is: hyperlipidemia, hyperglycemia, obesity, fatty liver; the complications are: myocardial ischemia diseases.
As a preferred embodiment of the invention, the solvents used for diluting P7C3-A20 are dimethyl sulfoxide and castor oil.
As a preferred embodiment of the invention, the medicament is prepared into a clinically acceptable medicinal preparation according to a conventional preparation method of the medicament.
As a preferred embodiment of the present invention, the pharmaceutical preparation is granules, powders, capsules, tablets or oral liquids.
As a preferred embodiment of the present invention, the pharmaceutical preparation can be administered to an individual in need of treatment in the form of a dosage form by oral, intraperitoneal, subcutaneous, intravenous, intramuscular, mucosal administration, or the like.
The dosage of the invention is generally 1-1000 mg/kg body weight/day, and can be changed according to the age, illness condition and the like of an individual. The percentages used are percentages by mass, unless otherwise specified.
The invention has the advantages that:
1. the compound of the invention can effectively reduce blood fat and blood sugar, lose weight, prevent and treat fatty liver and protect ischemic myocardial damage.
2. The carbazole compound P7C3-A20 is used for preparing the medicine for treating metabolic diseases and complications thereof, the medicine can be applied to individuals needing to be treated by oral administration, intraperitoneal injection, subcutaneous injection, intravenous injection, intramuscular injection, mucosal administration and other ways according to dosage forms, and the use method is wide and convenient for patients to use.
3. Provides a new medicine research and development direction for metabolic diseases and complications thereof, and has good application prospect.
Drawings
FIG. 1 is a bar graph of the triglyceride concentrations of the mice after normal diet, high-fat and high-sugar diet, and high-fat and high-sugar diet + P7C3-A20 of example 4, showing that: administration of P7C3-a20 decreased the rise in blood triglycerides from a high-fat, high-sugar diet (. about.p <0.01, n ═ 10).
FIG. 2 is a bar graph of the total cholesterol concentration after normal diet, high-fat and high-sugar diet, and high-fat and high-sugar diet + P7C3-A20 in the mice of example 4, showing that: P7C3-a20 administration reduced the rise in blood cholesterol levels caused by a high-fat, high-sugar diet (P <0.01, n: 10).
FIG. 3 is a bar graph of blood glucose concentration after normal diet, high-fat and high-sugar diet, and high-fat and high-sugar diet + P7C3-A20 in mice of example 4. The results show that: administration of P7C3-a20 decreased the rise in blood glucose levels resulting from a high-fat, high-sugar diet (. about.p <0.01, n ═ 8).
FIG. 4 is a bar graph of body weight after normal diet, high-fat and high-sugar diet, and high-fat and high-sugar diet + P7C3-A20 in the mice of example 4. The results show that: administration of P7C3-a20 decreased the rise in blood glucose levels resulting from a high-fat, high-sugar diet (. about.p <0.01, n ═ 8).
FIG. 5 is a graph of fat deposition and intensity of oil red O staining of liver tissue after normal diet, high-fat and high-sugar diet + P7C3-A20 in mice according to example 4, showing that: the administration of P7C3-A20 can reduce liver tissue lipopathy (P <0.01, n is 10) caused by high-fat and high-sugar diet.
FIG. 6 is an analysis chart of the results of the cell number experiment of example 5, showing that: P7C3-a20 prevented a decrease in cardiomyocyte number due to hypoxia and glucose deprivation (P <0.05, P <0.01vs hypoxia and no P7C3-a 20).
FIG. 7 is an analysis chart of the cell viability experiment results of example 5, showing that: P7C3-a20 prevented decrease in cardiomyocyte viability due to hypoxia and glucose deprivation (P <0.05, P <0.01vs hypoxia and no P7C3-a 20).
FIG. 8 is an analysis chart of the cell damage experiment result of example 5, which shows that: P7C3-a20 prevented cardiomyocyte destruction due to hypoxia and glucose deprivation, with higher levels of LDH indicating more cardiomyocyte destruction, (. about.p <0.01vs hypoxia and no P7C3-a 20).
Detailed Description
The invention will be further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.
EXAMPLE 1 preparation of a medicament for the treatment of metabolic disorders and complications thereof
P7C3-a20 was purchased from shanghai lanke pharmaceutical science and technology development ltd, 10mgP7C3-a20 was dissolved in 100 microliters of dimethyl sulfoxide (purchased from Sigma, commercially available), 1ml of castor oil (purchased from shanghai pharmaceutical chemicals, commercially available) was added, and then 5% dextrose (purchased from shanghai pharmaceutical chemicals, commercially available) was added to make a volume of 10ml, which was used for administration.
EXAMPLE 2 preparation of a medicament for the treatment of metabolic disorders and complications thereof (II)
P7C3-a20 was purchased from shanghai lan ke pharmaceutical science and technology development limited company, 10mgP7C3-a20 was dissolved in 100 microliters of dimethyl sulfoxide (purchased from Sigma, commercially available), 1ml of castor oil (purchased from shanghai pharmaceutical chemicals, commercially available) was added, 5% dextrose (purchased from shanghai pharmaceutical chemicals, commercially available) was added to the solution to a volume of 10ml, and the obtained drug was granulated, dried, sized, quality-checked, sub-dosed, packaged and stored according to the conventional preparation method of granules, to obtain granules.
Example 3 preparation of a medicament for the treatment of metabolic disorders and complications thereof (III)
P7C3-a20 was purchased from shanghai lanke pharmaceutical science and technology development limited company, 10mgP7C3-a20 was dissolved in 100 microliters of dimethyl sulfoxide (purchased from Sigma, commercially available), 1ml of castor oil (purchased from shanghai pharmaceutical chemicals, commercially available) was added, 5% dextrose (purchased from shanghai pharmaceutical chemicals, commercially available) was added to the solution to a volume of 10ml, and the prepared drug was mixed, filled, cleaned, inspected, and packaged according to the conventional capsule preparation method.
EXAMPLE 4 evaluation of Effect of treating metabolic diseases
First, experiment method
1. Preparation and grouping of animal models of hyperlipidemia, hyperglycemia, obesity and fatty liver
Dozens of ICR mice of 8 weeks of age purchased from the Shanghai laboratory animal center of Chinese academy of sciences were used, and their males and females were half. The groups were randomized into three groups: before the experiment, the biochemical indexes such as body weight, blood fat and blood sugar of three groups of mice are not different in a normal diet group, a high-fat high-sugar diet group and a high-fat high-sugar diet + P7C3-A20 group. In the high-fat high-sugar diet used by us, the high-concentration lard (fat) and sucrose (sugar) are contained, and long-term eating of the high-fat high-sugar diet can cause remarkable metabolic disorders, including the rise of blood fat and blood sugar, the rise of body weight and the appearance of fatty liver. The specific formula of the high-fat high-sugar diet is as follows:
| name of raw materials | Proportioning (g/100g) |
| Mouse breeding material | 55.7 |
| Lard oil | 17.8 |
| Sucrose | 11.3 |
| Casein protein | 11.2 |
| Premix |
2 |
| Maltodextrin | 2 |
| Total up to | 100 |
For these three groups of mice, the treatments were as follows:
normal diet group mice: normal feed feeding was continued for 4 months.
High fat high sugar diet group: mice were fed a high fat, high sugar diet for 4 months.
High fat high sugar diet + P7C3-a20 group: high fat and high sugar diets have been used for feeding. After 2 months of feeding the high-fat high-sugar diet, the P7C3-a20 was administered for gavage in an amount of 20mg/kg while continuing to administer the high-fat high-sugar diet for an additional 2 months for a total of 4 months.
2. Experimental detection
After 4 months, blood glucose, blood lipids (including blood triglyceride and total cholesterol concentration), body weight, lipid deposition in the liver, and impaired liver function were measured. The blood sugar detection uses a US Qiangshenghuo steady blood sugar meter and matched blood sugar test paper, and mainly detects the blood sugar concentration of the tail artery of a mouse. The detection of blood fat is carried out by using a special kit, and the kit information is as follows: triglycerides (cat # F001-1) and total cholesterol (cat # F002-1) were purchased from the institute of bioengineering, Hemijing. Body weight was weighed using a mettler balance. Lipid deposition in the liver was measured by staining with oil red O, purchased from Sigma, usa. The liver function status is detected by detecting alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) in blood using a Beckman full-automatic biochemical analyzer.
Second, experimental results
1. P7C3-A20 has blood lipid reducing effect
The blood triglyceride concentration profile of the three groups of mice is shown in FIG. 1, and the total cholesterol concentration profile of the three groups of mice is shown in FIG. 2. The concentration of triglyceride and total cholesterol in the mice in the high-fat high-sugar diet group is obviously higher than that in the mice in the normal diet group, which indicates that the high-fat high-sugar diet causes hyperlipidemia; the blood triglyceride and total cholesterol concentration of mice in the group of high-fat high-sugar diet and P7C3-A20 administration is obviously reduced, which indicates that P7C3-A20 has the function of treating hyperlipidemia.
2. P7C3-A20 has blood sugar lowering effect
Fasting plasma glucose in three groups of mice is shown in figure 3. It can be seen that the blood glucose concentration of the mice in the high-fat high-sugar diet group is obviously higher than that of the mice in the normal diet group, which indicates that the high-fat high-sugar diet causes hyperglycemia; while the blood glucose of the mice in the high-fat high-sugar diet + P7C3-a20 group was significantly lower than that in the model group (i.e., the high-fat high-sugar diet group). This result indicates that P7C3-A20 can improve the effect of hyperglycemia.
3. P7C3-A20 has weight reducing effect
As shown in fig. 4, the average body weight of the mice in the high fat and high sugar diet group was close to 43g and about 43% (about 30g) higher than that of the mice in the normal diet group after feeding the high fat and high sugar diet for 4 months, which indicates that the high fat and high sugar diet caused significant obesity, whereas the high fat and high sugar diet + P7C3-a20 group showed a very significant decrease in the mice in the higher fat and high sugar diet group, indicating that P7C3-a20 had an obesity-suppressing effect.
4. P7C3-A20 has effect of relieving fatty liver pathological changes
It is clear from the oil red O staining method (FIG. 5) that the liver of the mice in the normal diet group had substantially no lipid deposition, and thus had substantially no positive area (red) for oil red O staining. However, after 4 months after the mice in the high-fat and high-sugar diet had been fed with the high-fat and high-sugar diet, large red areas were observed in the liver sections after oil red O staining, which means that the liver of the mice in the high-fat and high-sugar diet had significant lipid deposition. Whereas in mice treated with P7C3-A20, the areas stained with oil-Red-O were significantly reduced, indicating a significant reduction in liver lipid deposition after 2 months of P7C3-A20 treatment.
EXAMPLE 5 evaluation of Effect of treating ischemic myocardial injury disease
First, experiment method
1. Preparation of model for myocardial cell injury of anoxic and glucose-deficient neurons
Selecting a plurality of newborn 24h SD rats with unlimited males and females, sterilizing the whole body with 75% alcohol, fixing the heads and the broken heads of four limbs of the suckling rats with pins, shearing off the skin of the chest in a layering manner under an aseptic condition, sterilizing subcutaneous tissues with 75% alcohol, replacing tweezers and scissors, opening the chest, taking out the heart, putting the heart into a flat dish containing D-Hanks solution, removing the atria, shearing off the ventricles, and repeatedly washing to remove residual blood. Then cutting the heart into pieces with the size of 1mm3, transferring the heart pieces into a 15ml centrifuge tube, adding about 5ml of digestive juice (containing 0.08% of pancreatin and 0.05% of collagenase II and prepared by using D-Hanks solution with the pH value of 7.2-7.8), digesting in an incubator at 37 ℃ for 10min, naturally precipitating, discarding the supernatant, adding about 5ml of digestive juice, digesting on a water bath shaker at 37 ℃ for 20min, blowing and beating for 1min by using a glass pipette, adding the digestive stop solution into the upper suspension, collecting the upper suspension, adding about 5ml of digestive juice into the remaining tissue, digesting for 30mi, and stopping digestion. All suspensions were screened through a 200 mesh screen, the filtrate was collected, centrifuged at 1000rpm for 10min, the supernatant was discarded, 2ml of the culture solution was added to the precipitate, and the mixture was pipetted to prepare a cell suspension. The cells were placed in a flask and incubated in a carbon dioxide incubator (37 ℃ C. + 5% CO2) for 2 hours. Then, the cell fluid was aspirated and transferred to a 6-well plate previously coated with polylysine for culture (differential adherence). The cell density was 1 × 106/well.
After 4 days of primary cardiomyocytes culture, they were placed in an anoxic incubator to achieve an oxygen content below 0.5% (v/v), and cultured in a sugar-free DMEM medium (purchased from Sigma) to simulate the ischemic state in vitro, while 1. mu.M, 3. mu.M, 10. mu.M, 30. mu.M, and 100. mu.M of P7C3-A20 were administered, and the control group was administered with a solvent control. After 24 hours of culture, the protective effect of nicotinamide mononucleotide on neuronal cells was evaluated by 3 different methods, respectively.
2. Cell number assay
The sugar-deficient hypoxia simulates myocardial ischemia, and after 24 hours of culture, the number of cells per culture well was measured using trypan blue.
3. Cell viability assay
The glucose deprivation and hypoxia simulate myocardial ischemia, and after 24 hours of culture, the cell viability in each culture well was tested using the CCK-8 method (CCK-8 kit purchased from the Biotech institute of Mount Jiangsu Haimebi Yunnan Biotech).
4. Cell injury assay
The glucose-deficient hypoxia simulates myocardial ischemia, and after 24 hours of culture, the cell viability in each culture well was measured using the LDH kit method (LDH kit purchased from Nanjing Biotech Co.).
Second, experimental results
Cell number experiments show that P7C3-A20 with the concentration of 10 mu M or more can prevent the reduction of the number of the myocardial cells caused by oxygen deficiency (as shown in figure 6) and has dose dependence. P7C3-A20 at 1. mu.M and 3. mu.M had no significant effect.
Cell viability experiments showed that: P7C3-A20 with the concentration of more than 10 mu M can prevent the reduction of the activity of the myocardial cells caused by oxygen deficiency and sugar deficiency (as shown in figure 7), and the P7C3-A20 with the concentration of 1 mu M and 3 mu M has no obvious effect on the dosage dependence.
Cell injury experiments show that P7C3-A20 with the concentration of 10 mu M or more can prevent LDH content in a myocardial cell culture medium caused by oxygen deficiency, which shows that P7C3-A20 can prevent myocardial cell damage caused by oxygen deficiency (as shown in figure 8) and has dose dependence, and no obvious effect is observed in P7C3-A20 with the concentration of 1 mu M and 3 mu M.
Third, conclusion of experiment
The results of this example show that: the P7C3-A20 has the effect of resisting myocardial ischemia, and can reduce myocardial cell damage caused by hypoxia-hypoglycemia stress.
The examples 4 and 5 show that the carbazole P7C3-A20 can effectively reduce blood fat and blood sugar, reduce weight, prevent and treat fatty liver and protect ischemic myocardial injury, is used for preparing the medicines for treating the metabolic diseases and the complications thereof, provides a new medicine research and development direction for the metabolic diseases and the complications thereof, and has good application prospect.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and additions can be made without departing from the principle of the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.
Claims (5)
1. An application of carbazole compounds P7C3-A20 in preparing medicines for treating obesity and fatty liver is disclosed, wherein the carbazole compounds P7C3-A20 have the following structural formula:
2. the use of claim 1, wherein the solvents used for dilution of P7C3-A20 are dimethyl sulfoxide and castor oil.
3. The use of claim 1, wherein the medicament is prepared into a clinically acceptable pharmaceutical preparation according to a conventional pharmaceutical preparation method.
4. The use according to claim 3, wherein the pharmaceutical formulation is a granule, powder, capsule, tablet, oral liquid or injection.
5. The use according to claim 4, wherein the pharmaceutical formulation is administered to the individual in need of treatment in a dosage form by oral, intraperitoneal, subcutaneous, intravenous, intramuscular, mucosal routes.
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| NAMPT对非酒精性脂肪肝的调控作用;周灿灿;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20160315(第03期);E064-133，特别是摘要 * |
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