CN109096190B - Sinomenine derivative, preparation method, application and pharmaceutical composition thereof - Google Patents
Sinomenine derivative, preparation method, application and pharmaceutical composition thereof Download PDFInfo
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Abstract
The invention discloses a structure of sinomenine derivative compound sino-wcj-43 shown as a formula (I), a preparation method thereof and application thereof in inflammatory diseases and aplastic anemia. The derivative of the invention relates to a novel structural derivative sino-wcj-43 synthesized by taking sinomenine hydrochloride as a raw material. The invention discloses sino-wcj-43 or pharmaceutically acceptable salts thereof, which have simple preparation method, obvious anti-inflammatory and aplastic anemia treating effects, and can be applied to clinical treatment of inflammatory diseases and aplastic anemia in a monomer or medicinal composition form.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to a preparation method of a sinomenine derivative or a pharmaceutically acceptable salt thereof, a medicinal composition containing the sinomenine derivative or the pharmaceutically acceptable salt thereof and application of the sinomenine derivative or the pharmaceutically acceptable salt thereof in inflammatory diseases and aplastic anemia.
Background
Aplastic anemia (called aplastic anemia for short, AA) is an acquired bone marrow hematopoietic failure disease caused by chemical, physical, biological factors or unknown reasons, and is characterized by low bone marrow hematopoietic function, pancytopenia, anemia, hemorrhage and infection syndromes. The pathogenesis or mechanism is very complex, and is considered to be related to internal defects of hematopoietic stem cells, abnormal hematopoietic microenvironment and immune dysfunction of the body at present. Although specific pathogenesis is not well defined, there is a relatively broad consensus on the key role of immune mediation in pathogenesis. Currently, immunosuppressants are the main treatment means, and commonly used immunosuppressants comprise antithymglobulin/antilymphoglobulin, cyclosporine, methylprednisolone and the like. These drugs are expensive, have large side effects and high recurrence rate, and their therapeutic effects are often unsatisfactory. It is therefore important and urgent to find other ways and drugs that are more effective in treatment.
Sinomenine (sinomenine) is the main active component of Sinomenine of Fangji family, has pharmacological activities of anti-inflammation, analgesia, blood pressure reduction, arrhythmia resistance and the like, and has been clinically used for treating diseases such as rheumatoid arthritis, arrhythmia and the like. However, sinomenine has short biological half-life, large clinical dosage and allergic side effect. In order to obtain the sinomenine derivative with high efficiency and low toxicity, researchers in the field also try to carry out structural modification on each active site on the four rings of sinomenine A, B, C and D. Among a plurality of synthesized sinomenine derivatives, the novel sinomenine derivative sino-wcj-43 shown in the formula (I) has better anti-inflammatory activity than sinomenine and relatively lower toxicity, and further, the systematic pharmacological experiment result shows that sino-wcj-43 has obvious anti-inflammatory and aplastic anemia treating effects and is an active compound with deep research value. The research on the structure and the pharmacological activity of the compound is not reported so far.
Disclosure of Invention
In order to overcome the defects of the prior art, the first aspect of the technical scheme of the invention aims to provide a sinomenine derivative sino-wcj-43 with novel chemical structure characteristics (I) and a pharmaceutically acceptable salt thereof,
in a second aspect of the first embodiment of the present invention, there is provided a process for the preparation of said compound of formula (i):
taking sinomenine hydrochloride sinono as a raw material, carrying out heating reflux reaction with paraformaldehyde to generate 1-hydroxymethylene sinomenine shown in a formula 1, and carrying out esterification reaction on the 1-hydroxymethylene sinomenine, cinnamic acid, EDC and DMAP at room temperature to obtain the sinomenine derivative shown in the formula (I).
The third aspect of the technical scheme of the invention provides an application of sinomenine derivative sino-wcj-43 shown in formula (I) and pharmaceutically acceptable salts thereof in medicines for treating inflammatory diseases and aplastic anemia. The inflammatory diseases include rheumatic arthritis, bronchitis, asthma, chronic obstructive pulmonary disease, and nephritis. The aplastic anemia comprises acute and chronic aplastic anemia. Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of sino-wcj-43 and its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.
In order to achieve the above objects of the present invention and obtain better pharmacodynamic characteristics such as stronger anti-inflammatory activity, faster onset time and longer maintenance time, the present invention synthesizes new derivative sino-wcj-43 with sinomenine as mother nucleus, and its molecular formula is C38H37NO7It was named 1-cinaminocyromethyl-4-cinaminocyloxy-7, 8-didehydro-3, 7-dimethoxy-17-methyl-morphine-6-one. The method is characterized by comprising the following synthesis steps:
1) weighing 10.0g of sinomenine hydrochloride, dissolving in 200ml of water, adding 20.0g of paraformaldehyde (the mass of which is 2-3 times that of the sinomenine hydrochloride) while stirring, heating and refluxing for 4-12 h, and monitoring the reaction process by TLC. Reaction junctionAfter finishing, using CHCl3Extraction (100 mL. times.3 or the number of extractions can be increased), organic phase combination, anhydrous Na2SO4Drying, filtering, and evaporating to remove solvent to obtain white solid to obtain 1-hydroxymethylene sinomenine.
2) Dissolving about 50mg of 1-hydroxymethylene sinomenine in dichloromethane, adding EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (3eq-6eq), cinnamic acid (3eq-6eq) and a catalyst DMAP (4-dimethylaminopyridine) (1-5% of mass, namely catalytic amount) under stirring, and reacting under stirring for 40min-4h at the temperature of room temperature-40 ℃ (most preferably room temperature), wherein the raw materials are basically disappeared by thin-layer chromatography. 5mL of water was added to the reaction solution to stop the reaction, the solution was transferred to a separatory funnel, AcOEt was added (10 mL. times.3 times) for extraction, the aqueous layer was extracted once more with 5mL of ethyl acetate (AcOEt), and the organic layer was saturated with NH4Cl solution 3X 20mL Wash, NH4The Cl layers were combined with water and extracted once with 5 mLAcOEt. The organic layers were combined and anhydrous Na2SO4Drying, concentrating, and separating by column chromatography to obtain white compound sino-wcj-43.
To achieve the objects of the present invention, the present invention relates to sino-wcj-43 and its pharmaceutically acceptable salts, and the use of its pharmaceutical composition in inflammatory diseases and aplastic anemia.
Inflammation is a basic disease of inflammatory diseases such as rheumatoid arthritis, bronchitis, asthma, chronic obstructive pulmonary disease, nephritis, and the like, and anti-inflammatory therapy is an essential means for clinical treatment thereof. Sino-wcj-43 has remarkable inhibitory effect on LPS (lipopolysaccharide) induced generation of inflammatory factor NO of abdominal macrophages of primary mice in vitro, and IC (integrated Circuit) of the inhibitor50＝1.46×10-6mol/l; the single subcutaneous administration at the dosage of 50mg/kg and 100mg/kg has the inhibition effect on the croton oil-induced otitis of mice, and the inhibition rate is 14.7 percent and 22.7 percent respectively.
Aplastic anemia is a common disease in hematology. A mouse aplastic anemia model is prepared by cobalt-60 gamma rays and thymus immune cell inoculation, and the sino-wcj-43 is administrated by gastric lavage at the dose of 25, 50 mg/kg. The result shows that the sino-wcj-43 has a reversing effect on the decrease of food intake and organ index of the aplastic mouse; can improve various indexes of peripheral blood and bone marrow hematopoiesis functions: obviously improve the content of peripheral red blood cells, hemoglobin, white blood cells and platelets, obviously increase the number of peripheral blood reticulocytes and obviously increase the number of bone marrow cells and the proportion of CD34+ cells.
The invention has the advantages that: (1) the sinomenine derivative with a new structure has better pharmacodynamic characteristics and relatively less toxic and side effects; (2) the invention has obvious anti-inflammatory activity; (3) the invention can effectively prevent and treat aplastic anemia; (4) the product has easily obtained raw materials, simple preparation process, and easy standardized production.
The invention also relates to a pharmaceutical composition comprising a pharmaceutically effective amount of said compound and a pharmaceutically acceptable carrier. For this purpose, if desired, in combination with one or more solid or liquid pharmaceutical excipients and/or adjuvants, suitable administration forms or dosage forms for human use are prepared.
According to the present invention, the compounds of the present invention may exist in the form of isomers, and generally, the term "compounds of the present invention" includes isomers of the compounds.
The pharmaceutical compositions of the present invention may be administered in unit dosage form, either enterally or parenterally, for example orally, intramuscularly, subcutaneously, nasally, oromucosally, dermally, peritoneally or rectally, and the like.
The route of administration of the pharmaceutical composition of the present invention may be administration by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc. The administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The composition can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems.
In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, ethylparaben, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents such as dried starch, alginates, agar powder, brown algae starch, sodium hydrogen carbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid esters, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
For making the administration units into pills, a wide variety of carriers well known in the art can be used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc.
For making the administration unit into a suppository, various carriers well known in the art can be widely used. As examples of the carrier, there are, for example, polyethylene glycol, lecithin, cacao butter, higher alcohols, higher alcohol enzymes, gelatin, semisynthetic glycerase and the like.
To encapsulate the administration units, the active ingredient is mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin capsules or soft gelatin capsules. Or making into microcapsule, suspending in aqueous medium to form suspension, or making into hard capsule or injection.
For example, the composition of the present invention is formulated into an injectable preparation, such as a solution, a suspension solution, an emulsion, a lyophilized powder, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid enzyme, etc. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. These adjuvants are commonly used in the art.
In addition, if desired, colorants, preservatives, flavors, flavorings, sweeteners, or other materials may also be added to the pharmaceutical preparation.
The dose of the pharmaceutical composition of the present invention to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, character and individual response of the patient or animal, the administration route, the number of administrations, etc., and thus the therapeutic dose of the present invention can be widely varied. Generally, the dosage of the compounds of the present invention used is well known to those skilled in the art. The amount of the drug actually contained in the final formulation of the pharmaceutical composition of the present invention can be adjusted appropriately to achieve the requirement of a therapeutically effective amount thereof, thereby achieving the purpose of the present invention for treating inflammatory diseases and aplastic anemia.
In general, for a patient weighing about 75 kg, the compounds of the present invention are administered in a daily dose of 0.001mg/kg body weight to 200mg/kg body weight, preferably 1mg/kg body weight to 100mg/kg body weight. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms, which is limited by the clinical experience of the administering physician and the dosage regimen. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents.
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FIG. 1 is a graph showing the effect of sino-wcj-43 on LPS-induced levels of inflammation factor NO production by primary mouse peritoneal macrophages;
Detailed Description
The present invention is further illustrated by the following examples, but the present invention is not limited to these examples.
Example 1: preparation of sino-wcj-43
The molecular formula is as follows: c38H37NO7
Naming: 1-cinnamyloxymethylene-4-cinnamyloxy-7, 8-didehydro-3,7-dimethoxy-17-methyl-morphinan-6-one, 1-cinnamooxymethylene-4-cinnamoyloxy-7, 8-didehydro-3, 7-dimethoxy-17-methyl-morphinan-6-one.
The synthesis route of the compound is as follows:
step one, weighing 10.0g of sinomenine hydrochloride, dissolving in 200ml of water, adding 20.0g of paraformaldehyde (the mass of which is 2-3 times that of the sinomenine hydrochloride) while stirring, heating and refluxing for 4-12 h, and monitoring the reaction process by TLC. After the reaction is finished, CHCl is used3Extraction (100 mL. times.3 or the number of extractions can be increased), organic phase combination, anhydrous Na2SO4Drying, filtering, and evaporating to remove solvent to obtain white solid to obtain 1-hydroxymethylene sinomenine.
And step two, taking about 50mg of 1-hydroxymethylene sinomenine, dissolving in dichloromethane, adding EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (3eq-6eq), cinnamic acid (3eq-6eq) and a catalyst DMAP (4-dimethylaminopyridine) (1-5% of mass, namely catalytic amount) under stirring, reacting for 40min-4h under stirring at the temperature of room temperature-40 ℃ and most preferably at the room temperature, and displaying that the raw materials basically disappear by thin layer chromatography. The reaction was stopped by adding 5mL of water to the reaction solution, the solution was transferred to a separatory funnel and extracted by adding (10 mL. times.3 times) AcOEt, the aqueous layer was extracted once more with 5mL of ethyl acetate (AcOEt), the organic layer was washed with 3X 20mL of saturated NH4Cl solution, the NH4Cl aqueous layer was combined and extracted once with 5mL of AcOEt. The organic layers were combined, dried over anhydrous Na2S04, concentrated, and separated by column chromatography to give the white compound sino-wcj-43.
1H NMR (400MHz, CDCl3) for this compound: δ 8.03(1H, d, J16.0 Hz),7.73(1H, d, J16.0 Hz), 7.69-7.64 (2H, m), 7.56-7.49 (2H, m), 7.45-7.37 (6H, m),6.95(1H, s),6.70(1H, d, J16.0 Hz),6.47(1H, d, J16.0 Hz),5.47(1H, d, J1.6 Hz), 5.29-5.16 (2H, m), 4.03-3.88 (1H, m),3.77(3H, s),3.47(3H, s),3.35(1H, s),3.13(2H, d, J18.8), 2.70(1H, 70H, s),3.47(3H, s),3.35(1H, s),3.13(2H, d, J18.8), 2.70(1H, J1H, 5H, s), 2H, 5H, 5.49 Hz), 11H, 5H, s), 3.6H, 11H, 5H, 1.6Hz, d, 18.6H, d, 18.6H, d, J, 1.6H, d, 1H, d, 1.6H, d, 18.6H, 1.6H, d: 605,606(M + + H).
Pharmacological experiments:
experimental example 1: inhibition effect of sino-wcj-43 on LPS-induced generation of primary mouse abdominal cavity macrophage inflammatory polypeptide NO
Macrophages perform the nonspecific immune function of an organism, can generate inflammatory factors such as NO and the like under the induction of bacterial Lipopolysaccharide (LPS), participate and mediate inflammatory reaction, and have higher levels in the initial stage of various inflammatory immune processes and the pathological development process. The anti-inflammatory activity of the compound can be preliminarily observed in vitro by detecting the NO production amount of the macrophage in the abdominal cavity of the primarily cultured mouse.
The experimental method comprises the following steps:
inoculating primary mouse abdominal cavity macrophages into a 96-well plate, and adding compounds with different concentrations for pre-protection for 1 h; then, LPS was added to a final concentration of 1. mu.g/ml, and 5% CO was added at 37 ℃2After culturing for 24 hours in an incubator, collecting supernatant, determining the content of NO by adopting a Griess method,
meanwhile, the cell proliferation inhibition rate is measured by an MTT method; and determining the inhibition of NO production IC50(calculated using Probit weighted regression analysis).
The experimental results are as follows:
the results are shown in Table 1, compared with sinomenine, the lead compoundThe reconstructed sino-wcj-43 has the advantages of remarkably improved activity, low toxicity and remarkably lower toxicity than a positive control drug. Further determination results show that sino-wcj-43 induces IC generated by primary mouse peritoneal macrophage NO by LPS50＝1.46×10-6mol/L (as shown in FIG. 1).
TABLE 1 influence of sino-wcj-43 on LPS-induced production of NO by peritoneal macrophages of primary mice
Experimental example 2: effect of sino-wcj-43 on croton oil-induced otitis of mice
The experimental method comprises the following steps:
taking 18-20g of male Kunming mice, randomly grouping, and respectively coating 0.02ml of croton oil on the two sides of the left ear of each group of animals; after 30 minutes, animals of each group are respectively injected with 50mg/kg and 100mg/kg of the test compound subcutaneously, and model control groups are administered with the same volume of the solvent; after 4h of administration, the mice were sacrificed by removing their necks, ears were cut off along the auricle base line, and ear pieces at the same positions of the left and right ears were removed with a 6 mm-diameter punch, weighed on an analytical balance, and the degree of ear swelling (ear swelling ═ left ear weight-right ear weight) and the rate of inhibition of ear swelling [ ear swelling inhibition (%) (model group average degree of ear swelling-administration group ear swelling)/model group average ear swelling group × 100% ]werecalculated.
The experimental results are as follows:
as shown in Table 2, sino-wcj-43 has the effect of reducing ear swelling of croton oil-induced otitis in mice, wherein the 100mg/kg administration group has a significant difference (P <0.05) compared with the model control group. Compared with the sinomenine compound with the same dosage, the sino-wcj-43 has stronger inhibiting effect on the paenoia oil induced otitis of mice.
Table 2. effect of sino-wcj-43 on croton oil-induced otitis in mice (Mean ± SD, n ═ 10)
Note: compared to the model group, "-" indicates p < 0.05.
Experimental example 3: effect of sino-wcj-43 on immune-mediated aplastic anemia
The experimental method comprises the following steps:
18-20g of male BALB/c mice are randomly divided into a normal control group, a model control group, a positive control group (a reconstructed hematogen tablet 970mg/kg, and is administrated by intragastric administration) and a sino-wcj-43 group (25mg/kg, 50mg/kg, and is administrated by intragastric administration), and 16 mice are taken in each group. Except for the blank control group, animals in each group adopt cobalt-60 gamma rays (4.8Gy cobalt-60 gamma rays for one whole body irradiation) + DBA/2 mouse thymus: preparing a aplastic anemia model by intravenous injection inoculation of splenic immune cells (2: 1); the administration is started from the day of molding, 1 time per day, and is continued for 14 days. 1 hour after the last administration, orbital vein blood of mice was collected, EDTA-K2Anticoagulation, five-classification hematology analyzer detection blood routine and flow cytometry detection reticulocyte number; picking the thymus and spleen of the mouse, weighing the thymus and spleen by humidity, and calculating the organ index; taking the bone marrow of the right femur of the mouse, and detecting the bone marrow cell count and the CD34+ cell ratio by a flow cytometer.
The experimental results are as follows:
(1) influence of sino-wcj-43 on body weight and food intake of mice with aplastic anemia
The weight and the food intake are one of the important indexes for measuring the life quality of the patients. Patients with aplastic anemia are very likely to have functional disorders due to digestion, absorption and the like because of being in symptoms of anemia, bleeding, infection and the like for a long time. The effect of preliminary sino-wcj-43 on the general growth of the re-disabled mice was measured weekly in this experiment by weighing the body weight and feed intake of the experimental mice. The results are shown in tables 4.1 and 4.2. The results in Table 4.1 show that the body weight of the mice in the aplastic model is significantly reduced in 7 days and 14 days compared with the normal control group, while the sino-wcj-43 and the positive control drug have no significant influence on the body weight of the aplastic mice. The results in Table 4.2 show that compared with the normal control group, the food intake of the aplastic mouse is obviously reduced in 7 days and 14 days, and the sino-wcj-43 and the positive control drug can obviously increase the food intake of the aplastic mouse, which indicates that the sino-wcj-43 and the positive control drug can improve the digestive function damage of the mouse caused by aplastic.
TABLE 4.1 influence of sino-wcj-43 on the body weight growth of aplastic anemia mice (Mean Std, n ═ 16)
Remarking:#p＜0.05，##p is less than 0.01vs blank control group;*p＜0.05，**model control group with p less than 0.05vs
TABLE 4.2 influence of sino-wcj-43 on food intake in aplastic anemia mice (Mean. + -. Std, n ═ 16)
Remarking:#p＜0.05，##p is less than 0.01vs blank control group;*p＜0.05，**model control group with p less than 0.05vs
(2) Influence of sino-wcj-43 on thymus and spleen organ indexes of mice with aplastic anemia
In this experiment, after 1 hour from the last administration, thymus and spleen of each group of mice were extracted, and their wet weights were measured, and the organ index (organ index: weight of organ/weight of day × 100%) was calculated. The results are shown in Table 4.3. The results in Table 4.3 show that sino-wcj-43 can increase the thymus index of aplastic anemia mice, which indicates that it has the function of improving the hypoimmunity of aplastic anemia mice.
TABLE 4.3 influence of sino-wcj-43 on the immune organ index of aplastic anemia mice (Mean. + -. Std, n ═ 10)
Remarking:#p＜0.05，##p is less than 0.01vs blank control group;*p＜0.05，**model control group with p less than 0.05vs
(3) Influence of sino-wcj-43 on routine examination result of peripheral blood of mouse with aplastic anemia
Peripheral blood pancytopenia is the main cause of clinical symptoms such as aplastic anemia, hemorrhage, infection and the like, and is an indirect reflection index of bone marrow hematopoietic failure. Improvement of various indicators of peripheral blood, particularly red blood cells, hemoglobin, white blood cells, lymphocytes, and platelets, is the most direct evidence for effective treatment of aplastic. In the experiment, blood is taken from eyeballs of the mice 1 hour after the last administration, and various indexes of peripheral blood of the mice are detected by adopting a five-classification blood cell analyzer. The results are shown in tables 4.3A, 4.3B and 4.3C.
Influence of sino-wcj-43 on peripheral red blood cell count and hemoglobin content of aplastic anemia mice
As shown in the results of table 4.3A, sino-wcj-43 improved the decrease in peripheral red blood cell count in aplastic mice, and the difference was significant in the 50mg/kg dose group compared to the model control group (p < 0.05); the sino-wcj-43 has an improvement effect on the low peripheral blood hemoglobin content of the aplastic mice, but has no significant difference compared with a model control group; in addition, sino-wcj-43 has significant effects on peripheral Hematocrit (HCT), mean corpuscular hemoglobin content (MCH), and Mean Corpuscular Hemoglobin Concentration (MCHC) of the aplastic mice.
TABLE 4.3 influence of A sino-wcj-43 on peripheral red blood cell count and hemoglobin content in aplastic anemia mice (Mean Std, n 10)
Remarking: red Blood Cells (RBC), Hemoglobin (HGB), Hematocrit (HCT), mean volume of red blood cells (MCV), mean hemoglobin content of red blood cells (MCH), mean hemoglobin concentration of red blood cells (MCHC), standard deviation of red blood cell volume distribution width (RDW-SD), coefficient of variation of red blood cell volume distribution width (RDW-CV);#p＜0.05，##p is less than 0.01vs blank control group;*p＜0.05，**p <0.05 vs model control.
② influence of sino-wcj-43 on white blood cell number and lymphocyte number in peripheral blood of mouse with aplastic anemia
As shown in the results in Table 4.3B, when the sino-wcj-43 is administrated by gastric lavage to the aplastic anemia model mouse at the dose of 25, 50mg/kg, the leukocyte count, the lymphocyte count and the lymphocyte classification percentage (p is less than 0.05 or 0.01) in the peripheral blood of the mouse can be obviously increased, and the effect is better than that of the positive control drug-the regenerated hematopoietic tablet.
TABLE 4.3B influence of sino-wcj-43 on differential white blood counts in peripheral blood of aplastic anemia mice (Mean Std, n 10)
Remarking: leukocyte count (WBC), lymphocyte count (LYM #), monocyte count (Mon #), neutrophil count (NEUT #), eosinophil count (Eos #), basophil count (Bas #), lymphocyte percentage (LYM%), monocyte percentage (Mon%), neutrophil percentage (NEUT%), eosinophil percentage (Eos%), basophil percentage (Bas%);#p＜0.05，##p is less than 0.01vs blank control group;*p＜0.05，**p <0.05 vs model control.
③ Sino-wcj-43 influence on the peripheral blood platelet count of mouse with aplastic anemia
As shown in the results of Table 4.3C, sino-wcj-43 can improve the reduction of peripheral blood platelets of mice in a aplastic anemia model, and the difference of the group of 50mg/kg intragastric administration dosage compared with the model control group is significant (p < 0.05).
TABLE 3 influence of C sino-wcj-43 on platelets in peripheral blood of aplastic anemia mice (Mean. + -. Std, n ═ 10)
Remarking: platelet count (PLT), Mean Platelet Volume (MPV), platelet volume distribution width (PDW);#p＜0.05，##p is less than 0.01vs blank control group;*p＜0.05，**p <0.05 vs model control.
(4) Effect of sino-wcj-43 on the number of peripheral blood reticulocytes of mice with aplastic anemia
Reticulocytes are not fully mature erythrocytes, and the value in peripheral blood reflects the production function of bone marrow erythrocytes and the hematopoietic function of bone marrow, which is of great significance for the diagnosis of hematological diseases and the observation of therapeutic response. In the clinical treatment process of patients with aplastic anemia, the rise of reticulocyte parameters is an important index for the recovery of the bone marrow hematopoiesis function of the patients. In the experiment, after 1 hour of the last administration, blood is collected from orbital veins of each group of mice, peripheral blood reticulocyte is marked by fluorescent dye taking thiazole orange as RNA, the proportion of the peripheral blood reticulocyte is detected by adopting flow cytometry, and the peripheral blood reticulocyte count is calculated according to the peripheral blood erythrocyte count. The results are shown in Table 4.4. The results in Table 4.4 show that the proportion and the count of the reticulocytes in the peripheral blood of the mice in the aplastic anemia model group are remarkably reduced compared with those in the normal control group, while the proportion and the count of the reticulocytes in the peripheral blood of the mice in the aplastic anemia model group can be remarkably increased by intragastric administration of sino-wcj-43 at the dose of 25mg/kg and 50mg/kg (p is less than 0.05 or 0.01). Suggesting that sino-wcj-43 has obvious improvement effect on the bone marrow erythropoiesis function and the bone marrow hematopoiesis function of the mouse with aplastic anemia.
TABLE 4 effect of sino-wcj-43 on the number of peripheral blood reticulocytes in aplastic anemia mice (Mean. + -. Std n ═ 10)
Remarking:#p＜0.05，##p is less than 0.01vs blank control group;*p＜0.05，**model control group with p less than 0.05vs
(5) Effect of sino-wcj-43 on bone marrow cell count and CD34+ cell ratio of aplastic anemia mice
CD34+ cells are mainly expressed in early hematopoietic stem cells and progenitor cells, and may play a role in the adhesion and homing of hematopoietic stem cells and progenitor cells to bone marrow. Bone marrow CD34+ cells directly reflect the production of bone marrow hematopoietic cells. The marrow CD34+ cells of the aplastic anemia patients are obviously reduced compared with normal cells, so the marrow CD34+ cells have important significance for the research of pathogenesis of the aplastic anemia, and can also be used as an important index for the diagnosis, differential diagnosis and curative effect judgment of the aplastic anemia. In the experiment, after 1 hour of the last administration, the right femurs of each group of mice are taken, bone marrow cells are washed and collected, and the cell number and the CD34+ cell ratio in the bone marrow are measured by flow cytometry. The results are shown in Table 4.5. As shown in the results in Table 4.5, compared with the normal control group, the bone marrow cell count and the CD34+ cell ratio of the aplastic anemia mice are both significantly reduced, and the bone marrow cell count and the CD34+ cell ratio (p is less than 0.05 or 0.01) of the aplastic anemia mice can be significantly increased by the gastric lavage of the sino-wcj-43 at the dose of 25mg/kg and 50 mg/kg. The result indicates that sino-wcj-43 has an improving effect on bone marrow hematopoietic failure of aplastic anemia mice.
TABLE 4.5 influence of sino-wcj-43 on bone marrow cell count and CD34+ cell ratio in aplastic anemia mice (Mean Std, n 10)
Remarking:#p＜0.05，##p is less than 0.01vs blank control group;*p＜0.05，**model control group with p less than 0.05vs
The research results show that sino-wcj-43 can improve the diet condition of aplastic anemia mice, enhance the digestion and absorption functions of aplastic anemia mice, and increase the thymus index and spleen index of aplastic anemia mice; sino-wcj-43 can significantly improve peripheral red blood cell count, hemoglobin content, white blood cell count and platelet count of aplastic anemia mice, thereby reducing the occurrence of various clinical symptoms of anemia, bleeding, infection and the like of aplastic anemia, and relieving peripheral blood injury; meanwhile, sino-wcj-43 can significantly increase the count of peripheral blood reticulocytes, the count of bone marrow cells and the proportion of bone marrow CD34+ cells, thereby improving the hematopoietic function of aplastic anemia and playing an obvious therapeutic role in the aplastic anemia. In addition, sino-wcj-43 has not found any toxic or side effect, so that it has very wide application prospect in the treatment of aplastic anemia.
Claims (7)
1. A sinomenine derivative and its pharmaceutically acceptable salt have the structural formula shown in formula (I),
2. a process for preparing the sinomenine derivative of claim 1, comprising the steps of:
taking sinomenine hydrochloride sinono as a raw material, carrying out heating reflux reaction with paraformaldehyde to generate 1-hydroxymethylene sinomenine shown in a formula 1, and carrying out esterification reaction on the 1-hydroxymethylene sinomenine, cinnamic acid, EDC and DMAP at room temperature to obtain the sinomenine derivative shown in the formula (I).
3. A pharmaceutical composition comprising an effective amount of the derivative of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
4. The pharmaceutical composition according to claim 3, wherein said pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections.
5. The pharmaceutical composition according to claim 3, wherein said pharmaceutical composition is selected from the group consisting of a sustained release formulation and a controlled release formulation.
6. The use of a compound of claim 1 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment and/or prevention of diseases associated with inflammation and/or aplastic anemia.
7. The use according to claim 6, wherein the diseases associated with inflammation and aplastic anemia comprise: rheumatic arthritis, bronchitis, asthma, chronic obstructive pulmonary disease, nephritis, acute aplastic anemia, and chronic aplastic anemia.
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